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1
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Zhao Q, Wu T, Tang C, Li J, Wu M, Wu J, Wang Z, Zhu Y, Xu H, Li X. Biomimetic nanocrystals co-deliver paclitaxel and small-molecule LF3 for ferroptosis-combined chemotherapy for gastric cancer. Colloids Surf B Biointerfaces 2025; 251:114586. [PMID: 40010081 DOI: 10.1016/j.colsurfb.2025.114586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/14/2025] [Accepted: 02/19/2025] [Indexed: 02/28/2025]
Abstract
Combination chemotherapy is considered more effective than monotherapy in enhancing clinical outcomes. Ferroptosis, a unique form of regulated cell death, has been demonstrated to inhibit tumor growth and progression. Consequently, combining ferroptosis with chemotherapy represents a promising and innovative approach to antitumor therapy. In this study, we developed a novel TMTP1-modified biomimetic nanocrystal (TRNC@P + L) for the co-delivery of PTX and LF3, aiming to achieve ferroptosis-combined chemotherapy in gastric cancer. TRNC@P + L, which incorporates a tumor-homing peptide-modified red blood cell membrane, demonstrated efficient tumor targeting, prolonged circulation, enhanced drug bioavailability, and reduced non-specific toxicities of free PTX and LF3. By utilizing the synergistic effects of PTX and LF3, TRNC@P + L combination therapy significantly inhibited tumor growth, as demonstrated by both in vitro and in vivo studies. Mechanistically, TRNC@P + L triggers ferroptosis in tumor cells by downregulating GPX4 expression, the promotion of ROS accumulation, and the enhancement of lipid peroxidation. These processes synergistically enhance the anticancer efficacy of PTX.
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Affiliation(s)
- Qianqian Zhao
- Department of Geriatric Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China
| | - Ting Wu
- Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China
| | - Chunming Tang
- Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China
| | - Jie Li
- Department of Geriatric Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Min Wu
- Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China
| | - Jie Wu
- Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China
| | - Zhiji Wang
- Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China
| | - Yinxin Zhu
- Institute of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou 225300, China.
| | - Huae Xu
- Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China.
| | - Xiaolin Li
- Department of Geriatric Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
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Zheng Y, Jiang Z, Yuan L, Cheng X, He W, Chen X. Targeting fatty acid oxidation: A potential strategy for treating gastrointestinal tumors. Int J Cancer 2025; 157:7-17. [PMID: 40047558 DOI: 10.1002/ijc.35380] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 02/02/2025] [Accepted: 02/11/2025] [Indexed: 05/11/2025]
Abstract
Gastrointestinal cancers including esophageal squamous cell carcinoma (ESCC), gastric cancer (GC), and colorectal cancer (CRC) are common and highly lethal types of cancer worldwide. Metabolic reprogramming plays a critical role in cancer progression and involves metabolic processes such as glucose and lipid metabolism. Fatty acid oxidation (FAO) has a profound impact on cancer, with many genes and cytokines influencing cancer cell initiation, development, metastasis, and resistance by regulating FAO. Additionally, FAO further promotes cancer progression by affecting the tumor microenvironment (TME). The role of FAO in gastrointestinal cancers has garnered increasing attention, and related anticancer drugs are currently being developed.
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Affiliation(s)
- Yingsong Zheng
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, China
| | - Zhengchen Jiang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Li Yuan
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer, Zhejiang Cancer Hospital, Hangzhou, China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China
| | - Weiyang He
- Department of Gastric Surgery, Sichuan Clinical Research Centre for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Centre Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaodong Chen
- Department of Gastric Surgery, Sichuan Clinical Research Centre for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Centre Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
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3
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Song S, Fan Y, Zou G, Huo L, Kumar J, Li Y, Wang R, Dai E, Jin J, Scott AW, Shao S, Pizzi MP, Vykoukal JV, Katayama H, Hanash S, Calin GA, Zhang X, Lee MG, Wang Z, Lo YH, Gan Q, Waters RE, Yin F, Wang L, Cheng X, Ajani JA, Dhar SS. KAP1 promotes gastric adenocarcinoma progression by activating Hippo/YAP1 signaling via binding to HNRNPAB. Cancer Lett 2025; 621:217695. [PMID: 40189014 DOI: 10.1016/j.canlet.2025.217695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 03/31/2025] [Accepted: 04/03/2025] [Indexed: 04/15/2025]
Abstract
Gastric adenocarcinoma (GAC) remains a significant global health challenge, with over a million new cases annually. Peritoneal carcinomatosis (PC), detected in ∼20 % of cases at diagnosis and ∼45 % later, is uniformly fatal, with limited treatment options. This study investigated the role of KAP1 in GAC progression, focusing on its interaction with YAP1 and cancer stemness traits. Analysis of over 596 primary GACs and 72 PC samples revealed that high nuclear KAP1 expression correlates with poor prognosis. KAP1 knockdown reduced oncogenic activity and stemness traits in GAC cells. Mechanistically, KAP1 positively regulates YAP1 transcription by binding to its promoter and reducing H3K27ac levels. Mass spectrometry identified an interaction between KAP1 and HNRNPAB, further modulating YAP1 signaling. Expression of the KRAB domain of ZFP568 without its DNA-binding zinc fingers inhibited both KAP1 and YAP1 expression, significantly reducing colony formation and tumor growth in vivo. Additionally, emerging antisense oligonucleotides (ASOs) targeting KAP1 or YAP1 effectively suppressed mouse tumor progression. These findings establish KAP1 as a critical driver of tumor progression in GAC through YAP1 regulation and HNRNPAB interaction, highlighting its potential therapeutic target. This study advances our understanding and offers a preclinical framework to improve outcomes for GAC.
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Affiliation(s)
- Shumei Song
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yibo Fan
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gengyi Zou
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Longfei Huo
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Janani Kumar
- Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yuan Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, PR China
| | - Ruiping Wang
- Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Enyu Dai
- Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jiankang Jin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ailing W Scott
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shan Shao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Melissa Pool Pizzi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jody V Vykoukal
- Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hiroyuki Katayama
- Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Samir Hanash
- Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George A Calin
- Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xing Zhang
- Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Min Gyu Lee
- Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, 110001, PR China
| | - Yuan-Hung Lo
- Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qiong Gan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rebecca E Waters
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Feng Yin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Linghua Wang
- Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaodong Cheng
- Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Shilpa S Dhar
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Meng X, Sun Q, Liu Z, Cao S, Xu C, Di L, Wu Y, Zhang W. TIMELESS as a prognostic biomarker and therapeutic target in gastric cancer. J Genet Eng Biotechnol 2025; 23:100504. [PMID: 40390494 DOI: 10.1016/j.jgeb.2025.100504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 04/14/2025] [Accepted: 04/28/2025] [Indexed: 05/21/2025]
Abstract
BACKGROUND Gastric cancer (GC), one of the most prevalent malignancies worldwide, is characterized by complex etiological and pathological mechanisms. Emerging evidence on the dysregulation of circadian clock genes has revealed promising opportunities for improving the diagnosis, treatment, and prognosis of patients with GC. METHODS This study utilized a multifaceted approach combining machine learning algorithms, gene set enrichment analysis, immune infiltration profiling, survival prognosis analysis, drug sensitivity testing, and in vitro experiments to investigate the functional roles of core clock genes in GC. RESULTS By integrating data from The Cancer Genome Atlas, Gene Expression Omnibus datasets, and the National Center for Biotechnology Information database, we identified 29 differentially expressed clock genes in GC. Among these, the application of four distinct machine learning algorithms highlighted TIMELESS (TIM) and BHLHE41 as pivotal genes, with TIM demonstrating notable diagnostic performance (area under the receiver operating characteristic curve = 0.802). Elevated TIM expression was strongly associated with poor clinical prognosis and increased infiltration of immune cells in tumor tissues. Notably, a specific interaction was identified between TIM and the pyroptosis-associated molecule CASP8, indicating a potential synergistic role in GC pathogenesis. Additionally, bortezomib emerged as a potential targeted therapeutic agent capable of modulating TIM activity in GC. CONCLUSION TIM is identified as a promising diagnostic biomarker and therapeutic target in GC, offering valuable implications for improving patient prognosis and guiding personalized treatment strategies.
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Affiliation(s)
- Xiangrong Meng
- Department of Laboratory Diagnosis, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qi Sun
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Heilong Jiang University of Chinese Medicine, Harbin, China
| | - Zhongshuang Liu
- Department of Stomatology, Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy, Shenzhen, China
| | - Shenqi Cao
- Anesthesiology, Harbin Medical University, Harbin, China
| | - Chunyang Xu
- Department of Laboratory Diagnosis, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Longjiang Di
- School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan Wu
- Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenjing Zhang
- Department of Laboratory Diagnosis, the Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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5
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Fang X, Liu M, Ren Q, Li R, Wu G, Yuan H, Zheng Y, Gou X, Wang Y, Zhou Y. Multi-omics analysis identifies LANCL2 as a potential biomarker for the diagnosis and prognosis of gastric cancer. Sci Rep 2025; 15:18231. [PMID: 40414970 DOI: 10.1038/s41598-025-02745-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 05/15/2025] [Indexed: 05/27/2025] Open
Abstract
Gastric cancer (GC) constitutes a significant global public health burden due to its high morbidity rates and poor prognosis, underscoring the critical need for identifying novel therapeutic targets and elucidating their mechanisms. As a key member of the lanthionine synthetase C-like enzyme family, LANCL2 has shown aberrant expression in multiple malignancies. However, its biological significance in GC remains unclear. To this end, a series of exploration and research were conducted. Through integrated analyses of multi-omics databases and experimental validation, LANCL2 was up-regulated in STAD at both mRNA and protein levels. Moreover, elevated LANCL2 is closely associated with poor prognosis, and the constructed nomogram exhibited reliable predictive performance for 1, 3, and 5-year overall survival (OS) in the GC cohort. In addition, the genetic alteration status of LANCL2 was associated with new neoplasm event post initial therapy indicator, MSIsensor score, tumor mutation burden (TMB), and survival prognosis. Functional enrichment analysis indicated that LANCL2 is primarily associated with the regulation of immune checkpoints, the cell cycle and DNA repair. Furthermore, the expression of LANCL2 displayed significant correlations with immune infiltration, m6A methylation, ferroptosis, tumor cell stemness and drug reactivity. Finally, in vitro studies confirmed that silencing or overexpression of LANCL2 can significantly influence the changes of proliferation and cell cycle of GC cells. Overall, this study indicated LANCL2 as a critical regulator in GC pathogenesis, and highlighted its potential as a prognostic biomarker for gastric cancer management.
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Affiliation(s)
- Xidong Fang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Mengxiao Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Qian Ren
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Renpeng Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Guozhi Wu
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Hao Yuan
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ya Zheng
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xi Gou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yuping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China.
| | - Yongning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China.
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Yang J, Li ZX, Song MJ, Han SJ, Yang AJ, Zhang ZP, Sui CS, Qiao JL, Huang WH, He JQ. Prognostic value and therapeutic efficacy of interstitial circulating tumor cells in patients with advanced gastric cancer. World J Clin Oncol 2025; 16:101762. [DOI: 10.5306/wjco.v16.i5.101762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 03/08/2025] [Accepted: 04/08/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND The high mortality rate and recurrence/metastasis remain major challenges in the clinical management of gastric cancer (GC) patients. To optimize treatment stratification and management, there is an urgent need for efficient and non-invasive biomarkers. A meta-analysis on the prognostic role of circulating tumor cells (CTCs) in GC revealed a strong association between CTCs and patient prognosis. Among CTC subtypes, Interstitial CTCs (I-CTCs) exhibited the strongest invasiveness. This study innovatively investigated the expression profile of I-CTCs in advanced GC patients to evaluate their clinical utility.
AIM To evaluate the clinical utility of I-CTCs as a non-invasive prognostic biomarker in advanced GC. To investigate the correlation between I-CTC count thresholds and chemotherapy efficacy in advanced GC patients. To establish the potential of preoperative I-CTC profiling for optimizing treatment stratification and postoperative surveillance.
METHODS This study retrospectively analyzed 59 patients with advanced GC treated at the General Surgery Clinical Medical Center of Gansu Provincial Hospital between October 2019 and October 2020. The expression levels of I-CTCs were measured, and patient survival was monitored. The receiver operating characteristic curve was plotted to determine the optimal cut-off value for I-CTCs expression levels. Based on this cut-off value, 59 GC patients were grouped into positive and negative groups. The differences in clinicopathological characteristics between the two groups were analyzed. Patient survival was follow-up and recorded until October 2022. Plotting survival curves and performing univariate and multifactorial analyses of patient prognostic factors. The Kaplan-Meier method and Cox regression model were used, respectively.
RESULTS A total of 59 patients were included in this study, and receiver operating characteristic curve analysis showed that the best cut-off value for I-CTCs was 5, with an area under the curve of 0.8356 (95%CI: 0.7122-0.9590). The I-CTC count of ≥ 5 defines the positive group, while counts < 5 are classified as the negative group. Positive I-CTCs correlated with the degree of tumor differentiation and disease progression (P < 0.05). 16 of 59 patients received neoadjuvant chemotherapy. There were divided into progressive disease and disease control groups based on response to neoadjuvant chemotherapy. Patients in the I-CTCs-negative group had longer overall survival and disease-free survival than those in the positive group (P < 0.05). Multifactorial analysis revealed that I-CTCs positivity (HR = 13.323, 95%CI: 1.675-105.962, P = 0.014) was an independent risk factor for survival in patients with advanced GC.
CONCLUSION In patients with advanced GC, an I-CTC count of ≥ 5 is associated with both poor prognosis and reduced chemotherapy efficacy. I-CTCs may serve as a valuable preoperative biomarker for predicting the prognosis of advanced GC.
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Affiliation(s)
- Jing Yang
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, Guangdong Province, China
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730030, Gansu Province, China
| | - Zu-Xi Li
- Department of Peripheral Vascular Intervention, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou 730060, Gansu Province, China
| | - Mei-Juan Song
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Shang-Jun Han
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Ai-Jia Yang
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Ze-Ping Zhang
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Chang-Sheng Sui
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Ji-Lin Qiao
- The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Wen-Hua Huang
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, Guangdong Province, China
| | - Jun-Qiang He
- Department of General Surgery, Xinhui People’s Hospital of Southern Medical University, Jiangmen 529000, Guangdong Province, China
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Guo C, Tang H, Ren M, Zhang Y. BHLHE40-mediated RGS16 upregulation: a driver propelling gastric cancer progression via ferroptosis suppression. Hereditas 2025; 162:87. [PMID: 40413527 DOI: 10.1186/s41065-025-00447-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Accepted: 05/05/2025] [Indexed: 05/27/2025] Open
Abstract
BACKGROUND Gastric cancer (GC), a malignant neoplasm that arises from the epithelium of the gastric mucosa, endangers patients' lives and health severely. Regulator of G-protein signaling 16 (RGS16) has been found to be correlated with the malignant progression of various cancers, and BHLHE40 is highly expressed in GC. However, it remains unclear whether there is a regulatory mechanism between the them. METHODS The bioinformatics tools were applied to assess the differentially expressed genes in GC. Next, the expression levels of mRNA and protein were evaluated by qRT-PCR and Western blot. Cellular behaviors were assessed using CCK-8, EdU, Transwell, and flow cytometry assays. Meanwhile, the ferroptosis-related indicators were measured. Subsequently, the xenograft models were set up to estimate the role of RGS16 in vivo. Besides, the interaction between BHLHE40 and RGS16 was determined using ChIP assay and dual-luciferase reporter assay. RESULTS RGS16 exhibited an upregulated pattern in GC. In addition, silencing RGS16 impeded the proliferation, migration and invasion of GC cells while reinforcing apoptosis and ferroptosis. Moreover, RGS16 boosted the growth of tumors in vivo. Furthermore, BHLHE40 could bind to RGS16 and positively regulate its expression. Overexpression of RGS16 reversed the effects of silencing BHLHE40 on GC cells. CONCLUSION BHLHE40 curbed ferroptosis and oxidative stress of GC cells by modulating the expression of RGS16, thereby facilitating the malignant progression of GC.
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Affiliation(s)
- Caiyun Guo
- Department of Gastroenterology, Xi'an International Medical Center Hospital, Xi'an, 710117, Shaanxi, China
| | - Hua Tang
- Department of Gastroenterology, Xi'an International Medical Center Hospital, Xi'an, 710117, Shaanxi, China.
| | - Maifang Ren
- Department of Gastroenterology, Xi'an International Medical Center Hospital, Xi'an, 710117, Shaanxi, China
| | - Yongli Zhang
- Department of Gastroenterology, Tongchuan People's Hospital, Tongchuan, 727100, Shaanxi, China.
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Xu J, Yang J, Sun Q, Chang J, Wang F. Analyses of single-cell RNA sequencing uncover the role of intratumoral Helicobacter pylori in shaping tumor progression and immunity in gastric cancer. Cancer Immunol Immunother 2025; 74:218. [PMID: 40411560 PMCID: PMC12103440 DOI: 10.1007/s00262-025-04048-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 04/08/2025] [Indexed: 05/26/2025]
Abstract
The intratumoral microbiota is closely associated with tumor initiation and progression in multiple solid tumors, including gastric cancer (GC). Single-cell analysis of host-microbiome interactions (SAHMI) is a pipeline used to systematically recover and denoise microbial signals in human clinical tissues and examine tumor-microbiome interactions at the single-cell transcriptome level. In a large GC cohort, we used SAHMI to detect 12 bacteria, among which Helicobacter pylori (H. pylori) was widely present in multiple tumor and normal samples. Meanwhile, we verified the presence of H. pylori in GC tissues via fluorescence in situ hybridization and immunohistochemistry. We performed single-cell RNA sequencing to analyze 11 cell populations, including B cells, T cells, and epithelial cells, and these cell types contained large numbers of H. pylori. We detected obvious enrichment of H. pylori in cancer cells and identified 13 upregulated differentially expressed genes exhibiting significantly negative correlations with patient survival in the H. pylori-positive tumor group compared with the findings in the other groups, indicating that these genes could represent prognostic biomarkers or therapeutic targets for H. pylori-infected patients with GC. Moreover, H. pylori-enriched immune cells, including T cells, B cells, and macrophages, were associated with cell-type-specific gene expression and pathway activities, including cell fate and immune signaling. In summary, tumor-microbiome interactions might reflect or influence tumorigenesis in GC, which has implications for clinical practice.
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Affiliation(s)
- Jiao Xu
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Jin Yang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
- Phase I Clinical Trial Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Qi Sun
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Jingbo Chang
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Fan Wang
- Phase I Clinical Trial Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
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9
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Xia C, Liu Y, Qing X. Characteristic genes and immune infiltration analysis of gastric cancer based on bioinformatics analysis and machine learning. Discov Oncol 2025; 16:872. [PMID: 40407862 PMCID: PMC12102041 DOI: 10.1007/s12672-025-02624-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 05/08/2025] [Indexed: 05/26/2025] Open
Abstract
BACKGROUND Gastric cancer (GC), a common and deadly malignancy worldwide, is a serious burden on society and individuals. However, available diagnostic biomarkers for GC are very limited. The current study aimed to identify potential diagnostic biomarkers for GC and analyze the activity of infiltrating immune cells in this pathology. METHODS Microarray data for GC were acquired from the Gene Expression Omnibus (GEO) database. The limma package was utilized to normalize these data, thus identifying differentially expressed genes (DEGs). For normalized data of samples, we established a weighted gene co-expression network (WGCNA) to reveal key genes in the significant module. Afterward, we obtained overlapping genes by intersecting the DEGs and the key genes from the WGCNA module. Next, after applying the three algorithms (LASSO, RandomForest, and SVM-RFE) to analyze these overlapping genes and take the intersection, we established a GC diagnosis. The diagnostic significances of these identified genes were evaluated with receiver operating characteristic (ROC) curves and validated in the external dataset. Furthermore, ssGSEA and CIBERSORT were employed for evaluating the infiltrating immune cells and the association of the immune cells and diagnostic biomarkers. RESULTS Herein, we identified 49 overlapping genes, and the results of enrichment analysis demonstrated that these genes may be involved in the signaling transduction-related process. Finally, BANF1, DUSP14, and VMP1 were regarded as key biomarkers in GC patients based on the overlapping genes that we found, and these three biomarkers demonstrated great diagnostic significance. Additionally, the hub biomarkers had different levels of association with macrophages, neutrophils, memory B cells, and plasma cells. CONCLUSIONS BANF1, DUSP14, and VMP1 are promising diagnostic biomarkers for GC, and infiltrating immune cells may dramatically affect gastric carcinogenesis and progression.
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Affiliation(s)
- Chengwei Xia
- Department of Thyroid and Breast Surgery, Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College), Chengdu, China
| | - Yini Liu
- Department of Anesthesiology, The People's Hospital of Zhongjiang, Deyang, China
| | - Xin Qing
- Department of Hepatobiliary Vascular Surgery, Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College), Chengdu, China.
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10
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Jiang X, Wu A, Yan J, Chen J, Wen Y, Wu H, Yan N, Yang Z, Liu F, Li P. Eleutheroside A inhibits PI3K/AKT1/mTOR-mediated glycolysis in MDSCs to alleviate their immunosuppressive function in gastric cancer. Int Immunopharmacol 2025; 159:114907. [PMID: 40409102 DOI: 10.1016/j.intimp.2025.114907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Revised: 05/10/2025] [Accepted: 05/16/2025] [Indexed: 05/25/2025]
Abstract
BACKGROUND An immune-suppressive tumor microenvironment (TME) that encourages tumor growth is a hallmark of gastric cancer (GC), which is implicated in the development, metastasis, and unfavorable prognosis of GC. Acanthopanax senticosus (Rupr.&Maxim.) Harms (AS), also called Siberian Ginseng (Chinese: Ci wu jia), is a commonly used traditional Chinese herbal medicine with immune-enhancing, anti-tumor, anti-fatigue, neuroregulatory, blood circulation-improving, and antioxidant properties. Recently, it has also been demonstrated to improve anti-tumor immunity in GC. Eleutheroside A (EA), one of the primary bioactive saponins of AS, has immunoregulatory functions. Given the immunomodulatory and anti-tumor effects of EA, it is crucial to investigate its regulatory impact on the immune landscape of GC. MATERIALS AND METHODS To determine the effects of EA on immune responses in GC, a subcutaneous GC mouse model was established. Tumor growth, body weight changes, and immune responses in the mice treated with EA were measured. The proportion of CD4+T, CD8+T, B cells, NK cells, TAMs, DCs and MDSCs in the spleens were analyzed using flow cytometry. MDSCs and CD4+/CD8+ T cell infiltration in tumor tissue were analyzed using immunofluorescence. Bulk RNA sequencing (bulk RNA-seq) data from the Cancer Genome Atlas (TCGA) and two single-cell RNA sequencing (scRNA-seq) datasets (accession numbers GSE183904 and GSE150290) were used to examine changes in MDSCs and T cell infiltration within the TME of GC and to identify MDSCs-related targets. Network pharmacology analysis, protein-protein interaction (PPI) network analysis, dynamics simulations, molecular docking and surface plasmon resonance (SPR) were applied to explore the potential mechanisms underlying EA's intervention in MDSCs. Flow cytometry, qPCR, and western blotting and Seahorse assays were applied for analyzing MDSCs isolated from in vivo and in vitro-induced conditions, aiming to delineate the mechanism of EA on MDSCs glycolysis and immunosuppressive functions mediated by the PI3K/AKT1/mTOR signaling pathway. RESULTS In vivo, EA treatment effectively suppressed GC tumor growth and progression in mice, reducing the prevalence of MDSCs and increasing CD4+/CD8+ T cell levels. In vitro, EA not only decreased the frequency of MDSCs but also alleviated their immune-suppressing capabilities on CD4+/CD8+ T cells. Network pharmacology, coupled with scRNA-seq analysis, dynamic simulations, and molecular docking studies, suggested that EA might modulate the PI3K/AKT1/mTOR signaling pathway to influence glycolysis in MDSCs. Surface plasmon resonance (SPR) analysis confirmed that EA directly interacts with AKT1. Further validation experiments revealed that in the GC TME, EA treatment decreased the expression of p-PI3K, p-AKT1, p-mTOR, HIF1α, as well as glycolytic genes and glycolytic activity in MDSCs. Additionally, EA led to the downregulation of p-STAT3 and its downstream immunosuppressive factors within these cells. Restoring AKT1 activation could reverse the inhibitory effects of EA on MDSCs glycolysis and the downregulation of immunosuppressive molecules. Moreover, HIF-1α inhibition abolished EA's inhibitory effects on MDSCs. CONCLUSION EA can attenuate the immune-suppressive capacity of MDSCs in GC by inhibiting the PI3K/AKT1/mTOR pathway and suppressing HIF-1α-mediated glycolysis, thereby offering a novel therapeutic approach to targeting the immune-suppressive microenvironment in GC.
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Affiliation(s)
- Xiaotao Jiang
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Anzhou Wu
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China; The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Jiaxing Yan
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China; The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Jingming Chen
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China; The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Yi Wen
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Hui Wu
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China; The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Ning Yan
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Zehong Yang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Fengbin Liu
- Baiyun Hospital of The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510470, Guangdong, China; Lingnan Institute of Spleen and Stomach Diseases, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China.
| | - Peiwu Li
- Department of hepatobiliary diseases, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou 510405, Guangdong, China.
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11
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Meevassana J, Vongsuly CW, Nakbua T, Kamolratanakul S, Thitiwanichpiwong P, Bin-Alee F, Keelawat S, Kitkumthorn N. Selected Alu methylation levels in the gastric carcinogenesis cascade. PeerJ 2025; 13:e19485. [PMID: 40416611 PMCID: PMC12101442 DOI: 10.7717/peerj.19485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 04/27/2025] [Indexed: 05/27/2025] Open
Abstract
Background Genome-wide hypomethylation, a common epigenetic change that occurs during cancer development, primarily affects repetitive elements, such as Alu repeats. Consequently, Alu repeats can be used as a surrogate marker of genomic hypomethylation. Methods In this study, we aimed to investigate the correlation between Alu methylation levels and the multistage course of gastric carcinogenesis. Results We found that the Alu methylation levels in gastric cancer tissue decreased compared with those in normal gastric tissue, with the change in methylation levels and pattern being most significant between chronic gastritis and intestinal metaplasia. Moreover, Alu methylation levels were not associated with Helicobacter pylori or Epstein-Barr virus infection. Conclusions Finally, our sensitivity and specificity analyses suggested that Alu methylation level can be used to distinguish gastric cancer tissue from normal tissue. Thus, Alu methylation level shows promise as biomarker for gastric cancer diagnosis.
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Affiliation(s)
- Jiraroch Meevassana
- Center of Excellence in Burn and Wound Care, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Chawisa Wanda Vongsuly
- Center of Excellence in Burn and Wound Care, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Tanchanok Nakbua
- Center of Excellence in Burn and Wound Care, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Supitcha Kamolratanakul
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | | | - Fardeela Bin-Alee
- Faculty of Medicine, Princess of Naradhiwas University, Narathiwat, Thailand
| | - Somboon Keelawat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nakarin Kitkumthorn
- Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
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12
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Dong Z, Chen Z, Yu K, Zhao D, Jia J, Gao X, Wang D. Roles of plasma proteins in mediating the causal effect of the lipid species on gastric cancer: Insights from proteomic and two-step Mendelian randomization. Medicine (Baltimore) 2025; 104:e42485. [PMID: 40388730 PMCID: PMC12091653 DOI: 10.1097/md.0000000000042485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 05/02/2025] [Indexed: 05/21/2025] Open
Abstract
The change of plasma lipid species has close contacts with gastric cancer (GC). However, the specific mechanism still needs to be explored further. We aim to utilize plasma proteins to decipher the association between lipid species and GC, and seek possible drug targets for GC. We performed a two-step Mendelian randomization (MR) analysis to investigate causal relationships among 179 lipid species, 4907 plasma proteins, and GC. Using summary-data-based MR and colocalization, we first examined protein-GC associations in discovery (N = 35,559) and validation (N = 54,219) cohorts. Subsequent MR analyses assessed lipid-GC and lipid-protein relationships, followed by mediation analysis using error propagation methods. Finally, macromolecular docking of prioritized proteins identified potential therapeutic ligands. Our MR analysis revealed causal relationships between 12 lipid species and GC, as well as 3 plasma proteins and GC. Importantly, mediation analysis demonstrated that CCDC80 protein mediates 2.90% (95% CI: 0.30-5.5%) of the protective effect of diacylglycerol (16:1_18:1) against GC. Based on these findings, we identified valproic acid as a promising therapeutic candidate targeting CCDC80 for GC treatment. Our study demonstrates that reduced CCDC80 expression mediates the tumor-promoting effects of diacylglycerol (16:1_18:1) in GC pathogenesis. Molecular docking confirms valproic acid binds stably to CCDC80, suggesting its therapeutic potential. These findings advance GC etiology understanding and provide a new drug development direction.
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Affiliation(s)
- Zhenhua Dong
- Gastric and Colorectal Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhiqing Chen
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Kai Yu
- Urology Department, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Dingliang Zhao
- Second Urology Department, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jianling Jia
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xulei Gao
- Second Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Daguang Wang
- Gastric and Colorectal Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, China
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13
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Wang HN, An JH, Wang FQ, Hu WQ, Zong L. Predicting gastric cancer survival using machine learning: A systematic review. World J Gastrointest Oncol 2025; 17:103804. [DOI: 10.4251/wjgo.v17.i5.103804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 02/20/2025] [Accepted: 02/26/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) has a poor prognosis, and the accurate prediction of patient survival remains a significant challenge in oncology. Machine learning (ML) has emerged as a promising tool for survival prediction, though concerns regarding model interpretability, reliance on retrospective data, and variability in performance persist.
AIM To evaluate ML applications in predicting GC survival and to highlight key limitations in current methods.
METHODS A comprehensive search of PubMed and Web of Science in November 2024 identified 16 relevant studies published after 2019. The most frequently used ML models were deep learning (37.5%), random forests (37.5%), support vector machines (31.25%), and ensemble methods (18.75%). The dataset sizes varied from 134 to 14177 patients, with nine studies incorporating external validation.
RESULTS The reported area under the curve values were 0.669–0.980 for overall survival, 0.920–0.960 for cancer-specific survival, and 0.710–0.856 for disease-free survival. These results highlight the potential of ML-based models to improve clinical practice by enabling personalized treatment planning and risk stratification.
CONCLUSION Despite challenges concerning retrospective studies and a lack of interpretability, ML models show promise; prospective trials and multidimensional data integration are recommended for improving their clinical applicability.
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Affiliation(s)
- Hong-Niu Wang
- Department of Gastrointestinal Surgery, Changzhi People’s Hospital, The Affiliated Hospital of Changzhi Medical College, Changzhi 046000, Shanxi Province, China
- Graduate School of Medicine, Changzhi Medical College, Changzhi 046000, Shanxi Province, China
| | - Jia-Hao An
- Department of Graduate School of Medicine, Changzhi Medical College, Changzhi 046000, Shanxi Province, China
| | - Fu-Qiang Wang
- Department of Gastrointestinal Surgery, Changzhi People’s Hospital, The Affiliated Hospital of Changzhi Medical College, Changzhi 046000, Shanxi Province, China
| | - Wen-Qing Hu
- Department of Gastrointestinal Surgery, Changzhi People’s Hospital, The Affiliated Hospital of Changzhi Medical College, Changzhi 046000, Shanxi Province, China
| | - Liang Zong
- Department of Gastrointestinal Surgery, Changzhi People’s Hospital, The Affiliated Hospital of Changzhi Medical College, Changzhi 046000, Shanxi Province, China
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14
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Tian XY, Mu YP. Serum miR-30c serves as potential biomarkers for the diagnosis and prognosis of gastric cancer. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2025:1-9. [PMID: 40338037 DOI: 10.1080/15287394.2025.2495952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Gastric cancer (GC)，the fourth leading cause of cancer-related deaths globally and thus early detection, is considered critical for diagnosis and treatment of this disease. It is well known that measurement of microRNA (miRNA) may serve as diagnostic and prognostic biomarker for GC. The aim of this study was to determine whether miR-30c was present in patients with gastric cancer and to correlate relative expression with patient survival. A total of 162 GC patients and 150 healthy controls were recruited. miR-30c levels were quantified in serum using quantitative real-time PCR(QRT-PCR). The sensitivity and specificity of circulating miR-30c was compared to carbohydrate antigen (CA) CA72-4, CA19-9, and carcinoembryonic antigen (CEA), 3 known markers associated with GC. QRT-PCR demonstrated downregulation of gene expression of miR-30c in GC patients. Downregulation of miR-30c gene expression was significantly correlated with stage of cancer, lymphatic metastasis, and distal metastasis. The sensitivity to detect GC of miR-30c, CA72-4, CA19-9, and CEA in serum of GC was 80%, 43%, 21%, and 42%, respectively, while specificity was 89%, 57%, 30%, and 78% respectively. Kaplan-Meier survival analysis showed that the presence of low gene expression of miR-30c was effective in predicting poor prognosis in GC patients. Our data suggest that circulating serum miR-30c concentrations may serve as a reliable biomarker for GC occurrence. (212words).
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Affiliation(s)
- Xiao-Yan Tian
- Department of Clinical Test Laboratory, Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University, Inner Mongolia Cancer Center, Hohhot, China
| | - Yong-Ping Mu
- Department of Clinical Test Laboratory, Hohhot First Hospital, Hohhot, China
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15
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Liu M, Zou G, Lu M, Fu J, Chen H, Pan C, Liu HM, Fu L. Mechanism of Rabdosia rubescens extract against gastric cancer microenvironment by SIRT1/NF-κB/p53 pathway and promoting tumor-associated macrophage polarization. JOURNAL OF ETHNOPHARMACOLOGY 2025; 349:119935. [PMID: 40345273 DOI: 10.1016/j.jep.2025.119935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 04/23/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The traditional action of Rabdosia rubescens (Hemsl.) H. Hara is heat-clearing and detoxifying, relieve sore throat, dissipate binds and disperse swelling. DLC, as an extract prepared from Rabdosiae Rubescentis Herba, could regulate the polarization of tumor associated macrophages (TAMs). For TAMs play an important role in the tumor microenvironment. It is worthy to further explore the mechanism of DLC on the polarized function of macrophages. AIM OF THE STUDY The aim of this study is to investigate the activity and molecular mechanisms of DLC on dissipating binds and dispersing swelling by modulating the gastric cancer microenvironment and macrophage polarization. MATERIALS AND METHODS We conducted comprehensive qualitative and quantitative chromatographic analyses to characterize the main components of DLC. To evaluate its anti-tumor effects, immunofluorescence, MTT assay, plate cloning, transcriptomics analysis, western blotting, and siRNA knockdown experiments were performed to assess DLC's action on gastric cancer cell proliferation. Additionally, we utilized Trypan blue staining, a THP-1 and MGC-803 co-culture model, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and a mouse xenograft model with five distinct dosage groups to systematically investigate DLC's effects on macrophage polarization. RESULTS Key compounds in DLC were identified. The vivo tests demonstrated the tumor inhibition rate of the 5 g/kg DLC group reached 66.99 %, surpassing that of the 5-fluorouracil group (59.94 %). Mechanistically, DLC upregulated SIRT1 expression and suppressed NF-κB pathway, thereby preventing p65 from translocating into nuclear and modulating downstream p53/MDM2/USP7 signaling. Moreover, DLC enhanced M1 macrophage factors such as TNF-α, IL-6 while inhibiting M2 marker TGF-β, effectively repolarizing M2 TAMs toward an M1 phenotype. This effect was associated with suppressed protein expression of HIF-1α, p-p65, and p-PI3K. CONCLUSION This study provides insights into DLC's mechanisms in regulating tumor microenvironment remodeling and promoting macrophage polarization toward an anti-tumor phenotype. These results provide a solid basis for DLC's potential clinical treament in gastric cancer, highlighting its promise as a natural therapeutic agent.
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Affiliation(s)
- Mengran Liu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China
| | - Guona Zou
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China
| | - Mengyao Lu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China
| | - Jiayue Fu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China
| | - Han Chen
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China
| | - Chengxue Pan
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China
| | - Hong-Min Liu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China.
| | - Ling Fu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China.
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Liu Y, Ma Y, Zhou B, Bian B, Zhou Y, Chen S, Zhang P, Shen L, Chen H. Clofoctol impairs the stemness of gastric cancer and induces TNF-mediated necroptosis by directly binding to RanBP2. Cell Mol Life Sci 2025; 82:194. [PMID: 40325218 PMCID: PMC12052660 DOI: 10.1007/s00018-025-05723-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 04/10/2025] [Accepted: 04/21/2025] [Indexed: 05/07/2025]
Abstract
Gastric cancer stem cells (GCSCs) play a crucial role in the initiation, progression, recurrence and therapeutic resistance, contributing to a poor prognosis. Consequently, GCSCs are deemed to be a potential therapeutic target for gastric cancer (GC). Although β-catenin is a well-recognized therapeutic target for GC and several inhibitors have demonstrated potent anti-tumor effects, there is a dearth of therapeutic agents targeting β-catenin for clinical therapy. In this study, we carried out high-throughput screening of clinically approved drugs to identify effective inhibitors of β-catenin. The results revealed that the antibiotic drug, clofoctol (CFT) effectively reduced the β-catenin level, attenuated stemness traits both in vitro and in vivo, and induced necroptosis of GCSCs. Further analyzing of downstream genes and targeted proteins, we found that CFT inhibited GCSCs viability by binding to the SUMO E3 ligase RanBP2, thereby suppressing the SerpinE1/β-catenin axis and activating TNF-mediated necroptosis. These results indicate that CFT may exert potent therapeutic effects against GC by targeting β-catenin and inhibiting the viability of GCSCs.
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Affiliation(s)
- Yi Liu
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanhui Ma
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingqian Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Bingxian Bian
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yunlan Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Shiyu Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Peng Zhang
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Lisong Shen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China.
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Hui Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China.
- Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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17
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Hedayati N, Safari MH, Milasi YE, Kahkesh S, Farahani N, Khoshnazar SM, Dorostgou Z, Alaei E, Alimohammadi M, Rahimzadeh P, Taheriazam A, Hashemi M. Modulation of the PI3K/Akt signaling pathway by resveratrol in cancer: molecular mechanisms and therapeutic opportunity. Discov Oncol 2025; 16:669. [PMID: 40323335 PMCID: PMC12052642 DOI: 10.1007/s12672-025-02471-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/23/2025] [Indexed: 05/08/2025] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a critical intracellular signaling pathway that is pivotal in various cellular functions. It is in senescence, survival, and growth under normal physiological and pathological conditions, including neoplasms. Additionally, this pathway has been recognized as essential for the regulation of the cell cycle. Several previous studies have indicated that the PI3K/Akt signaling pathway can be influenced by various natural products, with resveratrol (3,4',5-trihydroxy-trans-stilbene) being a particularly important phytoalexin polyphenol in this context. This review explores the impact of the PI3K/Akt signaling pathway on the initiation and advancement of various cancerous conditions and the potential of resveratrol to target this signaling mechanism. The review begins by summarizing the anti-tumor capabilities of resveratrol and then emphasizes the significant role of the PI3K/Akt signaling pathway in the progression of multiple malignancies. Finally, we discuss the therapeutic effects of resveratrol on human neoplasms, from brain cancers to gastrointestinal malignancies, through regulation of this signaling cascade.
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Affiliation(s)
- Neda Hedayati
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohamad Hosein Safari
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergent Sciences Research Center, TeMs. C., Islamic Azad University, Tehran, Iran
| | - Seyedeh Mahdieh Khoshnazar
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Dorostgou
- Department of Biochemistry, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Elmira Alaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergent Sciences Research Center, TeMs. C., Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergent Sciences Research Center, TeMs. C., Islamic Azad University, Tehran, Iran.
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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18
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Qu C, Yang H. Prognostic Significance and Immune Environment Analysis Using PANoptosis Molecular Clustering in Gastric Cancer. Med Sci Monit 2025; 31:e947710. [PMID: 40317125 PMCID: PMC12057512 DOI: 10.12659/msm.947710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 02/27/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Stomach adenocarcinoma (STAD) is a common malignant tumor, known for its poor prognosis and challenges in early detection. PANoptosis, a recently discovered form of cell death, is characterized by the integrated activation of pyroptosis, apoptosis, and/or necroptosis pathways. The connection between PANoptosis and the initiation, progression, and prognosis of gastric cancer remains inadequately investigated. MATERIAL AND METHODS Previous research has identified 19 PANoptosis-related genes (PRGs). Using these genes, we performed an in-depth analysis of gastric cancer to identify differentially expressed genes related to prognosis (PRDEGs). These differentially expressed genes were subsequently identified. We analyzed the risk scores, prognoses, and immune landscapes of the patients. Confirmed PRGs and gene clusters have been linked to cancer initiation and progression, patient survival, and immunity. Risk scores were computed, and patients were categorized into 2 groups on the basis of prognostic characteristics linked to 8 specific genes. To increase the accuracy of predicting patient survival, we developed a nomogram that integrates the risk score with various clinical characteristics. RESULTS The analysis revealed that gastric cancer patients classified into high-risk subgroups experienced reduced survival times and a diminished response to immunotherapy. We also found that risk scores demonstrated correlations with immune cell infiltration, tumor microenvironment characteristics (TME), and cancer stem cell (CSC) levels. The differential expression of GPA33 and APOD between gastric tumor and normal tissues was validated by RT-qPCR and immunohistochemical data from the Human Protein Atlas (HPA). In conclusion, our research indicates that genes linked to PANoptosis may serve as key indicators for evaluating the prognosis and survival rates of patients with gastric cancer. CONCLUSIONS This research has the potential to improve the early detection of gastric cancer and contribute to the development of more effective therapeutic approaches.
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19
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Yang F, Shaibu Z, Liu Q, Zhu W. Cytokine profiles as predictive biomarkers for treatment outcomes in advanced gastric cancer patients undergoing PD-1 blockade immunochemotherapy: a meta-analysis. Clin Exp Med 2025; 25:136. [PMID: 40317367 PMCID: PMC12049293 DOI: 10.1007/s10238-025-01676-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/07/2025] [Indexed: 05/07/2025]
Abstract
Immunotherapy, specifically PD-1 blockade, is a promising treatment for advanced gastric cancer (AGC). However, predicting patient response is challenging. Cytokines, key immune response regulators, could be important biomarkers for forecasting patient outcomes and susceptibility to PD-1 blockade immunochemotherapy in AGC. This meta-analysis aims to evaluate the potential of cytokine profiles as predictive biomarkers for treatment outcomes in patients with AGC undergoing immunochemotherapy. Meta-analysis. Original studies on the evaluation of various serum samples of cytokines in AGC patients after immunochemotherapy were searched in PubMed, Google Scholar, Embase, Cochrane Library, and Web of Science, with a focus on literature published up to October 31, 2023. Data from multiple studies were pooled to analyze the impact of IL-2, IL-4, IL-6, IL-8, IL-10, and IFN-γ expression on treatment outcomes using RevMan 5.4.1. Prospero ID: CRD42024557837. Five studies were included. In AGC patients receiving immunochemotherapy, high levels of IL-4 were correlated with enhanced PFS following therapy. In contrast, there were no significant differences observed in the expression of IL-2, IL-6, IL-10, and IFN-γ for PFS in AGC after treatment. Notably, elevated IL-6 expression was significantly associated with poorer OS in AGC patients undergoing immunochemotherapy. The findings suggest that expression levels of cytokines, particularly IL-4 and IL-6, play a significant role in predicting treatment outcomes in AGC patients undergoing immunochemotherapy. Further research is warranted to validate these results and elucidate the underlying mechanisms driving these associations.
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Affiliation(s)
- Fumeng Yang
- School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University & The Second People's Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China
| | - Zakari Shaibu
- School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Qian Liu
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University & The Second People's Hospital of Lianyungang, Lianyungang, 222006, Jiangsu, China.
| | - Wei Zhu
- School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
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20
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Ma F, Zheng Y, Cui J, Li Z, Shi J, Ma T, Cao X, Yu T, Wu G, Zhao G, Song J, An Q. Survival benefits of postoperative adjuvant chemotherapy in adults aged ≥ 80 years with locally advanced gastric cancer: insights from a population-based study. Discov Oncol 2025; 16:653. [PMID: 40312566 PMCID: PMC12045904 DOI: 10.1007/s12672-025-02375-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 04/11/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND AND AIMS Postoperative adjuvant chemotherapy in older adults aged ≥ 80 years with locally advanced gastric cancer (LAGC) remains debated owing to concerns over treatment tolerance and limited data. We aimed to assess the effectiveness of postoperative adjuvant chemotherapy in adults aged ≥ 80 years with LAGC using data from the Surveillance, Epidemiology, and End Results database. METHODS AND RESULTS A total of 2395 patients with LAGC aged ≥ 80 years who underwent radical surgery between 2004 and 2015 were identified. Propensity score matching (1:1) was applied to pair 422 patients receiving adjuvant chemotherapy with 1973 patients who underwent surgery alone. Multivariate logistic regression identified independent predictors of adjuvant chemotherapy, including the period from 2012-2015, pN1-2 and pN3 stages, and radiation therapy. Conversely, age ≥ 85 years predicted decreased chemotherapy use. Cancer-specific survival (CSS) and overall survival (OS) were compared using multivariate Cox analysis, showing significantly longer OS and CSS in the adjuvant chemotherapy group, before and after matching. Subgroup analysis revealed that patients aged 80-84 years and those with N + stages benefited most from adjuvant chemotherapy, whereas patients aged ≥ 90 years did not show significant benefit. CONCLUSION Postoperative adjuvant chemotherapy should be considered for patients aged ≥ 80 years with LAGC, especially those with lymph node involvement, as it offers significant survival benefits. However, as age approaches 90 years, the benefits of adjuvant chemotherapy may diminish, warranting more cautious application.
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Affiliation(s)
- Fuhai Ma
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Yangyang Zheng
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Jian Cui
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Zijian Li
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Jinxin Shi
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Tianming Ma
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Xianglong Cao
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Tao Yu
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Guoju Wu
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Gang Zhao
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China
| | - Jinghai Song
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China.
| | - Qi An
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China.
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21
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Varvarousis DN, Marini AA, Ntritsos G, Barbouti A, Kitsoulis PV, Kanavaros PE. Relationship of lymphatic vessel invasion and density with clinicopathological parameters and survival in patients with gastric carcinoma: A systematic review and meta-analysis. Pathol Res Pract 2025; 269:155877. [PMID: 40024076 DOI: 10.1016/j.prp.2025.155877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/16/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025]
Abstract
The purpose of this study was to conduct a comprehensive review and meta-analysis to investigate the possible relationship of lymphatic vessel invasion (LVI) and lymphatic vessel density (LVD), evaluated using immunohistochemistry, with survival and clinicopathological parameters in patients with gastric carcinoma. The principal result of this meta-analysis was the statistically significant correlation between LVI and presence of lymph node metastasis. This finding, in view of previous data showing that lymph node metastasis is associated with decreased survival, suggests that LVI may be a negative prognostic factor in gastric carcinoma. In contrast, LVD, whether assessed overall, intratumorally, or peritumorally, showed no statistically significant correlation with survival. The major conclusion of this meta-analysis is that LVI is an important indicator of aggressiveness of gastric carcinomas and may be a negative prognostic factor because of the strong association between LVI and presence of lymph node metastasis.
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Affiliation(s)
| | - Aikaterini A Marini
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Greece
| | - Georgios Ntritsos
- Department of Economics, University of Ioannina, University Campus, Ioannina, Greece; Department of Informatics and Telecommunications, School of Informatics & Telecommunications, University of Ioannina, Arta, Greece
| | - Alexandra Barbouti
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Greece
| | - Panagiotis V Kitsoulis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Greece
| | - Panagiotis E Kanavaros
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Greece
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22
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Ji CF, Ji JF, Yu XB, Wang ZX. N‑methyladenosine reader YTHDF2‑mediated AC026691.1 degradation promotes gastric cancer cell proliferation, migration and M2 macrophage polarization. Mol Med Rep 2025; 31:120. [PMID: 40052573 PMCID: PMC11914866 DOI: 10.3892/mmr.2025.13485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 01/03/2025] [Indexed: 03/20/2025] Open
Abstract
The present study aimed to explore the effects of key N6‑methyladenosine (m6A)‑related long non‑coding RNAs (lncRNAs) on the malignant behavior and macrophage polarization of gastric cancer cells, and their preliminary mechanisms. Gastric cancer‑related lncRNA datasets were downloaded from The Cancer Genome Atlas database, and m6A‑related differentially expressed lncRNAs (DElncRNAs) were analyzed. Subsequently, Cox regression and lasso regression analyses were used to screen the m6A‑related DElncRNAs associated with the prognosis of patients with gastric cancer. Additionally, reverse transcription‑quantitative polymerase chain reaction (qPCR) was employed to detect the expression levels of m6A‑related lncRNAs in normal gastric epithelial cells (GES‑1) and human gastric cancer cells (AGS and MKN‑45). In addition, the methylation levels of lncRNAs were measured using a methylated RNA immunoprecipitation qPCR assay kit, and the interaction between m6A‑related lncRNAs and m6A‑related proteins was observed by RNA pull‑down assay. Subsequently, m6A‑related lncRNAs and proteins were knocked down separately or simultaneously in gastric cancer cell lines. Bioinformatics analysis revealed that m6A‑related AC026691.1 was significantly associated with the prognosis of patients with gastric cancer and had a potential binding site for YT521‑B homology domain family member 2 (YTHDF2). The RNA pull‑down assay indicated that YTHDF2 not only had binding sites with AC026691.1 but could also markedly promote the degradation of m6A‑related AC026691.1. Furthermore, AC026691.1 was lowly expressed in gastric cancer cells, whereas YTHDF2 was highly expressed. Knockdown of YTHDF2 inhibited the proliferation, migration and epithelial‑mesenchymal transition of gastric cancer cells, and reduced M2 macrophage polarization. By contrast, knocking down AC026691.1 showed the opposite trend. Knockdown of YTHDF2 and AC026691.1 further confirmed the stable impact of YTHDF2 on AC026691.1. In conclusion, the degradation of AC026691.1 modified by YTHDF2‑mediated m6A may promote gastric cancer cell proliferation, migration, epithelial‑mesenchymal transition and M2 macrophage polarization.
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Affiliation(s)
- Cong-Fei Ji
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu 226006, P.R. China
| | - Jin-Feng Ji
- Department of Integrative Chinese and Western Medicine, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu 226006, P.R. China
| | - Xiao-Bing Yu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhen-Xin Wang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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23
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Li J, Li S, Zhang Y, Ye S, Liu R, Shi W. The Efficacy and Safety of Nivolumab Combined with Nab-Paclitaxel or Oxaliplatin as a First-Line Treatment for Advanced or Metastatic Gastric Cancer and Gastroesophageal Junction Cancer. J Gastrointest Cancer 2025; 56:109. [PMID: 40293495 PMCID: PMC12037671 DOI: 10.1007/s12029-025-01211-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2025] [Indexed: 04/30/2025]
Abstract
OBJECTIVE This study aims to assess the therapeutic efficacy and safety of nivolumab combined with chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, specifically comparing the outcomes of oxaliplatin-based versus albumin-bound paclitaxel (nab-paclitaxel)-based therapies. METHODS We retrospectively analyzed 93 patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma treated at the First Medical Center of Chinese PLA General Hospital from September 2017 to November 2022. Patients were categorized into the nivolumab + oxaliplatin (N-OX group) or nivolumab + nab-paclitaxel (N-AP group) based on the chemotherapy regimen. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated as endpoints. RESULTS At the end of the follow-up period on September 31, 2023, we reported an ORR of 65.6% and DCR of 95.7% across all patients. The median PFS was 8.4 months, with no significant difference between the N-OX and N-AP groups (median, 7.8 vs 9.5 months; P = 0.450). Notably, patients with diffuse gastric cancer in N-AP group showed a 44.7% reduction in tumor progression risk compared with the N-OX group (P = 0.046). The overall safety profile was acceptable in two groups. CONCLUSIONS Our study suggested that nivolumab combined with chemotherapy was effective and safe as a first-line intervention for advanced gastric cancer. While both oxaliplatin and nab-paclitaxel regimens showed similar efficacy, the nab-paclitaxel may offer additional benefits for patients with diffuse gastric cancer. Further research is encouraged to confirm these findings and refine treatment strategies.
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Affiliation(s)
- Juan Li
- Department of Oncology, First Medical Center, General Hospital of the People'S Liberation Army, Beijing, 100089, China
| | - Shuman Li
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Ying Zhang
- Department of Oncology, First Medical Center, General Hospital of the People'S Liberation Army, Beijing, 100089, China
| | - Sisi Ye
- Department of Oncology, First Medical Center, General Hospital of the People'S Liberation Army, Beijing, 100089, China
| | - Rongrui Liu
- Department of Oncology, First Medical Center, General Hospital of the People'S Liberation Army, Beijing, 100089, China
| | - Weiwei Shi
- Department of Oncology, First Medical Center, General Hospital of the People'S Liberation Army, Beijing, 100089, China.
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24
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Luo HL, Luo HL. Analysis of the effect of multi-channel continuous nursing intervention on patients post-radical gastrectomy. World J Gastrointest Surg 2025; 17:100848. [PMID: 40291863 PMCID: PMC12019047 DOI: 10.4240/wjgs.v17.i4.100848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 02/08/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Radical gastrectomy (RGE) for gastric carcinoma (GC) has exerted definite therapeutic efficacy in treating patients with GC. However, a notable risk of postoperative complications (POCs) persists among middle-aged and elderly patients with compromised physiological functions. Hence, developing and implementing reliable nursing interventions to optimize the comprehensive management of these patients is deemed imperative. AIM To analyze the association of multi-channel continuous nursing intervention with POCs, negative emotions (NEs), and quality of life (QoL) of patients undergoing RGE for GC. METHODS This retrospective study selected 99 patients who underwent RGE for GC in our hospital from May 2020 to May 2023. Participants were categorized into the control (n = 49 cases) and research groups (n = 50 cases) receiving routine and multi-channel continuous nursing care, respectively. Comparative analysis involved data on postoperative rehabilitation (time to first anal exhaust, oral feeding and ambulation, and hospital stay), complications (nausea and vomiting, delayed gastric emptying, and abdominal distension), NEs [Self-rating Anxiety (SAS)/Depression Scale (SDS)], treatment compliance, self-efficacy, and QoL [World Health Organization QoL Brief Version (WHOQOL-BREF)]. RESULTS Compared to the control group, the research group demonstrated earlier first postoperative anal exhaust, oral feeding, and ambulation, shorter hospital stay, lower POC rate, and more reduced SAS and SDS scores postintervention, which was significantly lower than the baseline. The treatment compliance scores were significantly higher in the research group than in the control group in terms of medication adherence, daily exercise, reasonable diet, and regular review. Further, the research group demonstrated increased self-efficacy scores in terms of positive attitude, self-stress relief, and self-decision-making, as well as the overall score postintervention, which were higher than the control group. Moreover, the research group reported notably higher WHOQOL-BREF scores in domains such as physiology, psychology, social relations, and environment. CONCLUSION Multi-channel continuous nursing intervention prevents POCs in patients undergoing RGE for GC as well as significantly alleviates patients' NEs and boosts their QoL.
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Affiliation(s)
- Huan-Li Luo
- Department of Nursing, Henan Vocational College of Nursing, Anyang 455000, Henan Province, China
| | - Huan-Ling Luo
- Department of International Education, Henan Vocational College of Nursing, Anyang 455000, Henan Province, China
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25
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Wang LJ, Lei CL, Wang TA, Lin ZF, Feng SJ, Wei T, Li YQ, Shen MR, Li Y, Liao LF. Prognostic value of the preoperative systemic immune-inflammation nutritional index in patients with gastric cancer. World J Clin Oncol 2025; 16:102294. [PMID: 40290682 PMCID: PMC12019271 DOI: 10.5306/wjco.v16.i4.102294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/04/2024] [Accepted: 01/21/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related deaths in China. Many patients with GC frequently experience symptoms related to the disease, including anorexia, nausea, vomiting, and other discomforts, and often suffer from malnutrition, which in turn negatively affects perioperative safety, prognosis, and the effectiveness of adjuvant therapeutic measures. Consequently, some nutritional indicators such as nutritional risk index (NRI), prognostic nutritional index (PNI), and systemic immune-inflammatory-nutritional index (SIINI) can be used as predictors of the prognosis of GC patients. AIM To examine the prognostic significance of PNI, NRI, and SIINI in postoperative patients with GC. METHODS A retrospective analysis was conducted on the clinical data of patients with GC who underwent surgical treatment at the Guangxi Medical University Cancer Hospital between January 2010 and December 2018. The area under the receiver operating characteristic (ROC) curve was assessed using ROC curve analysis, and the optimal cutoff values for NRI, PNI, and SIINI were identified using the You-Review-HTMLden index. Survival analysis was performed using the Kaplan-Meier method. In addition, univariate and multivariate analyses were conducted using the Cox proportional hazards regression model. RESULTS This study included a total of 803 patients. ROC curves were used to evaluate the prognostic ability of NRI, PNI, and SIINI. The results revealed that SIINI had superior predictive accuracy. Survival analysis indicated that patients with GC in the low SIINI group had a significantly better survival rate than those in the high SIINI group (P < 0.05). Univariate analysis identified NRI [hazard ratio (HR) = 0.68, 95% confidence interval (CI): 0.52-0.89, P = 0.05], PNI (HR = 0.60, 95%CI: 0.46-0.79, P < 0.001), and SIINI (HR = 2.10, 95%CI: 1.64-2.69, P < 0.001) as prognostic risk factors for patients with GC. However, multifactorial analysis indicated that SIINI was an independent risk factor for the prognosis of patients with GC (HR = 1.65, 95%CI: 1.26-2.16, P < 0.001). CONCLUSION Analysis of clinical retrospective data revealed that SIINI is a valuable indicator for predicting the prognosis of patients with GC. Compared with NRI and PNI, SIINI may offer greater application for prognostic assessment.
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Affiliation(s)
- Li-Jing Wang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Cai-Lu Lei
- School of Pharmaceutical Science, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ting-An Wang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Feng Lin
- School of Pharmaceutical Science, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shi-Jie Feng
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Wei
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Qin Li
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Meng-Ru Shen
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan Li
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Liu-Feng Liao
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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26
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Wang G, Zhang Q, Pan S. Investigation of negative emotions and sleep quality in gastric cancer patients and intervention strategies. Front Neurol 2025; 16:1536736. [PMID: 40343181 PMCID: PMC12060187 DOI: 10.3389/fneur.2025.1536736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 04/03/2025] [Indexed: 05/11/2025] Open
Abstract
Objective This study investigates the prevalence of negative emotions and sleep disturbances in gastric cancer patients, explores their relationship, and suggests targeted interventions to enhance their physical and mental well-being. Methods A total of 650 gastric cancer patients from the First Affiliated Hospital of Soochow University (March 2020 to March 2023) were included. Negative emotions, including anxiety and depression, were assessed using the Positive and Negative Affect Schedule (PANAS), while sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Descriptive statistics and Pearson correlation analysis were employed to analyze the data and explore the relationship between negative emotions and sleep quality. Results Of the 650 patients, 533 (82%) exhibited negative emotions, and 560 (86.15%) experienced sleep disturbances. A significant positive correlation was found between negative emotion scores and sleep quality (r = 0.682, p < 0.05). Patients with poor sleep quality had significantly higher negative emotion scores (p < 0.05). Factors such as gender, age, tumor stage, and education level influenced negative emotion scores, while room type significantly impacted sleep quality (p < 0.05). Conclusion Negative emotions and sleep disturbances are common and interrelated in gastric cancer patients. Addressing psychological factors, particularly anxiety and depression, is crucial for improving sleep quality and overall recovery. Integrated psychological and sleep management interventions should be incorporated into routine care to improve patients' quality of life and treatment outcomes.
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Affiliation(s)
- Gang Wang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Quanquan Zhang
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Shengjie Pan
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China
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27
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Li Z, Lu Y, Wang L, Shi L, Wang T. Reactive oxygen species-dependent nanomedicine therapeutic modalities for gastric cancer. NANOSCALE ADVANCES 2025:d5na00321k. [PMID: 40308560 PMCID: PMC12038724 DOI: 10.1039/d5na00321k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2025] [Accepted: 04/15/2025] [Indexed: 05/02/2025]
Abstract
Reactive oxygen species (ROS) play a double-edged role in gastric cancer (GC). Higher levels of ROS in tumor cells compared to normal cells facilitate tumor progression. Once ROS concentrations rise rapidly to toxic levels, they cause GC cell death, which is instead beneficial for GC treatment. Based on these functions, nano-delivery systems taking the therapeutic advantages of ROS have been widely employed in tumor therapy in recent years, overcoming the drawbacks of conventional drug delivery techniques, such as non-specific systemic effects. In this review, the precise impacts of ROS on GC have been detailed, along with ROS-based nanomedicine therapeutic schemes. These strategies mainly focused on the use of excess ROS in the tumor microenvironment for controlled drug release and a substantial enhancement of ROS concentrations for tumor killing. The challenges and opportunities for the advancement of these anticancer therapies are also emphasized.
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Affiliation(s)
- Zhiyan Li
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Yanjun Lu
- Division of Gastric Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Lulu Wang
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Liuyi Shi
- Yangzhou University Medical College Yangzhou 225001 China
| | - Tao Wang
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
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Li X, Lu X, Liu M, Chen J, Lu X. Extracellular vesicles: messengers of cross-talk between gastric cancer cells and the tumor microenvironment. Front Cell Dev Biol 2025; 13:1561856. [PMID: 40309240 PMCID: PMC12040901 DOI: 10.3389/fcell.2025.1561856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Gastric cancer is a common malignancy characterized by an insidious onset and high mortality rate. Exosomes, a special type of extracellular vesicle, contain various bioactive molecules and have been found to play crucial roles in maintaining normal physiological functions and homeostasis in the body. Recent research has shown that the contents of exosome play a significant role in the progression and metastasis of gastric cancer through communication and regulatory functions. These mechanisms involve promoting gastric cancer cell proliferation and drug resistance. Additionally, other cells in the gastric cancer microenvironment can regulate the progression of gastric cancer through exosomes. These include exosomes derived from fibroblasts and immune cells, which modulate gastric cancer cells. Therefore, in this review, we provide a brief overview of recent advances in the contents and occurrence mechanisms of exosome. This review specifically focused on the regulatory mechanisms of exosomes derived from gastric cancer and other cellular subtypes in the tumor microenvironment. Subsequently, we summarize the latest research progress on the use of exosomes in liquid biopsy, discussing the potential of gastric cancer exosomes in clinical applications.
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Affiliation(s)
- Xiwen Li
- Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, China
| | - Xian Lu
- Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, China
| | - Mi Liu
- Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, China
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou, China
| | - Junjie Chen
- Department of Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong, China
| | - Xirong Lu
- Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, China
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Zhang C, Wang T, Yuan J, Wang T, Ma B, Xu B, Bai R, Tang X, Zhang X, Wu M, Lei T, Xu W, Guo Y, Li N. Potential predictive value of CD8A and PGF protein expression in gastric cancer patients treated with neoadjuvant immunotherapy. BMC Cancer 2025; 25:674. [PMID: 40221689 PMCID: PMC11993984 DOI: 10.1186/s12885-025-14046-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Immunoneoadjuvant therapy has gained significant attention due to its remarkable advancements in cancer treatment. This study aimed to investigate the molecular mechanisms underlying immunoneoadjuvant therapy through a comprehensive multiomics analysis of samples from a registered clinical trial cohort. METHODS Preoperative samples were collected from 16 patients, and postoperative samples were obtained from 12 among them. RNA sequencing (RNA-seq) and Olink proteomics were employed to identify key genes before and after neoadjuvant treatment. The weighted coexpression network was constructed using Weighted gene co-expression network analysis (WGCNA). Furthermore, the proportion of infiltrated immune cells was calculated using xCell based on normalized expression data derived from RNA-seq. RESULTS Patients were stratified into T1 (good efficacy) and T2 (poor efficacy) groups based on Tumor Regression Grade (TRG) to neoadjuvant immunotherapy. Compared to the T2 group (TRG2 and TRG3), the T1 group (TRG0 and TRG1) showed significant differences in pathways related to inflammatory response and myeloid leukocyte activation. Furthermore, the T1 group exhibited elevated levels of CD8+ T cells and B cells. The top two factors with the highest area under the Receiver Operating Characteristic (ROC) curve were CD8a molecule (CD8A) (1.000) and C-C motif chemokine ligand 20 (CCL20) (0.967). Additionally, the expression of placenta growth factor (PGF) and TNF receptor superfamily member 21 (TNFRSF21) proteins significantly increased in the T1 group compared to the T2 group. High expression of CD8A and PGF were associated with favorable and poor prognosis in gastric cancer patients, respectively. Immunoinfiltration analysis revealed a positive correlation between CD8A and dendritic cell (DC) levels, while a negative correlation was observed with myeloid-derived suppressor cell (MDSC) levels. CONCLUSIONS Through multiomics analysis, we discovered that CD8A is linked to enhanced treatment response and tumor regression. In contrast, PGF appears to exert adverse effects on treatment outcomes, suggesting a complex interplay of factors influencing the efficacy of immunoneoadjuvant therapy in gastric cancer.
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Affiliation(s)
- Chengjuan Zhang
- Center of Bio-Repository, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, Henan, P. R. China
| | - Tingjie Wang
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jing Yuan
- Center of Bio-Repository, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Tao Wang
- The Kids Research Institute Australia, School of Medicine, the University of Western Australia, Nedlands, WA, Australia
| | - Bin Ma
- School of Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, WA, Australia
| | - Benling Xu
- Department of Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Ruihua Bai
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xiance Tang
- Department of Medical Records, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaojie Zhang
- Department of Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Minqing Wu
- Center of Bio-Repository, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Tianqi Lei
- Center of Bio-Repository, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Wenhao Xu
- Center of Bio-Repository, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yongjun Guo
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, Henan, P. R. China.
| | - Ning Li
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
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Li R, Sun X, Yu Z, Zhu X, Zhao X, Li P, Liu N. Defining Optimal Lymph Node Yield in Gastrectomy: A Real-World Cohort Analysis. World J Surg Oncol 2025; 23:141. [PMID: 40217295 PMCID: PMC11992801 DOI: 10.1186/s12957-025-03787-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 03/29/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) has a high global mortality and incidence rate. Lymph node (LN) invasion is crucial in TNM staging, and an accurate LN staging system is vital for treatment decisions. However, the appropriate number of examined LNs remains uncertain. METHODS We retrospectively analyzed consecutive GC patients who underwent gastrectomy at the First Medical Center of the Chinese PLA General Hospital from January 2010 to December 2023. A new statistical model based on the β-binomial distribution and maximum likelihood method in R software was employed to calculate false-negative probabilities. RESULTS A total of 6463 GC patients were included. For cT1 patients, even with only five LNs excised, the likelihood of encountering occult positive LNs remained below 5%. For cT2 patients, 17 nodes were needed to rule out occult nodal disease with 90% confidence. While for cT3 and cT4 patients, even after the removal of 35 LNs, the likelihood of overlooking a positive node was still above 20%. Considering surgical extent, 25 nodes were required for patients who underwent proximal gastrectomy or distal gastrectomy to rule out occult nodal disease with 90% confidence, whereas those who received entire gastrectomy needed 59 nodes to achieve the same level of confidence. CONCLUSION Our study establishes a novel quantitative framework linking LN harvest thresholds to false-negative metastasis risk in GC, derived from real-world clinicopathological data.
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Affiliation(s)
- Rui Li
- School of Medicine, Nankai University, Tianjin, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, China
| | - Xu Sun
- School of Medicine, Nankai University, Tianjin, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, China
| | - Zhiyuan Yu
- School of Medicine, Nankai University, Tianjin, China
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, China
| | - Xiangchao Zhu
- Department of Gastrointestinal Surgery, Zibo Central Hospital, Zibo, China
| | - Xudong Zhao
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing, 100853, China
- Medical School of Chinese PLA, Beijing, China
| | - Peiyu Li
- School of Medicine, Nankai University, Tianjin, China.
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing, 100853, China.
- Medical School of Chinese PLA, Beijing, China.
| | - Na Liu
- Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Haidian District, Beijing, 100853, China.
- Medical School of Chinese PLA, Beijing, China.
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Serena P, Miutescu B, Gadour E, Burciu C, Mare R, Bende R, Seclăman E, Aragona G, Serena L, Sirli R. Delayed Diagnosis and Evolving Trends in Gastric Cancer During and After COVID-19: A Comparative Study of Staging, Helicobacter pylori Infection and Bleeding Risk in Western Romania. Diagnostics (Basel) 2025; 15:950. [PMID: 40310359 PMCID: PMC12026344 DOI: 10.3390/diagnostics15080950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 03/28/2025] [Accepted: 04/01/2025] [Indexed: 05/02/2025] Open
Abstract
Background and Objectives: Gastric cancer (GC) remains a leading cause of cancer mortality worldwide, and the COVID-19 pandemic posed new barriers in diagnosis and management. This study aimed to assess whether pandemic-related healthcare disruptions resulted in more advanced GC stages at presentation. We additionally examined the role of Helicobacter pylori (H. pylori) across non-cardia GC (NCGC) versus cardia GC (CGC) and evaluated the risk factors of upper gastrointestinal (GI) bleeding. Methods: A retrospective cohort of 121 adult patients with GC was enrolled from a tertiary Gastroenterology Unit in Western Romania, spanning pre-pandemic (March 2018-February 2020), pandemic (March 2020-February 2022), and post-pandemic (March 2022-February 2024) periods. Demographic profiles, TNM staging, histopathology, H. pylori status, and clinical outcomes-including GI bleeding-were extracted from medical records. Results: An increase in advanced GC (Stage III-IVB) was noted in the post-pandemic period (69.4% vs. 53.3% pre-pandemic; p = 0.021). H. pylori positivity remained higher in NCGC (70.6%) compared to CGC (44.6%; overall p = 0.041); however, CGC cases showed a rise in H. pylori prevalence post-pandemic (36.4% to 55.6%). One-year mortality was driven by an advanced stage (hazard ratio [HR] = 2.74, p = 0.002), diagnosis during the COVID-19 pandemic (HR = 1.66, p = 0.010), and age ≥70 years (HR = 1.88, p = 0.043). Conclusions: Our findings demonstrate that delayed diagnostic endoscopy correlated with a higher proportion of advanced GC in the post-pandemic phase. H. pylori was strongly linked to NCGC, though CGC showed an increasing trend in H. pylori prevalence. Patients on antithrombotic agents faced increased GI bleeding risks.
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Affiliation(s)
- Patricia Serena
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania; (P.S.); (R.M.); (R.B.); (R.S.)
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania;
| | - Bogdan Miutescu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania; (P.S.); (R.M.); (R.B.); (R.S.)
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania;
| | - Eyad Gadour
- Multi-Organ Transplant Centre of Excellence, Liver Transplantation Unit, King Fahad Specialist Hospital, Dammam 32253, Saudi Arabia;
- Department of Medicine, Faculty of Medicine, Zamzam University College, Khartoum 11113, Sudan
| | - Calin Burciu
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania;
- Department of Gastroenterology, Faculty of Medicine, Pharmacy and Dental Medicine, “Vasile Goldis” West University of Arad, 310414 Arad, Romania
| | - Ruxandra Mare
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania; (P.S.); (R.M.); (R.B.); (R.S.)
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania;
| | - Renata Bende
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania; (P.S.); (R.M.); (R.B.); (R.S.)
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania;
| | - Edward Seclăman
- Department IV—Biochemistry and Pharmacology, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy Timisoara, 2nd Eftimie Murgu Square, 300041 Timisoara, Romania;
| | - Giovanni Aragona
- Gastroenterology and Hepatology Unit, Guglielmo da Saliceto Hospital, 29121 Piacenza, Italy;
| | - Luca Serena
- Anaesthesia and Intensive Care Department, Guglielmo da Saliceto Hospital, 29121 Piacenza, Italy;
| | - Roxana Sirli
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania; (P.S.); (R.M.); (R.B.); (R.S.)
- Advanced Regional Research Center in Gastroenterology and Hepatology, “Victor Babes” University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania;
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Liu S, Qi L, Dong L, Sun W, Liu S, Li P, Zhang N. Prognostic implications of the interaction between intratumoral microbiome and immune response in gastric cancer. Microbiol Spectr 2025; 13:e0283024. [PMID: 40202312 PMCID: PMC12054076 DOI: 10.1128/spectrum.02830-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 03/08/2025] [Indexed: 04/10/2025] Open
Abstract
Gastric cancer (GC) prognosis is significantly influenced by intratumoral microbiomes, which modulate host-immune interactions. This study analyzed data from the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify immune genes associated with GC prognosis and conducted prognostic immune subtypes. GC patients were classified into two distinct prognostic immune phenotypes C1 and C2 based on the non-negative matrix factorization consensus clusters. Phenotype C2 exhibited a better prognosis and distinct immune characteristics, including enhanced presence of Th2 and Th17 cells and improved response to chemotherapy. In contrast, phenotype C1 showed higher expression levels of PDCD1LG2 and TLR9, which were critical immune factors involved in immune regulation. Both phenotypes were linked to immune genes influencing intratumoral microbiomes and GC immunotherapy responses. A prediction risk model was constructed using the LASSO regression analysis and showed great prognostic value for GC patients. The key genes were correlated with immune cells and suppressed the function of the host immune system. The intratumoral microbiomes were strongly associated with the hosts' immune infiltration and significantly interacted with host immune genes to influence GC outcomes. Candidatus Nitrosotenuis plays a significant role in predicting the prognosis of GC patients. This research underscores the pivotal role of intratumoral microbiomes in GC prognosis and supports the development of future personalized therapeutic approaches.IMPORTANCEIncreasing evidence confirms the presence of intratumoral microbiomes. However, the role of the intratumoral microbiomes in the progression of gastric cancer and their relationship with the immune microenvironment remain unclear. Our study classified gastric cancer patients into two immune prognostic subtypes, C1 and C2, using non-negative matrix factorization consensus clusters. The C2 subtype exhibited a better prognosis and more pronounced immune characteristics. Microbiome analyses revealed associations between both subtypes and immune genes that affect intratumoral microbiomes and their responses to immunotherapy. The intratumoral microbiomes were closely linked with host immune infiltration and significantly interacted with immune genes, which influence the prognosis of gastric cancer. Notably, Candidatus Nitrosotenuis showed a significant prognostic value in gastric cancer patients. Our findings highlight the critical role of the intratumoral microbiomes in affecting gastric cancer prognosis and its interaction with the immune microenvironment, supporting future personalized therapeutic approaches.
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Affiliation(s)
- Sifan Liu
- Department of Gastroenterology, State Key Laboratory for Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lingyu Qi
- Department of Gastroenterology, State Key Laboratory for Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lu Dong
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Wenjing Sun
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Siying Liu
- Department of Gastroenterology, State Key Laboratory for Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Peng Li
- Department of Gastroenterology, State Key Laboratory for Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Nan Zhang
- Department of Gastroenterology, State Key Laboratory for Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Ma GF, Huang YY, Chen YC, Luo Z, Li XP. Premature death patterns and trends of stomach cancer in Pudong, Shanghai: a population based study. BMC Cancer 2025; 25:618. [PMID: 40188108 PMCID: PMC11972478 DOI: 10.1186/s12885-025-14024-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 03/26/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Estimating the disease burden of stomach cancer is essential to developing evidence-based prevention and treatment strategies. AIMS To analyze the number of deaths and the temporal trends in the mortality and years of life lost (YLL) in relation to gender, age, and the impact of aging and comorbidity via non-communicable diseases on stomach cancer burden in one of the most developed regions of a transitioning country. METHODS Mortality data of stomach cancer were collected from the Vital Statistics System of the Pudong New Area, Shanghai, China, from 2005 to 2019. The long-term trends in crude mortality rates (CMR), age-standardized mortality rates worldwide (ASMRW), and rate of YLL(YLLr) were analyzed using the Joinpoint regression program. The aging and non-aging factors affecting the mortality rate were evaluated by the decomposition method. RESULTS A total of 11,609 deaths from stomach cancer occurred from 2005 to 2019. The CMR and ASMRW of stomach cancer were 29.83/105 person-year and 12.20/105 person-year, respectively. The CMR, ASMRW, and YLLr in males were nearly twice as higher as those in females(CMR: 35.47/105 vs. 19.83/105, ASMRW: 15.64/105 vs. 7.74/105, YLLr: 378.63/105 vs. 229.13/105). The main co-morbidities involved the circulatory (24.64%) and respiratory system (20.62%). The main metastatic sites were liver (9.08%), lung (2.79%) and peritoneum (2.33%). The long-term trends in CMR and ASMRW were significantly decreasing in males, females, and the total population from 2005 to 2019. A total of 9,460 (81.48%) elderly people aged ≥ 60 years died of stomach cancer. The top three age groups with the highest CMR were ≥ 80 years, 70-79 years, and 60-69 years. The CMR and YLLr of people aged ≥ 80 years showed the largest significantly decreasing trends. The CMR caused by aging showed significantly upward trends [average annual percent changes (AAPC) 95%CI = 37.63(14.95,64.79)%, P < 0.001], which caused by non-aging factor showed significantly downward trends [AAPC 95%CI = -18.17(-22.83,-13.22)%, P < 0.001]. CONCLUSION Age is an important factor affecting the trend of disease burden of stomach cancer. Paying attention to high-risk people may help to reduce the YLL.
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Affiliation(s)
- Gui-Fen Ma
- Department of Radioation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Center for Cancer Prevention and Treatment, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of Radioation Oncology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, 362000, China
| | - Ya-Yu Huang
- Department of Radioation Oncology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, 362000, China
| | - Yi-Chen Chen
- Center for Disease Control and Prevention, Pudong New Area, Shanghai, 200136, China
- Pudong Institute of Preventive Medicine, Fudan University, Shanghai, 200136, China
| | - Zheng Luo
- Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, 201318, China
| | - Xiao-Pan Li
- Department of Health Management Center, Zhongshan Hospital, Fudan University, No. 180 Fenling Rd., Xuhui, Shanghai, 200032, China.
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Wen Y, Chen P, Wang Y, Lu C, Li C, Peng L, Cheng X, Guo Y, Quan J, Wen Y, Yang L. Integrative analysis and prognostication in gastric cancer: unveiling the role of mitochondrial genomics with the MLRScore model. Discov Oncol 2025; 16:470. [PMID: 40186721 PMCID: PMC11972275 DOI: 10.1007/s12672-025-02203-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 03/21/2025] [Indexed: 04/07/2025] Open
Abstract
Gastric cancer, a leading cause of cancer-related mortality globally, presents significant challenges in prognosis and treatment due to its heterogeneity. This study aimed to elucidate the role of mitochondrial-related genes (MRGs) in gastric cancer and develop a prognostic model. We analyzed RNA sequencing data and clinical information of 412 gastric cancer samples from The Cancer Genome Atlas (TCGA). A comprehensive list of 1136 MRGs was curated from the MitoCarta3.0 database, leading to the identification of 110 differentially expressed MRGs between gastric cancer and normal tissues. Using univariate and multivariate Cox regression analyses, we constructed the Mitochondrial-Related Risk Score (MLRScore), a prognostic model incorporating five key MRGs. The model was validated in training and testing cohorts and exhibited promising prognostic capability. Additionally, we investigated the relationship between MLRScore and immune cell infiltration, somatic mutations, tumor mutation burden (TMB), and response to chemotherapy. The MLRScore was found to correlate with distinct immune landscapes and chemotherapeutic sensitivities, suggesting its potential utility in guiding personalized treatment strategies. Our study not only provides a novel tool for prognostic assessment in gastric cancer but also underscores the importance of mitochondrial dynamics in tumor biology and patient stratification.
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Affiliation(s)
- Yiru Wen
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China
- West China School of Nursing, Sichuan University, Chengdu, China
| | - Peng Chen
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China
| | - Yong Wang
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China
| | - Chunyan Lu
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China
- West China School of Nursing, Sichuan University, Chengdu, China
| | - Cao Li
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China
| | - Liu Peng
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China
| | - Xiaohong Cheng
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China
| | - Yulan Guo
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China
| | - Jun Quan
- West China School of Nursing, Sichuan University, Chengdu, China
- Mental Health Center Word 3, West China Hospital, Sichuan University, Chengdu, China
| | - Yue Wen
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China.
- West China School of Nursing, Sichuan University, Chengdu, China.
| | - Lie Yang
- Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, Sichuan, China.
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Morgan DR, Corral JE, Li D, Montgomery EA, Riquelme A, Kim JJ, Sauer B, Shah SC. ACG Clinical Guideline: Diagnosis and Management of Gastric Premalignant Conditions. Am J Gastroenterol 2025; 120:709-737. [PMID: 40072510 DOI: 10.14309/ajg.0000000000003350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 12/13/2024] [Indexed: 03/14/2025]
Abstract
Gastric premalignant conditions (GPMC) are common and include atrophic gastritis, gastric intestinal metaplasia, dysplasia, and certain gastric epithelial polyps. GPMC have an increased risk of progression to gastric adenocarcinoma. Gastric cancer (GC) in the United States represents an important cancer disparity because incidence rates are 2- to 13-fold greater in non-White individuals, particularly early-generation immigrants from regions of high GC incidence. The US 5-year survival rate for GC is 36%, which falls short of global standards and is driven by the fact that only a small percentage of GC in the US is diagnosed in the early, curable stage. This document represents the first iteration of American College of Gastroenterology guidelines on this topic and encompasses endoscopic surveillance for high-risk patients with GPMC, the performance of high-quality endoscopy and image-enhanced endoscopy for diagnosis and surveillance, GPMC histology criteria and reporting, endoscopic treatment of dysplasia, the role of Helicobacter pylori eradication, general risk reduction measures, and the management of autoimmune gastritis and gastric epithelial polyps. There is insufficient evidence to make a recommendation on upper endoscopic screening for GC/GPMC detection in US populations deemed high-risk for GC. Surveillance endoscopy is recommended for individuals at high risk for GPMC progression, as defined by endoscopic, histologic, and demographic factors, typically every 3 years, but an individualized interval may be warranted. H. pylori testing, treatment, and eradication confirmation are recommended in all individuals with GPMC. Extensive high-quality data from US populations regarding GPMC management are lacking, but continue to accrue, and the quality of evidence for the recommendations presented herein should be interpreted with this dynamic context in mind. The GPMC research and education agendas are broad and include high-quality prospective studies evaluating opportunistic endoscopic screening for GC/GPMC, refined delineation of what constitutes "high-risk" populations, development of novel biomarkers, alignment of best practices, implementation of training programs for improved GPMC/GC detection, and evaluation of the impact of these interventions on GC incidence and mortality in the US.
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Affiliation(s)
- Douglas R Morgan
- Division of Gastroenterology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Juan E Corral
- Division of Gastroenterology, Prisma Health, Greenville, South Carolina, USA
| | - Dan Li
- Department of Gastroenterology, Kaiser Permanente Medical Center, Santa Clara, California, USA
- Kaiser Permanente Northern California Division of Research, Oakland, California, USA
| | - Elizabeth A Montgomery
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Arnoldo Riquelme
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Center for Control and Prevention of Cancer (CECAN), Santiago, Chile
| | - John J Kim
- Division of Gastroenterology, Los Angeles General Medical Center, Los Angeles, California, USA
| | - Bryan Sauer
- Division of Gastroenterology, University of Virginia, Charlottesville, Virginia, USA
| | - Shailja C Shah
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
- Gastroenterology Section, Jennifer Moreno Veterans Affairs Medical Center, La Jolla, California, USA
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Liang J, Rastegar R, El Helou M, Mathur K, Larson BK, Waters K, Vasireddy A, Randhawa N, Mubarak M, Advani R, Osipov A, Gong J, Hendifar A, Liu Q, Park KH, Watson R, Pandol SJ, Lo S, Gaddam S. Incidence Trends in Upper Gastrointestinal Cancer in Young Adults: A Nationwide Time-Trend Analysis Using 2001-2019 US Cancer Statistics Databases. Am J Gastroenterol 2025; 120:890-904. [PMID: 39225338 DOI: 10.14309/ajg.0000000000003068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 06/27/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION Upper gastrointestinal (UGI) cancers, comprising malignancies of the esophagus, stomach, duodenum, pancreas, liver, biliary tract, and gallbladder, are the second leading cause of cancer-related mortality in the United States and are associated with significant comorbidities. Recent studies show a disproportionate rise in pancreatic and stomach cancer among young adults. This study aims to use a nationwide, population-based cohort to (i) evaluate the trend of all UGI cancer as an aggregate and (ii) examine the role of demographics, histology, and tumor stage in UGI cancer incidence among young adults. METHODS Individuals diagnosed with UGI cancer in the United States from 2001 to 2019 were identified and obtained from the Surveillance, Epidemiology, and End Results-National Program of Cancer Registries database. The primary outcomes were incidence rates of UGI cancer (calculated per 100,000, age-adjusted to the year 2000 US population), stratified by sex and age (< 55 years for young adults and ≥ 55 years for older adults). Trends, annual percentage change, and average annual percentage change were calculated using the parametric method. Sensitivity analysis was performed according to primary site and histology; further analysis examining race and cancer stage was performed in the young adult subgroup. RESULTS A total of 2,333,161 patients with UGI cancer were identified. Most cases were male, and 14.3% were < 55 years of age. Incidence of UGI cancer increased most in women younger than 55 years, driven primarily by pancreatic and stomach cancers, as well as neuroendocrine tumor and gastrointestinal stromal tumor histology. African American race and localized tumors and malignancy with distant spread are also contributing to the disparate increase among young women. UGI mortality rates have not changed significantly in young adults. DISCUSSION The overall incidence rate of upper gastrointestinal cancer is increasing significantly in young women compared with men. Increased endoscopic procedures and disparate exposure to risk factors are likely contributing to these trends.
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Affiliation(s)
- Jeff Liang
- Cedars-Sinai Health Systems, Los Angeles, California, USA
| | - Ryan Rastegar
- University of California Los Angeles, Los Angeles, California, USA
| | | | | | - Brent K Larson
- Cedars-Sinai Health Systems, Los Angeles, California, USA
| | - Kevin Waters
- Cedars-Sinai Health Systems, Los Angeles, California, USA
| | | | | | | | - Rashmi Advani
- Mt. Sinai Soth Nassau Center for Digestive Health, Bellmore, New York, USA
| | | | - Jun Gong
- Augusta University, Augusta, Georgia, USA
| | | | - Quin Liu
- Cedars-Sinai Health Systems, Los Angeles, California, USA
| | - Kenneth H Park
- Cedars-Sinai Health Systems, Los Angeles, California, USA
| | | | | | - Simon Lo
- Cedars-Sinai Health Systems, Los Angeles, California, USA
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Chen C, Wang Z, Lin Q, Li M, Xu L, Fu Y, Zhao X, Ma Z, Xu J, Zhou S, Zhang M, Qian Y, Bao L, Wang B, Wang M, Ding Q, Wang Q, Wang S. NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410263. [PMID: 39985269 PMCID: PMC12005778 DOI: 10.1002/advs.202410263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 12/21/2024] [Indexed: 02/24/2025]
Abstract
The relationship between patterns of RNA modifications and gastric cancer (GC) liver metastasis (GCLM) remains unclear. Here, by single-cell sequencing, clinical sample analysis, and mouse model studies, an abnormal increase in the expression of the RNA acetyltransferase N-acetyltransferase 10 (NAT10) in liver metastatic GC cells is identified. NAT10-mediated N4-acetylcytidine modification of CXCL2 and KLF5 mRNA increases their stability. Then, secreted CXCL2 is found to promote the infiltration and polarization of M2-like macrophages to produce oncostatin M, which transcriptionally activates NAT10 expression via STAT3 signaling. In addition, organoid models confirm that NAT10 promotes the adhesion of GC cells to hepatocytes. Mechanistically, KLF5 transcriptionally activates ITGαV, facilitating GC cell attachment to hepatocytes. Intriguingly, high expression of NAT10/KLF5 axis is associated with poor prognosis of GC patients and targeting this axis significantly reduces GCLM in preclinical murine models. Collectively, these findings suggest the clinical significance of NAT10 in developing targeted therapies for GC patients with liver metastasis.
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Affiliation(s)
- Chen Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor ImmunotherapyAnhui Province Key Laboratory of Tumor Immune Microenvironment and ImmunotherapyHefei230022China
| | - Zhangding Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor ImmunotherapyAnhui Province Key Laboratory of Tumor Immune Microenvironment and ImmunotherapyHefei230022China
| | - Qingfeng Lin
- Department of OncologyJiangyin Clinical College of Xuzhou Medical UniversityJiangyin Hospital Affiliated to Nantong UniversityJiangyin People's HospitalJiangyin214400China
| | - Mengmeng Li
- Medical School of Nanjing UniversityNanjing210093China
| | - Lei Xu
- Department of GastroenterologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008China
| | - Yao Fu
- Department of PathologyThe First Affiliated Hospital of Anhui Medical UniversityHefei230022China
| | - Xiaoya Zhao
- Medical School of Nanjing UniversityNanjing210093China
| | - Zhuang Ma
- Medical School of Nanjing UniversityNanjing210093China
| | - Jiawen Xu
- Medical School of Nanjing UniversityNanjing210093China
| | - Shimeng Zhou
- Medical School of Nanjing UniversityNanjing210093China
| | - Mingyue Zhang
- Medical School of Nanjing UniversityNanjing210093China
| | - Yun Qian
- Medical School of Nanjing UniversityNanjing210093China
| | - Linsen Bao
- Division of Gastric SurgeryDepartment of General SurgeryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008China
| | - Bo Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor ImmunotherapyAnhui Province Key Laboratory of Tumor Immune Microenvironment and ImmunotherapyHefei230022China
| | - Meng Wang
- Division of Gastric SurgeryDepartment of General SurgeryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008China
| | - Qingqing Ding
- Department of Geriatric OncologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjing210029China
| | - Qiang Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor ImmunotherapyAnhui Province Key Laboratory of Tumor Immune Microenvironment and ImmunotherapyHefei230022China
| | - Shouyu Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor ImmunotherapyAnhui Province Key Laboratory of Tumor Immune Microenvironment and ImmunotherapyHefei230022China
- Medical School of Nanjing UniversityNanjing210093China
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Li D, Morgan DR, Corral JE, Montgomery EA, Riquelme A, Shah SC. Gastric Cancer Screening in the United States: A Review of Current Evidence, Challenges, and Future Perspectives. Am J Gastroenterol 2025; 120:765-777. [PMID: 40072512 DOI: 10.14309/ajg.0000000000003301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 12/18/2024] [Indexed: 03/14/2025]
Abstract
Gastric cancer remains a leading cause of cancer-related mortality worldwide. In the United States, gastric cancer incidence and mortality are substantially higher among non-White racial and ethnic groups and new immigrants from high-incidence countries. This is in large part related to the higher prevalence of Helicobacter pylori -associated gastric premalignant changes in these populations. Apart from primary prevention, early detection of gastric cancer is the principal strategy to reduce gastric cancer mortality and improve survival. Extensive evidence in Asian countries has demonstrated the benefits of endoscopic screening in detecting early-stage gastric cancer and reducing gastric cancer-related mortality. By contrast, direct, high-quality US-based data, such as from large clinical trials or observational studies, on important outcomes of gastric cancer screening are still lacking. In this review, we evaluate and summarize the latest global evidence on the epidemiology and predisposing factors of gastric cancer as well as the efficacy, benefits vs. risks, and cost-effectiveness of gastric cancer screening. We further discuss the critical knowledge gaps and challenges in promoting gastric cancer screening in the United States. Dedicated research is urgently needed to enrich the US-based data on gastric cancer primary and secondary prevention to inform clinical practice and reduce gastric cancer-related morbidity and mortality in a cost and resource efficient manner.
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Affiliation(s)
- Dan Li
- Department of Gastroenterology, Kaiser Permanente Medical Center, Santa Clara, California, USA
- Kaiser Permanente Northern California Division of Research, Oakland, California, USA
| | - Douglas R Morgan
- Division of Gastroenterology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Juan E Corral
- Division of Gastroenterology, Prisma Health, Greenville, South Carolina, USA
| | - Elizabeth A Montgomery
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Arnoldo Riquelme
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Center for Control and Prevention of Cancer (CECAN), Santiago, Chile
| | - Shailja C Shah
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
- Gastroenterology Section, Jennifer Moreno Department of Veterans Affairs Medical Center, La Jolla, California, USA
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Tian J, Cai Q, Li S, Guo Z, Liu Y, Zhang Z, Huo Z. Identification of novel biomarkers for gastric adenocarcinoma through two-sample Mendelian randomization analysis of the human plasma proteome. Scand J Gastroenterol 2025; 60:394-404. [PMID: 40052612 DOI: 10.1080/00365521.2025.2472198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Papillary gastric adenocarcinoma (PGC), a histological subtype of gastric cancer (GC), is characterized by malignant potential and poor prognosis. Therefore, identifying novel biomarkers is urgently needed to enhance PGC diagnosis and treatment outcomes. METHODS This study utilized two-sample Mendelian randomization (MR) to explore potential causal relationships between human blood plasma proteins and GC. Heterogeneity testing, pleiotropy assessment, and directionality analyses were performed to evaluate identified plasma proteins. Additionally, pathway enrichment analysis was conducted to elucidate the molecular mechanisms underlying the causal associations between plasma proteins and GC development. RESULTS MR analysis of 4,907 plasma proteins related to GC risk identified 90 proteins with potential causal relationships. The findings revealed that DNAJB9, CHCHD10, and suppressor of cytokine signaling 3 exhibited protective effects against GC, while Syntaxin-8, alcohol dehydrogenase 7, and UDP-glucose 4-epimerase were associated with increased GC risk at the genetic level. CONCLUSION In the present study, the six plasma proteins identified through comprehensive MR analysis may serve as potential biomarkers for GC, offering new insights for future molecular diagnosis and therapeutic strategies.
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Affiliation(s)
- Jingjing Tian
- School of Clinical Medicine, Hebei University of Engineering, Handan, China
- Department of Oncology, Affiliated Hospital of Hebei University of Engineering, Handan, China
| | - Qingrui Cai
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Hebei University of Engineering, Handan, China
| | - Shiying Li
- Department of Rehabilitation Medicine, Handan Central Hospital, Handan, China
| | - Zhanfei Guo
- School of Clinical Medicine, Hebei University of Engineering, Handan, China
| | - Yanbao Liu
- School of Clinical Medicine, Hebei University of Engineering, Handan, China
| | - Zhiwei Zhang
- School of Clinical Medicine, Hebei University of Engineering, Handan, China
- Department of Oncology, Affiliated Hospital of Hebei University of Engineering, Handan, China
| | - Zhongchao Huo
- School of Clinical Medicine, Hebei University of Engineering, Handan, China
- Department of Oncology, Affiliated Hospital of Hebei University of Engineering, Handan, China
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Gu Y, Liu B, Xia X, Luo C, Ren Y. Chemoprotective effect of nimbolide against N-methyl-N-nitrosourea induced gastric cancer via alteration of apoptosis and NF-κB signaling pathway. Acta Cir Bras 2025; 40:e402125. [PMID: 40172365 PMCID: PMC11960577 DOI: 10.1590/acb402125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 12/29/2024] [Indexed: 04/04/2025] Open
Abstract
PURPOSE Gastric cancer (GC) ranks as the third most common cause of cancer related mortality and as the fifth most frequently diagnosed cancer globally. Less than 30% of people with GC survive for more than five years. METHODS Nimbolide has been shown to have anticancer, anti-inflammatory, antiparasitic, and antioxidant properties. The current investigation showed the anticancer effect of nimbolide against N-methyl-N-nitrosourea (MNU) induced GC in rats. Rats were given MNU (100 mg/kg) orally to induce GC and received the oral administration of nimbolide (10, 20 and 40 mg/kg). The different biochemical parameters were estimated. RESULTS Nimbolide significantly (p < 0.001) altered the level of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), cytochrome P450, cytochrome B5 and histone deacetylase (HDAC) activity. Nimbolide treatment significantly (p < 0.001) altered the level of antioxidant parameters like superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), malondialdehyde (MDA); cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-6; inflammatory parameters viz., cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the serum and stomach tissue. Nimbolide considerably altered (p < 0.001) the level of apoptosis parameters (Bcl-2, Bax and caspase-3), and the mRNA expression of VCAM-1, ICAM-1, TNF-α, IL-1β, IL-6, MCP-1, TLR4 and NF-κB. CONCLUSION Nimbolide treatment considerably altered the GC against MNU induced GC via alteration of apoptosis and NF-κB signaling pathway.
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Affiliation(s)
- Yizhong Gu
- Shanghai No. 3 Rehabilitation Hospital – Department of Pain Rehabilitation – Shanghai – China
| | - Binguo Liu
- No. 983 Hospital of the Chinese People’s Liberation Army – Department of Pharmacy – Tianjin,300142 – China
| | - Xiaoting Xia
- Shanghai Integrated Traditional Chinese and Western Medicine Hospital – Department of Oncology – Shanghai – China
| | - Chunlei Luo
- Fudan University – Jing’an District Central Hospital Affiliated – Department of Traditional Chinese Medicine – Shanghai – China
| | - Yi Ren
- Shanghai Putuo District Hospital of Traditional Chinese Medicine – Department of Medical Ward – Shanghai – China
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Guo X, Wang W, Cheng X, Song Q, Wang X, Wei J, Xu S, Lv X, Ji G. Diagnostic efficacy of an extracellular vesicle-derived lncRNA-based liquid biopsy signature for the early detection of early-onset gastric cancer. Gut 2025:gutjnl-2024-333657. [PMID: 40113244 DOI: 10.1136/gutjnl-2024-333657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 02/25/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Early-onset gastric cancer (EOGC) is a lethal malignancy. It differs from late-onset gastric cancer (LOGC) in clinical and molecular characteristics. The current strategies for EOGC detection have certain limitations in diagnostic performance due to the rising trend in EOGC. OBJECTIVE We developed a liquid biopsy signature for EOGC detection. DESIGN We use a systematic discovery approach by analysing genome-wide transcriptomic profiling data from EOGC (n=43), LOGC (n=31) and age-matched non-disease controls (n=37) tissue samples. An extracellular vesicle-derived long non-coding RNA (EV-lncRNA) signature was identified in blood samples from a training cohort (n=299), and subsequently confirmed by qPCR in two external validation cohorts (n=462 and n=438), a preoperative/postoperative cohort (n=66) and a gastrointestinal tumour cohort (n=225). RESULTS A three EV-lncRNA (NALT1, PTENP1 and HOTTIP) liquid biopsy signature was developed for EOGC detection with an area under the receiver operating characteristic curve (AUROC) of 0.924 (95% CI 0.889 to 0.953). This EV-lncRNA signature provided robust diagnostic performance in two external validation cohorts (Xi'an cohort: AUROC, 0.911; Beijing cohort: AUROC, 0.9323). Furthermore, the EV-lncRNA signature reliably identified resectable stage EOGC patients (stage I/II) and demonstrated better diagnostic performance than traditional GC-related biomarkers in distinguishing early-stage EOGC (stage I) from precancerous lesions. The low levels of this biomarker in postsurgery and other gastrointestinal tumour plasma samples indicated its GC specificity. CONCLUSIONS The newly developed EV-lncRNA signature effectively identified EOGC patients at a resectable stage with enhanced precision, thereby improving the prognosis of patients who would have otherwise missed the curative treatment window.
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Affiliation(s)
- Xin Guo
- Department of General Surgery, Xijing 986th Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weidong Wang
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xin Cheng
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qiying Song
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xinxin Wang
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jiangpeng Wei
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Shenhui Xu
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaohui Lv
- Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Gang Ji
- Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
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Yuan H, Bao M, Chen M, Fu J, Yu S. Advances in Immunotherapy and Targeted Therapy for Gastric Cancer: A Comprehensive Review. Br J Hosp Med (Lond) 2025; 86:1-24. [PMID: 40135294 DOI: 10.12968/hmed.2024.0759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
Gastric cancer remains one of the most prevalent and lethal malignancies worldwide, characterized by poor survival rates, particularly in advanced stages. In recent years, a paradigm shift in gastric cancer treatment has been witnessed with the introduction of immunotherapy and targeted therapies. This review provides a detailed examination of current immunotherapeutic strategies, including adoptive cell therapy (ACT), immune checkpoint inhibitors (ICIs), and cancer vaccines. Additionally, it explores advancements in targeted therapies, focusing on the human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor receptor (VEGFR) signaling pathways, as well as emerging targets such as claudin 18.2. Clinical trials investigating chimeric antigen receptor T-cell (CAR-T) therapy, T-cell receptor-engineered T-cell (TCR-T) therapy, and natural killer (NK) cell-based treatments have shown promise, particularly when combined with conventional chemotherapeutic regimens. However, challenges such as cytokine release syndrome, immune-related toxicities, and scalability issues remain significant. The combination of immunotherapy with targeted therapies represents a promising approach to enhance treatment outcomes. Future directions emphasize the need to overcome resistance mechanisms and refine treatment strategies to improve efficacy while reducing adverse effects. This review aims to elucidate the current landscape of immunotherapy and targeted therapy in gastric cancer and to explore their potential in shaping the future of clinical management for this devastating disease.
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Affiliation(s)
- Hui Yuan
- Department of Hepatobiliary and Pancreatic Surgery, Jinhua Municipal Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Miao Bao
- The Second Ward, Department of Pediatrics, Jinhua Maternal & Child Health Hospital, Jinhua, Zhejiang, China
| | - Minqiang Chen
- Department of Hepatobiliary and Pancreatic Surgery, Jinhua Municipal Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Junhao Fu
- Central Laboratory, Jinhua Municipal Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Shian Yu
- Department of Hepatobiliary and Pancreatic Surgery, Jinhua Municipal Central Hospital, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
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She X, Geng L, Zhao Q, Guo H, Rong G, Luo Y, Li X, Xu L, Ran F, Liu S. Targeting hypoxia-induced HIF-1α/JMJD3/Notch axis in gastric cancer therapy. J Bioenerg Biomembr 2025:10.1007/s10863-025-10057-y. [PMID: 40138042 DOI: 10.1007/s10863-025-10057-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 03/08/2025] [Indexed: 03/29/2025]
Abstract
Hypoxia has been reported to induce high expression of HIF-1α in multiple cancer tissues, and HIF-1α significantly influences cancer progression, including gastric cancer (GC). However, the mechanism of HIF-1α in the GC process is not clearly elucidated. HIF-1α and JMJD3 expressions in GC tissues were first determined by qRT-PCR and western blot. Meanwhile, the prognosis of HIF-1α, and the relationship between HIF-1α and JMJD3 were analyzed through bioinformatics. Then, we silenced HIF-1α, knocked down or overexpressed JMJD3, or treated gamma-secretase inhibitor (DAPT) in GC cells under hypoxic conditions. Cell proliferation, apoptosis, and Notch activation was determined both in vivo and vitro. We initially proved that both HIF-1α and JMJD3 were highly expressed in GC tissues, high expression of HIF-1α was associated with a poor prognosis. Functionally, we observed that HIF-1α knockdown attenuated GC cell proliferation and enhanced apoptosis under hypoxic conditions, while JMJD3 knockdown exerted the opposite effect in hypoxia-induced GC cells. Besides, JMJD3 overexpression promoted proliferation and reduced apoptosis by upregulating Notch in GC cells under hypoxia conditions. Furthermore, HIF-1α knockdown inhibited tumor growth and altered the pathological structure in the tumors of GC model nude mouse. In GC cells, HIF-1α knockdown inhibited cell proliferation and promoted apoptosis by affecting JMJD3/Notch axis. Therefore, we demonstrated that HIF-1α/JMJD3/Notch axis might be a new therapeutic target for GC.
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Affiliation(s)
- Xin She
- Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Lijun Geng
- Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Qianwen Zhao
- Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Haonan Guo
- Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Guihong Rong
- Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Yun Luo
- Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Xia Li
- Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Longkuan Xu
- Department of Pathology, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Fulin Ran
- Department of Gastroenterology Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Shanshan Liu
- Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
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Wang S, Xie B, Deng H, Ma X, Tang B, Ma L, Zhu J, Li J, Li L. Effect of PRKD3 on cell cycle in gastric cancer progression and downstream regulatory networks. Med Oncol 2025; 42:135. [PMID: 40131654 DOI: 10.1007/s12032-025-02663-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Accepted: 03/04/2025] [Indexed: 03/27/2025]
Abstract
Protein kinase D3 (PRKD3), belonging to the protein kinase D family, significantly influences tumor development and progression. The role of PRKD3 in advancing gastric cancer (GC) and its effects on the cell cycle are not well understood, necessitating detailed investigation. Assessment of PRKD3 expression in both malignant and normal gastric tissues was performed using bioinformatics databases. The influence of PRKD3 on GC's malignant characteristics was evaluated through in vitro experiments utilizing cell line models of GC. Additionally, proteomic analyses were conducted to investigate the potential mechanisms of PRKD3 in GC progression. PRKD3 was notably overexpressed in GC tissues, correlating with adverse outcomes for patients. PRKD3 knockdown impaired GC cell malignancy, manifesting as a 2.12-fold decline in proliferation(p < 0.01), 2.64-fold suppression of migration(p < 0.01), 2.16-fold inhibition of invasion(p < 0.01), and G2/M phase arrest. Proteomic and Western blot analyses had revealed a substantial enrichment in differentially expressed proteins (DEPs) associated with tumor-related signaling pathways, including FoxO and p53, which was paralleled by significant alterations in the levels of key cell cycle proteins such as CDK1, CyclinB1, CHK1 and PLK1, with a 6.8-fold elevation in CHK1 levels(p < 0.05). The overexpression of PRKD3 was intricately linked with the aggressive behaviors of GC. Targeting PRKD3 activity offers potential for effective treatments of GC.
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Affiliation(s)
- Shuaiyang Wang
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- Cuiying Biomedical Research Center, Lanzhou University Lanzhou Second Hospital, Lanzhou, 730000, Gansu, China
| | - Bei Xie
- Department of Immunology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China.
| | - Haohua Deng
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- Cuiying Biomedical Research Center, Lanzhou University Lanzhou Second Hospital, Lanzhou, 730000, Gansu, China
| | - Xingyuan Ma
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- Cuiying Biomedical Research Center, Lanzhou University Lanzhou Second Hospital, Lanzhou, 730000, Gansu, China
| | - Baoyuan Tang
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- Cuiying Biomedical Research Center, Lanzhou University Lanzhou Second Hospital, Lanzhou, 730000, Gansu, China
| | - Lei Ma
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- Cuiying Biomedical Research Center, Lanzhou University Lanzhou Second Hospital, Lanzhou, 730000, Gansu, China
| | - Jinmei Zhu
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- Cuiying Biomedical Research Center, Lanzhou University Lanzhou Second Hospital, Lanzhou, 730000, Gansu, China
| | - Jing Li
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
| | - Linjing Li
- Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China.
- Cuiying Biomedical Research Center, Lanzhou University Lanzhou Second Hospital, Lanzhou, 730000, Gansu, China.
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Wang S, Li J, Zhang Z, Cao S, Zhang Z, Bian Y, Xu Y, Ma C. Advances in nanomedicine and delivery systems for gastric cancer research. Front Bioeng Biotechnol 2025; 13:1565999. [PMID: 40190709 PMCID: PMC11968739 DOI: 10.3389/fbioe.2025.1565999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 03/05/2025] [Indexed: 04/09/2025] Open
Abstract
The early diagnosis rate of gastric cancer is low, and most patients are already at an advanced stage by the time they are diagnosed, posing significant challenges for treatment and exhibiting high recurrence rates, which notably diminish patients' survival time and quality of life. Therefore, there is an urgent need to identify methods that can enhance treatment efficacy. Nanomedicine, distinguished by its small size, high targeting specificity, and strong biological compatibility, is particularly well-suited to address the toxic side effects associated with current diagnostic and therapeutic approaches for gastric cancer. Consequently, the application of nanomedicine and delivery systems in the diagnosis and treatment of gastric cancer has garnered increasing interest from researchers. This review provides an overview of recent advancements in the use of nanomaterials as drugs or drug delivery systems in gastric cancer research, encompassing their applications in diagnosis, chemotherapy, radiotherapy, surgery, and phototherapy, and explores the promising prospects of nanomedicine in the treatment of gastric cancer.
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Affiliation(s)
- Sizhe Wang
- Henan University of Chinese Medicine(The Second Clinical Medical College of Henan University of Chinese Medicine), Zhengzhou, Henan, China
| | - Jilei Li
- Henan Province Hospital of TCM, Zhengzhou(The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou, Henan, China
| | - Zhenyu Zhang
- Henan University of Chinese Medicine(The Second Clinical Medical College of Henan University of Chinese Medicine), Zhengzhou, Henan, China
| | - Shasha Cao
- Henan University of Chinese Medicine(The Second Clinical Medical College of Henan University of Chinese Medicine), Zhengzhou, Henan, China
| | - Zihan Zhang
- Henan University of Chinese Medicine(The Second Clinical Medical College of Henan University of Chinese Medicine), Zhengzhou, Henan, China
| | - Yifan Bian
- Henan University of Chinese Medicine(The Second Clinical Medical College of Henan University of Chinese Medicine), Zhengzhou, Henan, China
| | - Yanchao Xu
- Henan Province Hospital of TCM, Zhengzhou(The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou, Henan, China
| | - Chunzheng Ma
- Henan Province Hospital of TCM, Zhengzhou(The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou, Henan, China
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Ma J, Hou S, Gu X, Guo P, Zhu J. Analysis of shared pathogenic mechanisms and drug targets in myocardial infarction and gastric cancer based on transcriptomics and machine learning. Front Immunol 2025; 16:1533959. [PMID: 40191191 PMCID: PMC11968731 DOI: 10.3389/fimmu.2025.1533959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/28/2025] [Indexed: 04/09/2025] Open
Abstract
Background Recent studies have suggested a potential association between gastric cancer (GC) and myocardial infarction (MI), with shared pathogenic factors. This study aimed to identify these common factors and potential pharmacologic targets. Methods Data from the IEU Open GWAS project were used. Two-sample Mendelian randomization (MR) analysis was used to explore the causal link between MI and GC. Transcriptome analysis identified common differentially expressed genes, followed by enrichment analysis. Drug target MR analysis and eQTLs validated these associations with GC, and the Steiger direction test confirmed their direction. The random forest and Lasso algorithms were used to identify genes with diagnostic value, leading to nomogram construction. The performance of the model was evaluated via ROC, calibration, and decision curves. Correlations between diagnostic genes and immune cell infiltration were analyzed. Results MI was linked to increased GC risk (OR=1.112, P=0.04). Seventy-four genes, which are related mainly to ubiquitin-dependent proteasome pathways, were commonly differentially expressed between MI and GC. Nine genes were consistently associated with GC, and eight had diagnostic value. The nomogram built on these eight genes had strong predictive performance (AUC=0.950, validation set AUC=0.957). Immune cell infiltration analysis revealed significant correlations between several genes and immune cells, such as T cells, macrophages, neutrophils, B cells, and dendritic cells. Conclusion MI is associated with an increased risk of developing GC, and both share common pathogenic factors. The nomogram constructed based on 8 genes with diagnostic value had good predictive performance.
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Affiliation(s)
- Junyang Ma
- School of Clinical Medicine, Jining Medical University, Jining, China
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Shufu Hou
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Xinxin Gu
- Jinzhou Medical University, Shanghai Fengxian District Central Hospital Postgraduate Training Base, Shanghai, China
| | - Peng Guo
- College of Clinical and Basic Medicine, Shandong First Medical University, Jinan, China
| | - Jiankang Zhu
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
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Zhang X, Ren B, Liu B, Wang R, Li S, Zhao Y, Zhou W. Single-cell RNA sequencing and spatial transcriptomics reveal the heterogeneity and intercellular communication of cancer-associated fibroblasts in gastric cancer. J Transl Med 2025; 23:344. [PMID: 40102930 PMCID: PMC11917039 DOI: 10.1186/s12967-025-06376-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 03/12/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Gastric cancer is a highly aggressive malignancy characterized by a complex tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), which are a key component of the TME, exhibit significant heterogeneity and play crucial roles in tumor progression. Therefore, a comprehensive understanding of CAFs is essential for developing novel therapeutic strategies for gastric cancer. METHODS This study investigates the characteristics and functional information of CAF subtypes and explores the intercellular communication between CAFs and malignant epithelial cells (ECs) in gastric cancer by analyzing single-cell sequencing data from 24 gastric cancer samples. CellChat was employed to map intercellular communication, and Seurat was used to integrate single-cell sequencing data with spatial transcriptome data to reconstruct a comprehensive single-cell spatial map. The spatial relationship between apCAFs and cancer cells was analyzed using multicolor immunohistochemistry. RESULTS Cells were categorized into nine distinct categories, revealing a positive correlation between the proportions of epithelial cells (ECs) and fibroblasts. Furthermore, six fibroblast subpopulations were identified: inflammatory (iCAFs), pericytes, matrix (mCAFs), antigen-presenting (apCAFs), smooth muscle cells (SMCs), and proliferative CAFs (pCAFs). Each of these subpopulations was linked to various biological processes and immune responses. Malignant ECs exhibited heightened intercellular communication, particularly with CAF subpopulations, through specific ligand-receptor interactions. High-density regions of CAF subpopulations displayed spatial exclusivity, with pericytes serving as a source for iCAFs, mCAFs, and apCAFs. Notably, malignant ECs and apCAFs showed increased interactions, with certain ligand-receptor pairs potentially impacting the prognosis of gastric cancer. Multiplex immunohistochemistry (mIHC) confirmed the close spatial proximity of apCAFs to cancer cells in gastric cancer. CONCLUSION Our study provided a comprehensive characterization of CAF heterogeneity in gastric cancer and revealed the intricate intercellular networks within the TME. The identified CAF subpopulations and their interactions with malignant cells could serve as potential therapeutic targets.
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Affiliation(s)
- Xijie Zhang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Bo Ren
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Bo Liu
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Rui Wang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Sen Li
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Yuzhou Zhao
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
| | - Wence Zhou
- The Second Clinical Medical School, Lanzhou University, Lanzhou, China.
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China.
- Key Laboratory of Environmental Oncology of Gansu Province, Lanzhou, China.
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Li N, Zhang Y, Zhang Q, Jin H, Han M, Guo J, Zhang Y. Machine learning reveals glycolytic key gene in gastric cancer prognosis. Sci Rep 2025; 15:8688. [PMID: 40082583 PMCID: PMC11906761 DOI: 10.1038/s41598-025-93512-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 03/07/2025] [Indexed: 03/16/2025] Open
Abstract
Glycolysis is recognized as a central metabolic pathway in the neoplastic evolution of gastric cancer, exerting profound effects on the tumor microenvironment and the neoplastic growth trajectory. However, the identification of key glycolytic genes that significantly affect gastric cancer prognosis remains underexplored. In this work, five machine-learning algorithms were used to elucidate the intimate association between the glycolysis-associated gene phosphofructokinase fructose-bisphosphate 3 (PFKFB3) and the prognosis of gastric cancer patients. Validation across multiple independent datasets confirmed the prognostic significance of PFKFB3. Further, we delved into the functional implications of PFKFB3 in modulating immune responses and biological processes within gastric cancer patients, as well as its broader relevance across multiple cancer types. Results underscore the potential of PFKFB3 as a prognostic biomarker and therapeutic target in gastric cancer. Our project can be found at https://github.com/PiPiNam/ML-GCP .
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Affiliation(s)
- Nan Li
- China Academy of Electronics and Information Technology, National Engineering Research Center for Public Safety Risk Perception and Control by Big Data (RPP), Beijing, China
| | - Yuzhe Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China
| | - Qianyue Zhang
- China Academy of Electronics and Information Technology, National Engineering Research Center for Public Safety Risk Perception and Control by Big Data (RPP), Beijing, China
| | - Hao Jin
- China Academy of Electronics and Information Technology, National Engineering Research Center for Public Safety Risk Perception and Control by Big Data (RPP), Beijing, China
| | - Mengfei Han
- China Academy of Electronics and Information Technology, National Engineering Research Center for Public Safety Risk Perception and Control by Big Data (RPP), Beijing, China
| | - Junhan Guo
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, China.
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Xia Y, Jia J, Ma H, Tang S, Zhai S, Zhang T, Zhao Y, Shi J, Liu L. Impact of PSMD2 on Gastric Cancer Tissue Stiffness Investigated via Motor-Piezoceramic Coupled Atomic Force Microscopy. NANO LETTERS 2025; 25:3931-3938. [PMID: 40016166 DOI: 10.1021/acs.nanolett.4c06514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Gastric cancer is one of the deadliest malignant tumors of the digestive tract, and its development and metastasis are regulated by various factors. Some studies have shown that PSMD2 is involved in cancer development by regulating the tumor microenvironment stiffness. However, the exact mechanism is unclear, and effective means to quantify the effect of PSMD2 on gastric cancer tissue hardness are lacking. Herein, we revealed the mechanical heterogeneity of tumor tissues in gastric cancer patients using a large-scale AFM-based in situ method. Gastric cancer cryosections were probed by this method under aqueous condition. The in situ fluorescence images were measured to correlate tissue stiffness with PSMD2 expression. Experimental results clearly revealed the specific distribution of mechanics in gastric cancer tissues under differences in PSMD2 expression. The study unveils the effect of PSMD2 expression levels on cancer invasion and increased matrix stiffness, providing a novel insight into gastric cancer research.
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Affiliation(s)
- Yixiao Xia
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Junkai Jia
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Hongying Ma
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Si Tang
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shenghang Zhai
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tianbiao Zhang
- Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110122, China
| | - Ying Zhao
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Jialin Shi
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
| | - Lianqing Liu
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
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Zhang G, Wang N, Ma S, Zhang Y, Tao P, Cai H. Comprehensive Analysis of Potential Common Pathogenic Mechanisms for COVID-19 Infection and Gastric Cancer. Anal Cell Pathol (Amst) 2025; 2025:5106674. [PMID: 40224213 PMCID: PMC11991771 DOI: 10.1155/ancp/5106674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/16/2024] [Accepted: 01/25/2025] [Indexed: 04/15/2025] Open
Abstract
A growing body of data suggests that the prevalence of COVID-19 pneumonia in patients with stomach cancer is much higher than in the general population. However, these mechanisms are still not fully understood. After a thorough examination of shared differentially expressed genes (DEGs) for gastric cancer (GC) and COVID-19 pneumonia, we performed functional annotation, protein-protein interaction (PPI) networks, module design, and pivot gene identification. qPCR was used to verify the expression of hub genes in GC. Finally, a pivotal gene transcription factor-gene regulatory network was created and validated. According to functional enrichment analysis, common genes are mainly enriched in biological processes such as extracellular matrix tissue and extracellular structural tissue. Finally, five genes were found to be pivotal genes in the pathogenesis of GC and COVID-19 pneumonia: BGN (biglycan), UBE2C (ubiquitin-conjugating enzymes 2C), SPP1 (secreted phosphoprotein 1), THBS2 (thrombospondin 2), and COL1A1 (type I collagen alpha 1). These shared pathways and pivotal genes could provide new insights for more mechanistic studies.
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Affiliation(s)
- Guiqian Zhang
- Otorhinolaryngology Head and Neck Surgery, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Ning Wang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
| | - Shixun Ma
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
| | - Yan Zhang
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
| | - Pengxian Tao
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China
- Cadre Ward of General Surgery Department, Gansu Provincial Hospital, Lanzhou, China
| | - Hui Cai
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
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