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1
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Shi H, Cao X. Potential Targets Related to Skin Aging: Based on eQTL and GWAS Datasets. Clin Cosmet Investig Dermatol 2025; 18:677-686. [PMID: 40144806 PMCID: PMC11937646 DOI: 10.2147/ccid.s508946] [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] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/05/2025] [Indexed: 03/28/2025]
Abstract
Background The aging of skin has important impact on various systems, and certain skin aging (SG) markers can not only help with early diagnosis, but also provide new ideas for pathophysiological research and treatment strategies. Objective To identify target genes related to SG through bioinformatics technology and provide ideas for skin anti-aging. Methods Differential expression genes (DEGs) related to SG were screened through transcriptome information from GEO datasets (GSE85358 and GSE670988). Based on eQTL and GWAS datasets, Mendelian Randomization (MR) analysis was applied to identify associations between gene expression and SG. Then, aging skin related important genes (AS-IGs) were obtained based on above two steps, and functional and pathway analyses were performed to explore the potential mechanisms AS-IGs in SG. Finally, the CIBERSORT evaluation was used to assess the infiltration of immune cells related to SG. Results Seven AS-IGs were selected through intersection from 612 DEGs and 399 eQTL genes. Then, enrichment analysis results showed there were 60 GO terms may involved in the process of SG, like fatty-acyl-CoA metabolic process, while KEGG enrichment pathways identified mainly involved in mechanisms related to fatty acid metabolism, energy generation, and inflammation regulation. The CIBERSORT evaluation showed that NK cells resting were the main infiltrating cells. Conclusion AS-IGs may play important roles in the process of SG in the body. These molecules involve multiple systems and mechanisms in the body, such as immune function, metabolic function, and neuroendocrine function.
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Affiliation(s)
- Hanping Shi
- School of Public Health, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
- Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
| | - Xianwei Cao
- School of Public Health, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
- Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
- Department of Dermatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China
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2
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El-Arabey AA, Alkhalil SS, AlAfaleq NO, Al-Shouli S, Mohamed SSEM, Al-Shouli ST, Abdalla M. Wild-Type TP53 Predicts Poor Prognosis in Lower-Grade Glioma via TP53-CXCL14-GATA3 Axis. J Mol Neurosci 2025; 75:37. [PMID: 40102292 DOI: 10.1007/s12031-025-02323-w] [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: 12/17/2024] [Accepted: 02/13/2025] [Indexed: 03/20/2025]
Abstract
Low-grade gliomas (LGG) are malignant brain tumors that arise from the brain's support cells (glial cells). LGG are the most common kind of central nervous system tumors in children and adolescents, accounting for around half of all cases. Tumor Protein p53 (TP53) regulates or promotes DNA damage and repair via a variety of cell cycle, apoptosis, and genomic stability pathways. However, the clinical role of TP53 status in LGG patients is still unknown. Hence, we analyzed clinical data from the Cancer Genomic Atlas (TCGA) of LGG patients to see if TP53 status affects clinical outcomes, molecular signatures of chemokines and microRNAs, and immune cell infiltrations within the tumor's microenvironment of LGG patients. According to our findings, the most common phenotype in LGG patients is wild-type TP53, which is related to poor clinical outcomes and the expression of Chemokine ligand 14 (CXCL14) in many clinical parameters such as age, gender, stage, race, and purity. Besides, in LGG patients, wild-type TP53 controls prognostic microRNAs such as has-miR-10a-3p and has-miR-155-5p. Furthermore, through activating GATA Binding Protein 3 (GATA3) and decreasing Fatty Acid Synthase (FASN), wild-type TP53 orchestrates M1 macrophage and CD8+ T cell infiltration, as well as the formation of brown adipose tissue and decreased white adipose tissue. In this regard, the TP53-CXCL14-GATA3 axis has the potential to predict poor clinical outcomes in patients with wild-type TP53 LGG.
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Affiliation(s)
- Amr Ahmed El-Arabey
- Applied College, King Khalid University, P. O. Box 9004, 61413, Abha, Saudi Arabia.
- Center of Bee Research and Its Products, King Khalid University, P. O. Box 9004, 61413, Abha, Saudi Arabia.
| | - Samia S Alkhalil
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Alquwayiyah, Riyadh, Saudi Arabia
| | - Nouf Omar AlAfaleq
- Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Sawsan Al-Shouli
- Pharmacy Department, Security Forces Hospital, 11481, Riyadh, Saudi Arabia
| | - Samah Saif Eldin M Mohamed
- Clinical laboratory sciences department, College of Applied Medical Sciences/Alqwyiyah, Shaqra University, Riyadh, Saudi Arabia
| | - Samia T Al-Shouli
- Immunology Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Mohnad Abdalla
- Research Institute of Pediatrics, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, 250022, China
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3
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Li M, Tian Y, Si L, Fu H, Lai T, Guo R. OTUD4-mediated inhibition of YAP1 signaling pathway in ovarian cancer: Implications for macrophage polarization and recruitment. Int Immunopharmacol 2025; 147:114011. [PMID: 39778277 DOI: 10.1016/j.intimp.2024.114011] [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: 09/29/2024] [Revised: 12/26/2024] [Accepted: 12/31/2024] [Indexed: 01/11/2025]
Abstract
Ovarian cancer is a malignancy gynecologic oncology with high incidence and high mortality rate. M2-like tumor-associated macrophages promote cancer cell migration and metastasis. Ovarian tumor family deubiquitinase 4 (OTUD4) belongs to deubiquitinating enzyme family. The roles of OTUD4 in tumor microenvironments in ovarian cancer remains unknow. In this work, OTUD4 was overexpressed or knocked down in high-grade serous ovarian cancer cells OVCAR8 and CAOV3. Ovarian cells were co-cultured with THP-1 macrophages to simulate the tumor microenvironment. We found that OTUD4-expressed ovarian cells inhibited macrophage chemotaxis and M2 polarization. Besides, in ovarian tumor-bearing mouse model, OTUD4 suppressed tumor metastasis and remodeling tumor-associated macrophages phenotype (pro-tumor M2 to anti-tumor M1). In mechanism, OTUD4 protein bound to YAP1 protein, and downregulation of OTUD4 enhanced K63 ubiquitination and nuclear translocation of YAP1, thus increasing CCL2 transcription and subsequent macrophage recruitment. OTUD4 might inhibit CCL2 expression to regulate tumor-associated macrophages in ovarian tumor microenvironment. Those findings present a potential therapeutic strategy for ovarian cancer.
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Affiliation(s)
- Mingyue Li
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Yanpeng Tian
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Lulu Si
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Hanlin Fu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Tianjiao Lai
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Ruixia Guo
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China.
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Luan F, Cui Y, Huang R, Yang Z, Qiao S. Comprehensive pan-cancer analysis reveals NTN1 as an immune infiltrate risk factor and its potential prognostic value in SKCM. Sci Rep 2025; 15:3223. [PMID: 39863609 PMCID: PMC11762998 DOI: 10.1038/s41598-025-85444-x] [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: 08/25/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
Netrin-1 (NTN1) is a laminin-related secreted protein involved in axon guidance and cell migration. Previous research has established a significant connection between NTN1 and nervous system development. In recent years, mounting evidence indicates that NTN1 also plays a crucial role in tumorigenesis and tumor progression. For instance, inhibiting Netrin-1 has been shown to suppress tumor growth and epithelial-mesenchymal transition (EMT) characteristics in endometrial cancer. To further elucidate the influence of genes on tumors, we utilized a variety of machine learning techniques and found that NTN1 is strongly linked to multiple cancer types, suggesting it as a potential therapeutic target. This study aimed to elucidate the role of NTN1 in pan-cancer using multi-omics data and explore its potential as a prognostic biomarker in SKCM. Analysis of the TCGA, GTEx, and UALCAN databases revealed significant differences in NTN1 expression at both the mRNA and protein levels. Prognostic value was evaluated through univariate Cox regression and Kaplan-Meier methods. Mutation and methylation analyses were conducted using the cBioPortal and SMART databases. We identified genes interacting with and correlated to NTN1 through STRING and GEPIA2, respectively. Subsequently, we performed GO and KEGG enrichment analyses. The results suggested that NTN1 might be involved in crucial biological processes and pathways related to cancer development and progression, including cell adhesion, axon guidance, immune response, and various signaling pathways. We then explored the correlation between NTN1 and immune infiltration as well as immunotherapy using the ESTIMATE package, TIMER2.0, TISIDB, TIDE, TIMSO, and TCIA. The relationship between NTN1 and tumor heterogeneity, stemness, DNA methyltransferases, and MMR genes was also examined. Lastly, we constructed a nomogram based on NTN1 in SKCM and investigated its association with drug sensitivity. NTN1 expression was significantly associated with tumor immune infiltration, molecular subtypes, and clinicopathological features in various cancers. Genetic analysis revealed that Deep deletions were the most common type of NTN1 alteration. Additionally, a positive correlation was observed between NTN1 CNAs and its expression levels. In most cancers, NTN1 showed positive correlations with immune and stromal scores, as well as with specific immune cell populations. Its predictive value for immunotherapy response was comparable to that of tumor mutational burden. Furthermore, NTN1 exhibited positive correlations with tumor heterogeneity, stemness, DNA methyltransferase genes, and MMR genes. In SKCM, NTN1 was identified as an independent risk factor and demonstrated potential associations with multiple drugs. NTN1 exhibits substantial clinical utility as a prognostic marker and indicator of immune response across various tumor types. This comprehensive analysis provides insights into its potential implications in pan-cancer research.
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Affiliation(s)
- Fuxiang Luan
- The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Yuying Cui
- The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Ruizhe Huang
- The First Clinical College of Changsha Medical University, Changsha, China
| | - Zhuojie Yang
- Academy of medical sciences, Zhengzhou University, Zhengzhou, 450000, China
| | - Shishi Qiao
- The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, 450052, Henan, China.
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Sun L, Ma Y, Geng C, Gao X, Li X, Ru Q, Zhu S, Zhang P. DPP4, a potential tumor biomarker, and tumor therapeutic target: review. Mol Biol Rep 2025; 52:126. [PMID: 39821530 DOI: 10.1007/s11033-025-10235-6] [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: 11/14/2024] [Accepted: 01/07/2025] [Indexed: 01/19/2025]
Abstract
Dipeptidyl peptidase 4 (DPP4) is a serine protease widely distributed in membrane-bound and soluble forms in various tissues and organs throughout the body. DPP4 plays a role in inflammation, immune regulation, cell growth, migration and differentiation. The role of DPP4 in tumors has garnered increasing attention. Previous research has demonstrated that DPP4 contributes to the promotion of cancer in most cancers, and it may play a specific biological function through the variation in tumor cell types and expression forms. However, the expression of DDP4 in different tumor types and its specific mechanism remains unclear. In this review, we describe the structure of DPP4, summarize the recent research progress of its expression and potential mechanisms in common tumors, and discuss the development prospects of DPP4 inhibitors in tumor therapy. Although current research emphasizes the potential of DPP4 as a drug target, the incomplete understanding of its regulatory mechanisms impedes the discovery and development of new therapies against it. Further research on DPP4-related tumors is anticipated to promote its clinical application as a potential therapeutic target.
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Affiliation(s)
- Lu Sun
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Yuhui Ma
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Chenchen Geng
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Xiaoqian Gao
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Xinbing Li
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Qi Ru
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China
| | - Shuzhen Zhu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
- Department of Clinical Laboratory, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, 266035, China.
| | - Ping Zhang
- Department of Ultrasound, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China.
- Health Management Center, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266035, China.
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6
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Zhang Q, Han L, Luo X, Bao Y, Wang S, Li T, Huo J, Meng X. Enhancing inhibitory effect in SMMC-7721 hepatoma cells through combined treatment of gallic acid and hUC-MSCs-Exos. Int Immunopharmacol 2025; 144:113704. [PMID: 39608175 DOI: 10.1016/j.intimp.2024.113704] [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: 05/02/2024] [Revised: 09/23/2024] [Accepted: 11/21/2024] [Indexed: 11/30/2024]
Abstract
BACKGROUND Clinically, hepatoma patients are more frequently encountered in the intermediate and advanced stages. Consequently, the majority of patients miss out on the chance to undergo liver transplantation or radical surgery. Radiotherapy and chemotherapy often fall short of delivering satisfactory outcomes. The incidence and mortality rates for liver cancer approach nearly 100%. In recent years, both exosomes (Exos) and natural chemical compounds have demonstrated robust anti-cancer properties; however, the synergistic effect of their combination remains unexplored. METHODS Exos were extracted from human umbilical cord mesenchymal stem cells (hUC-MSCs). The impact of gallic acid (GA), hUC-MSCs-Exos, and their combined administration on the proliferation inhibition rate and apoptosis of SMMC-7721 hepatoma cells was assessed to ascertain the efficacy differences before and after the combined treatment. A combination of cells metabolomics and network pharmacology techniques was employed to investigate the underlying mechanisms of action. The pivotal targets associated with glycolysis, inflammation, and oxidative stress pathways were confirmed through ELISA assays. RESULTS The findings elucidate that GA profoundly impedes the proliferation of SMMC-7721 hepatoma cells and instigates apoptotic processes therein. While the impact of hUC-MSCs-Exos alone was inconspicuous, a notable augmentation in effect ensued upon their combined application. Concomitantly, a marked reduction was observed in the expressionlevels of key enzymes including HK, PFK, PK, LDH, TNF-α, IL-1β, CAT, SOD and GSH-Px in the malignant hepatocytes, while IL-6 and MDA exhibited heightened expression. Pathway enrichment analysis underscored selenocompound metabolism and cysteine and methionine metabolism as pivotal pathways. CONCLUSION The potentiated efficacy of GA conjunction with hUC-MSCs-Exos may be attributed to their synergistic modulation of anti-inflammatory, antioxidant, and glycolytic functions, thereby influencing selenocompound metabolism and cysteine and methionine metabolism. This study reveals the efficacy and mechanism of Exos and GA combined therapy for hepatoma, providing new methods and ideas for the clinical treatment of hepatoma.
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Affiliation(s)
- Qiang Zhang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Liaoning Dalian China
| | - Liying Han
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Liaoning Dalian China
| | - Xi Luo
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Liaoning Dalian China
| | - Yongrui Bao
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Liaoning Dalian China; Professional Innovation Technology Center for Multidimensional Analysis of Traditional Chinese Medicine, Liaoning Dalian China; Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Liaoning Dalian China
| | - Shuai Wang
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Liaoning Dalian China; Professional Innovation Technology Center for Multidimensional Analysis of Traditional Chinese Medicine, Liaoning Dalian China; Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Liaoning Dalian China
| | - Tianjiao Li
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Liaoning Dalian China; Professional Innovation Technology Center for Multidimensional Analysis of Traditional Chinese Medicine, Liaoning Dalian China; Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Liaoning Dalian China
| | - Jinnan Huo
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Liaoning Dalian China
| | - Xiansheng Meng
- College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Liaoning Dalian China; Professional Innovation Technology Center for Multidimensional Analysis of Traditional Chinese Medicine, Liaoning Dalian China; Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Liaoning Dalian China.
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7
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Elghawy O, Patel R, Mullapudi A, Kurian M, Wang J, Xu J, Kaur V. Immune-related adverse events not associated with survival in advanced or metastatic gastroesophageal cancers. J Chemother 2025:1-7. [PMID: 39773445 DOI: 10.1080/1120009x.2024.2448644] [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: 09/30/2024] [Revised: 11/22/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have shown promise in the treatment of gastric and oesophageal cancers (GEC). Despite their promising efficacy, ICIs have been associated with unique side effects known as immune-related adverse events (IRAEs). Several studies have shown improved treatment responses in patients with IRAEs compared to those without IRAEs in various cancer types such as melanoma and non-small cell lung cancer. We performed a single-institution retrospective study to characterize IRAE incidence and association with treatment response in advanced GEC. We identified 70 patients with GEC who received ICI therapy; 20 (29%) developed an IRAE of any magnitude. The most common were colitis (35%) hypothyroidism (25%) and pneumonitis (20%). Median PFS and OS were not statistically different between IRAE and nonIRAE groups (10.4 vs. 11.3 months p = 0.6 and 11.0 vs. 12.9 months p = 1.0, respectively). This is in contrast to studies in other cancer types that have suggested association between IRAE and improved outcomes.
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Affiliation(s)
- Omar Elghawy
- Department of Internal Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Reema Patel
- Department of Internal Medicine, Division of Hematology & Oncology, University of Virginia Health, Charlottesville, VA, USA
| | - Abhishek Mullapudi
- Department of Internal Medicine, Division of Hematology & Oncology, University of Virginia Health, Charlottesville, VA, USA
| | - Martin Kurian
- Department of Internal Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - John Wang
- Department of Internal Medicine, McGaw Medical Center of Northwestern University, Chicago, IL, USA
| | - Jessica Xu
- Department of Internal Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Varinder Kaur
- Department of Internal Medicine, Division of Hematology & Oncology, University of Virginia Health, Charlottesville, VA, USA
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8
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Peng Y, Li Y, Wang L, Lin S, Xu H. Impact of pan-cancer analysis of the exportins family on prognosis, the tumor microenvironment and its potential therapeutic efficacy. Clin Exp Med 2024; 25:18. [PMID: 39708137 DOI: 10.1007/s10238-024-01534-6] [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: 09/20/2024] [Accepted: 12/04/2024] [Indexed: 12/23/2024]
Abstract
This study aims to comprehensively analyze the role of the exportin (XPO) family in the development and progression of cancer. These nuclear transport proteins have been increasingly recognized for their involvement in oncogenic processes and tumor growth. We utilized updated public databases and bioinformatics tools to assess the expression levels of the XPO family and their associations with key oncological markers including patient survival, immune subtypes, tumor microenvironment, stemness scores, drug sensitivity, and DNA methylation across various cancers. Expression levels of XPO family proteins varied significantly across different cancer types, indicating cancer-specific roles. Specific XPO proteins were linked to adverse prognosis in particular cancers. Additionally, expression levels were correlated with classifications of immune subtypes and tumor purity; notably, lower expression levels were often found in tumors with elevated stromal and immune scores. A marked correlation was observed between XPO proteins and RNA stemness scores, whereas the correlation with DNA stemness scores varied. Furthermore, XPO expression levels significantly influenced cancer cell drug sensitivity and generally showed correlations with gene methylation patterns, although these correlations differed among cancer types. Our findings underscore the distinct roles of XPO family members in cancer, linking them to immune infiltration, the tumor microenvironment, and drug sensitivity. These insights not only enhance our understanding of the prognostic and therapeutic potentials of XPO proteins in cancer but also lay the groundwork for further studies into their mechanisms and applications in cancer diagnosis and treatment.
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Affiliation(s)
- Ying Peng
- Department of Pathology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, 518000, Guangdong, People's Republic of China
- First Clinical College of Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
- Nanshan District Clinical Pathological Diagnosis Center, Shenzhen, 518000, Guangdong, People's Republic of China
| | - Youheng Li
- Department of Pathology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, 518000, Guangdong, People's Republic of China
| | - Lingmei Wang
- Department of Pathology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, 518000, Guangdong, People's Republic of China
| | - Shenglai Lin
- Department of Pathology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, 518000, Guangdong, People's Republic of China
| | - Hong Xu
- Department of Pathology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, 518000, Guangdong, People's Republic of China.
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9
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Guo H, Wei J, Zhang Y, Wang L, Wan J, Wang W, Gao L, Li J, Sun T, Ma L. Protein ubiquitination in ovarian cancer immunotherapy: The progress and therapeutic strategy. Genes Dis 2024; 11:101158. [PMID: 39253578 PMCID: PMC11382211 DOI: 10.1016/j.gendis.2023.101158] [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: 06/04/2023] [Revised: 09/04/2023] [Accepted: 10/10/2023] [Indexed: 09/11/2024] Open
Abstract
Ovarian cancer is a common cancer for females, and the incidence and mortality rates are on the rise. Many treatment strategies have been developed for ovarian cancer, including chemotherapy and immunotherapy, but they are often ineffective and prone to drug resistance. Protein ubiquitination is an important class of post-translation modifications that have been found to be associated with various human diseases and cancer development. Recent studies have revealed that protein ubiquitination is involved in the progression of ovarian cancer and plays an important role in the tumor immune process. Moreover, the combination of ubiquitinase/deubiquitinase inhibitors and cancer immunotherapy approaches can effectively reduce treatment resistance and improve treatment efficacy, which provides new ideas for cancer treatment. Herein, we review the role of protein ubiquitination in relation to ovarian cancer immunotherapy and recent advances in the use of ubiquitinase/deubiquitinase inhibitors in combination with cancer immunotherapy.
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Affiliation(s)
- Huiling Guo
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Clinical Laboratory of Henan Province, Zhengzhou, Henan 450052, China
| | - Jianwei Wei
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yuyan Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Li Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Junhu Wan
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Clinical Laboratory of Henan Province, Zhengzhou, Henan 450052, China
| | - Weiwei Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ling Gao
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450052, China
| | - Jiajing Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ting Sun
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Clinical Laboratory of Henan Province, Zhengzhou, Henan 450052, China
| | - Liwei Ma
- Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Clinical Laboratory of Henan Province, Zhengzhou, Henan 450052, China
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10
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Alkhalil SS, Almanaa TN, Altamimi RA, Abdalla M, El-Arabey AA. Interactions between microbiota and uterine corpus endometrial cancer: A bioinformatic investigation of potential immunotherapy. PLoS One 2024; 19:e0312590. [PMID: 39475915 PMCID: PMC11524446 DOI: 10.1371/journal.pone.0312590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 10/09/2024] [Indexed: 11/02/2024] Open
Abstract
Microorganisms in the gut and other niches may contribute to carcinogenesis while also altering cancer immune surveillance and therapeutic response. However, determining the impact of genetic variations and interplay with intestinal microbes' environment is difficult and unanswered. Here, we examined the frequency of thirteen mutant genes that caused aberrant gut in thirty different types of cancer using The Cancer Genomic Atlas (TCGA) database. Substantially, our findings show that all these mutated genes are quite frequent in uterine corpus endometrial cancer (UCEC). Further, these mutant genes are implicated in the infiltration of different subset of immune cells within the Tumor Microenvironment (TME) of UCEC patients. The top-ranking mutant genes that promote immune cell invasion into the TME of UCEC patients were PGLYRP2, OLFM4, and TLR5. In this regard, we used the same deconvolution of the TCGA database to analyze the microbiome that have a strong association with immune cells invasion with TME of UCEC patients. Several bacteria and viruses have been linked to the invasion of immune cells, such as B cell memory and T cell regulatory (Tregs), into the TME of UCEC patients. As a result, our findings pave the way for future research into generating novel immunizations against bacteria or viruses as immunotherapy for UCEC patients.
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Affiliation(s)
- Samia S. Alkhalil
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Alquwayiyah, Riyadh, Saudi Arabia
| | - Taghreed N. Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Raghad A. Altamimi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Mohnad Abdalla
- Pediatric Research Institute, Children’s Hospital Affiliated to Shandong University, Jinan, China
| | - Amr Ahmed El-Arabey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
- Center of Bee Research and its Products (CBRP), Unit of Bee Research and Honey Production, King Khalid University, Abha, Saudi Arabia
- Applied College, King Khalid University, Abha, Saudi Arabia
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11
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Wang N, Yuan Y, Jia Y, Han Y, Yu X, Fu Y, Li X. TFE3 and TP53 were novel diagnostic biomarkers related to mitochondrial autophagy in chronic rhinosinusitis with nasal polyps. Front Genet 2024; 15:1423778. [PMID: 39440241 PMCID: PMC11493635 DOI: 10.3389/fgene.2024.1423778] [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: 04/26/2024] [Accepted: 08/28/2024] [Indexed: 10/25/2024] Open
Abstract
Background Chronic rhinosinusitis with nasal polyps (CRSwNP) belongs to a subtype of Chronic rhinosinusitis which is a heterogeneous inflammatory condition. It has been reported that mitophagy may provide a new therapeutic option for CRSwNP. Methods The GSE136825 (training dataset) and GSE179265 (validation dataset) were scoured from the Gene Expression Omnibus database. The candidate genes related to mitophagy were identified by differential expression analysis. Subsequently, the biomarkers were selected from the machine learning, Receiver Operating Characteristic curves, and expression level verification. A backpropagation (BP) neural network was generated to evaluate the diagnostic ability of biomarkers. In addition, the infiltration abundance of immune cells, potential drugs, and related ear-nose-throat (ENT) diseases were analyzed based on the biomarkers. Finally, qPCR analysis was performed to verify these biomarkers. Results A total of 8 candidate genes were identified by overlapping 3,400 differentially expressed genes (DEGs) and 72 mitophagy-related genes Subsequently, TFE3 and TP53 were identified as biomarkers of CRSwNP, and the area under the curves (AUC) of the BP neural network was 0.74, which indicated that the biomarkers had excellent abilities. TFE3 and TP53 were co-enriched in the cancer pathway, cell cycle, endocytosis, etc. What's more, Macrophage and Immature dendritic cells had significant correlations with biomarkers. The drugs (Doxorubicin, Tetrachlorodibenzodioxin, etc.) and the ear-nose-throat diseases (hearing loss, sensorineural, tinnitus, etc.) related to biomarkers were predicted. Ultimately, qPCR results showed that the expression levels of TFE3 and TP53 in polyp tissue of CRSwNP were increased. Conclusion Overall, TFE3 and TP53 could be used as biomarkers or potential therapeutic targets to diagnose and treat CRSwNP.
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Affiliation(s)
- Ning Wang
- Department of Otolaryngology-Head and Neck Surgery, Qilu Hospital of Shandong University, Qingdao, China
| | - Ying Yuan
- Department of Otolaryngology-Head and Neck Surgery, Qilu Hospital of Shandong University, Qingdao, China
| | - Yanjun Jia
- Department of Otolaryngology-Head and Neck Surgery, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Yue Han
- Department of Otolaryngology-Head and Neck Surgery, Qilu Hospital of Shandong University, Qingdao, China
| | - Xuemin Yu
- Department of Otolaryngology-Head and Neck Surgery, Qilu Hospital of Shandong University, Qingdao, China
| | - Ying Fu
- Department of Otolaryngology-Head and Neck Surgery, Qilu Hospital of Shandong University, Qingdao, China
| | - Xiao Li
- Department of Otolaryngology-Head and Neck Surgery, Qilu Hospital of Shandong University, Qingdao, China
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12
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Dai C, Man Y, Zhang L, Zhang X, Xie C, Wang S, Zhang Y, Guo Q, Zou L, Hong H, Jiang L, Shi Y. Identifying SLC2A6 as the novel protective factor in breast cancer by TP53-related genes affecting M1 macrophage infiltration. Apoptosis 2024; 29:1211-1231. [PMID: 38622369 DOI: 10.1007/s10495-024-01964-3] [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] [Accepted: 04/04/2024] [Indexed: 04/17/2024]
Abstract
The high heterogeneity of breast cancer (BC) caused by pathogenic gene mutations poses a challenge to immunotherapy, but the underlying mechanism remains unknown. The difference in the infiltration of M1 macrophages induced by TP53 mutations has a significant impact on BC immunotherapy. The aim of this study was to develop a TP53-related M1 macrophage infiltration molecular typing risk signature in BC and evaluate the biological functions of the key gene to find new immunotherapy biomarkers. Weighted correlation network analysis (WGCNA) and negative matrix factorization (NMF) were used for distinguishing BC subtypes. The signature and the nomogram were both constructed and evaluated. Biological functions of the novel signature gene SLC2A6 were confirmed through in vitro and in vivo experiments. RNA-Sequencing and protein profiling were used for detecting the possible mechanism of SLC2A6. The results suggested that four BC subtypes were distinguished by TP53-related genes that affect M1 macrophage infiltration. The signature constructed by molecular typing characteristics could evaluate BC's clinical features and tumor microenvironment. The nomogram could accurately predict the prognosis. The signature gene SLC2A6 was found to have an abnormally low expression in tumor tissues. Overexpression of SLC2A6 could inhibit proliferation, promote mitochondrial damage, and result in apoptosis of tumor cells. The HSP70 family member protein HSPA6 could bind with SLC2A6 and increase with the increased expression of SLC2A6. In summary, the risk signature provides a reference for BC risk assessment, and the signature gene SLC2A6 could act as a tumor suppressor in BC.
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Affiliation(s)
- Chao Dai
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yuxin Man
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Luhan Zhang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Xiao Zhang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Chunbao Xie
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
- Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Shan Wang
- National Center for Integrated Traditional and Western Medicine, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Yinjie Zhang
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Qian Guo
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Liang Zou
- School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China
| | - Huangming Hong
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
| | - Lingxi Jiang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
- Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Yi Shi
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
- Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
- Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, Sichuan, China.
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13
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Hadad S, Khalaji A, Sarmadian AJ, Sarmadian PJ, Janagard EM, Baradaran B. Tumor-associated macrophages derived exosomes; from pathogenesis to therapeutic opportunities. Int Immunopharmacol 2024; 136:112406. [PMID: 38850795 DOI: 10.1016/j.intimp.2024.112406] [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: 01/30/2024] [Revised: 05/19/2024] [Accepted: 06/02/2024] [Indexed: 06/10/2024]
Abstract
Tumor-associated macrophages (TAMs) exert profound influences on cancer progression, orchestrating a dynamic interplay within the tumor microenvironment. Recent attention has focused on the role of TAM-derived exosomes, small extracellular vesicles containing bioactive molecules, in mediating this intricate communication. This review comprehensively synthesizes current knowledge, emphasizing the diverse functions of TAM-derived exosomes across various cancer types. The review delves into the impact of TAM-derived exosomes on fundamental cancer hallmarks, elucidating their involvement in promoting cancer cell proliferation, migration, invasion, and apoptosis evasion. By dissecting the molecular cargo encapsulated within these exosomes, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and proteins, the review uncovers key regulatory mechanisms governing these effects. Noteworthy miRNAs, such as miR-155, miR-196a-5p, and miR-221-3p, are highlighted for their pivotal roles in mediating TAM-derived exosomal communication and influencing downstream targets. Moreover, the review explores the impact of TAM-derived exosomes on the immune microenvironment, particularly their ability to modulate immune cell function and foster immune evasion. The discussion encompasses the regulation of programmed cell death ligand 1 (PD-L1) expression and subsequent impairment of CD8 + T cell activity, unraveling the immunosuppressive effects of TAM-derived exosomes. With an eye toward clinical implications, the review underscores the potential of TAM-derived exosomes as diagnostic markers and therapeutic targets. Their involvement in cancer progression, metastasis, and therapy resistance positions TAM-derived exosomes as key players in reshaping treatment strategies. Finally, the review outlines future directions, proposing avenues for targeted therapies aimed at disrupting TAM-derived exosomal functions and redefining the tumor microenvironment.
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Affiliation(s)
- Sara Hadad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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14
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Pignata S, Califano D, Lorusso D, Arenare L, Bartoletti M, De Giorgi U, Andreetta C, Pisano C, Scambia G, Lombardi D, Farolfi A, Cinieri S, Passarelli A, Salutari V, De Angelis C, Mignogna C, Priolo D, Capoluongo ED, Tamberi S, Scaglione GL, Arcangeli V, De Cecio R, Scognamiglio G, Greco F, Spina A, Turinetto M, Russo D, Carbone V, Casartelli C, Schettino C, Perrone F. MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy. Ann Oncol 2024; 35:667-676. [PMID: 38704093 DOI: 10.1016/j.annonc.2024.04.007] [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: 08/23/2023] [Revised: 02/28/2024] [Accepted: 04/25/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.
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Affiliation(s)
- S Pignata
- Uro-Gynecological Medical Oncology, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples.
| | - D Califano
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples
| | - D Lorusso
- Gynecologic Oncology Unit, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome; Catholic University of Sacred Heart, Rome
| | - L Arenare
- Clinical Trial Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples
| | - M Bartoletti
- Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano
| | - U De Giorgi
- Dipartimento Oncologico, IRCCS Istituto Romagnolo per lo studio dei Tumori (IRST Dino Amadori), Meldola
| | - C Andreetta
- Dipartimento di Oncologia, ASU FC S. Maria della Misericordia-Udine, Meldola
| | - C Pisano
- Uro-Gynecological Medical Oncology, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples
| | - G Scambia
- Gynecologic Oncology Unit, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome; Catholic University of Sacred Heart, Rome
| | - D Lombardi
- Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano
| | - A Farolfi
- Clinical and Experimental Oncology Unit, Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, IRCCS, Meldola
| | - S Cinieri
- U.O.C. Oncologia Medica-Ospedale Senatore Antonio Perrino, Brindisi
| | - A Passarelli
- Uro-Gynecological Medical Oncology, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples
| | - V Salutari
- Gynecologic Oncology Unit, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome
| | - C De Angelis
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples
| | - C Mignogna
- Division of Anatomic Pathology and Cytopathology, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples
| | - D Priolo
- Oncology Unit, S Vincenzo Hospital, Taormina
| | - E D Capoluongo
- Department of Molecular Medicine and Medical Biotechnology, Università degli Studi di Napoli Federico II, Naples; Azienda Ospedaliera per L'Emergenza, Catania
| | - S Tamberi
- Oncology Unit, Santa Maria Hospital, Ravenna AUSL Romagna, Ravenna
| | - G L Scaglione
- Istituto Dermopatico Dell'Immacolata IDI-IRCSS, Rome
| | - V Arcangeli
- UO Oncologia-Ospedale degli Infermi Rimini, Rimini
| | - R De Cecio
- Division of Anatomic Pathology and Cytopathology, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples
| | - G Scognamiglio
- Division of Anatomic Pathology and Cytopathology, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples
| | - F Greco
- Medical Oncology Unit, AULSS 9 Regione Veneto, Scaligera-Ospedale Generale Mater Salutis, Legnago
| | - A Spina
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples
| | - M Turinetto
- Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Turin
| | - D Russo
- Microenvironment Molecular Targets Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples
| | - V Carbone
- Gynecologic Oncology Unit, Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome
| | - C Casartelli
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - C Schettino
- Clinical Trial Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples
| | - F Perrone
- Clinical Trial Unit, Istituto Nazionale Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G Pascale, Naples
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15
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Song M, Cheng H, Zou H, Ma K, Lu L, Wei Q, Xu Z, Tang Z, Zhang Y, Wang Y, Sun C. Genomic profiling informs therapies and prognosis for patients with hepatocellular carcinoma in clinical practice. BMC Cancer 2024; 24:673. [PMID: 38825709 PMCID: PMC11145829 DOI: 10.1186/s12885-024-12407-2] [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: 08/31/2023] [Accepted: 05/21/2024] [Indexed: 06/04/2024] Open
Abstract
Hepatocellular carcinoma (HCC) genomic research has discovered actionable genetic changes that might guide treatment decisions and clinical trials. Nonetheless, due to a lack of large-scale multicenter clinical validation, these putative targets have not been converted into patient survival advantages. So, it's crucial to ascertain whether genetic analysis is clinically feasible, useful, and whether it can be advantageous for patients. We sequenced tumour tissue and blood samples (as normal controls) from 111 Chinese HCC patients at Qingdao University Hospital using the 508-gene panel and the 688-gene panel, respectively. Approximately 95% of patients had gene variations related to targeted treatment, with 50% having clinically actionable mutations that offered significant information for targeted therapy. Immune cell infiltration was enhanced in individuals with TP53 mutations but decreased in patients with CTNNB1 and KMT2D mutations. More notably, we discovered that SPEN, EPPK1, and BRCA2 mutations were related to decreased median overall survival, although MUC16 mutations were not. Furthermore, we found mutant MUC16 as an independent protective factor for the prognosis of HCC patients after curative hepatectomy. In conclusion, this study connects genetic abnormalities to clinical practice and potentially identifies individuals with poor prognoses who may benefit from targeted treatment or immunotherapy.
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Affiliation(s)
- Mengqi Song
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Haoyue Cheng
- Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Hao Zou
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Kai Ma
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Lianfang Lu
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Qian Wei
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zejiang Xu
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Zirui Tang
- Software Engineering, Northeastern University, Shenyang, Liaoning, China
| | - Yuanzheng Zhang
- Collage of Medicine and Biological Information Engineering, Northeastern University, Shenyang, Liaoning, China
| | - Yinan Wang
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
| | - Chuandong Sun
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
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16
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Qin L, Chen C, Gui Z, Jiang Y. IRX5's influence on macrophage polarization and outcome in papillary thyroid cancer. Front Oncol 2024; 14:1399484. [PMID: 38868535 PMCID: PMC11167072 DOI: 10.3389/fonc.2024.1399484] [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: 03/12/2024] [Accepted: 05/10/2024] [Indexed: 06/14/2024] Open
Abstract
Background With a rise in recent years, thyroid cancer (TC) is the most prevalent hormonal cancer worldwide. It is essential to investigate the inherent variability at the molecular level and the immune environment within tumors of various thyroid cancer subtypes in order to identify potential targets for therapy and provide precise treatment for patients with thyroid adenocarcinoma. Methods First, we analyzed the expression of IRX5 in pan-cancer and papillary thyroid carcinoma by bioinformatics methods and collected paired samples from our center for validation. Subsequently, we analyzed the significance of IRX5 on the prognosis and diagnosis of PTC. Next, we explored the possible mechanisms by which IRX5 affects the prognosis of thyroid cancer patients by GO/KEGG enrichment analysis, and further investigated the effect of IRX5 on immune infiltration of thyroid cancer. Ultimately, by conducting experiments on cells and animals, we were able to show how IRX5 impacts the aggressive characteristics of thyroid cancer cells and its influence on macrophages within the immune system of thyroid cancer. Results In 11 malignant tumors, including PTC, IRX5 is overexpressed and associated with a poor prognosis. IRX5 may affect the prognosis of PTC through embryonic organ development, ossification, mesenchyme development, etc. Increased IRX5 expression decreases the presence of cytotoxic and Th17 cells in papillary thyroid cancer. IRX5 was highly expressed in different PTC cell lines, such as K-1 and TPC-1. Silencing IRX5 effectively halted the growth and movement of PTC cells while also decreasing M2 polarization and enhancing M1 polarization in tumor-associated macrophages. Conclusion IRX5 could impact the outlook of individuals with PTC by stimulating the shift of macrophages to M2 in the immune surroundings of thyroid cancer growths, suggesting a potential new focus for treating thyroid cancer, particularly through immunotherapy.
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Affiliation(s)
- Lu Qin
- Department of Thyroid Vascular Surgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, ;China
| | - Cheng Chen
- Department of Nuclear Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, ;China
| | - Zhengwei Gui
- Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Department of Thyroid and Breast Surgery, Wuhan, ;China
| | - Yun Jiang
- Department of Ultrasound, Hubei Hospital of Integrated Traditional Chinese and Western Medicines, Wuhan, ;China
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Kajdaniuk D, Hudy D, Strzelczyk JK, Młynarek K, Słomian S, Potyka A, Szymonik E, Strzelczyk J, Foltyn W, Kos-Kudła B, Marek B. Transforming growth factors β and their signaling pathway in renal cell carcinoma and peritumoral space-transcriptome analysis. Clin Transl Oncol 2024; 26:1229-1239. [PMID: 38085441 PMCID: PMC11026247 DOI: 10.1007/s12094-023-03350-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: 09/05/2023] [Accepted: 11/03/2023] [Indexed: 04/20/2024]
Abstract
PURPOSE The aim of the study was to verify hypotheses: Are transforming growth factors TGFβ1-3, their receptors TGFβI-III, and intracellular messenger proteins Smad1-7 involved in the pathogenesis of kidney cancer? What is the expression of genes of the TGFβ/Smads pathway in renal cell carcinoma (RCC) tissues, peritumoral tissues (TME; tumor microenvironment), and in normal kidney (NK) tissue?. METHODS Twenty patients with RCC who underwent total nephrectomy were included into the molecular analysis. The mRNA expression of the genes was quantified by RT-qPCR. RESULTS The study showed that the expression of the genes of TGFβ/Smads pathway is dysregulated in both RCC and the TME: TGFβ1, TGFβ3 expression is increased in the TME in comparison to the NK tissues; TGFβ2, TGFβ3, TGFβRI, TGFβRIII, Smad1, Smad2, Smad3, and Smad6 are underexpressed in RCC comparing to the TME tissues; TGFβRI, TGFβRIII, and Smad2 are underexpressed in RCC in comparison to the NK tissues. CONCLUSION On the one hand, the underexpression of the TGFβ signaling pathway genes within the malignant tumor may result in the loss of the antiproliferative and pro-apoptotic activity of this cytokine. On the other hand, the overexpression of the TGFβ/Smads pathway genes in the TME than in tumor or NK tissues most probably results in an immunosuppressive effect in the space surrounding the tumor and may have an antiproliferative and pro-apoptotic effect on non-neoplastic cells present in the TME. The functional and morphological consistency of this area may determine the aggressiveness of the tumor and the time in which the neoplastic process will spread.
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Affiliation(s)
- Dariusz Kajdaniuk
- Department of Pathophysiology, Chair of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, H. Jordana 19, Zabrze, 41-808, Katowice, Poland.
| | - Dorota Hudy
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Joanna Katarzyna Strzelczyk
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Krystyna Młynarek
- Department of Urology, Regional Specialist Hospital No. 3, Rybnik, Poland
| | - Szymon Słomian
- Department of Urology, Regional Specialist Hospital No. 3, Rybnik, Poland
| | - Andrzej Potyka
- Department of Urology, Regional Specialist Hospital No. 3, Rybnik, Poland
| | - Ewa Szymonik
- Department of Anesthesiology and Intensive Care, Brothers Hospitallers of Saint John of God Hospital in Katowice, Katowice, Poland
| | - Janusz Strzelczyk
- Department of Endocrinology and Neuroendocrine Tumors, Chair of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Wanda Foltyn
- Department of Endocrinology and Neuroendocrine Tumors, Chair of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Beata Kos-Kudła
- Department of Endocrinology and Neuroendocrine Tumors, Chair of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Bogdan Marek
- Department of Pathophysiology, Chair of Pathophysiology and Endocrinology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, H. Jordana 19, Zabrze, 41-808, Katowice, Poland
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Chen R, Chen J, Chen M, Zhou S, Jiang P. Metformin suppresses proliferation and glycolysis of gastric cancer by modulating ADAMTS12. Genes Environ 2024; 46:1. [PMID: 38167385 PMCID: PMC10763268 DOI: 10.1186/s41021-023-00296-z] [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: 07/26/2023] [Accepted: 12/17/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignancy with its morbidity increasing worldwide. Hence, it is imperative to develop effective treatments. Studies have shown that metformin has potential antitumor effects. The objective of this study was to probe the antitumor mechanism of metformin in GC. METHODS The expression of ADAMTS12 in GC tissues and its enrichment pathways were analyzed by bioinformatics methods. ADAMTS12 expression in GC cells was assessed by qRT-PCR. Cell viability and proliferation were analyzed by CCK-8 and colony formation assays, respectively. Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of GC cells in different treatment groups were analyzed by Seahorse XP 96, and glycolysis metabolites were detected by corresponding kits. Western blot was employed to analyze the level of glycolysis pathway related protein HK-2, and cell functional assays were conducted to verify the functions of metformin on GC cells. A xenograft model was constructed to validate the inhibitory role of metformin in GC. RESULTS ADAMTS12 expression was elevated in GC tissues/cells and concentrated in glycolysis pathway. Cell functional assays found that ADAMTS12 promoted the proliferation and glycolysis of GC cells. Rescue experiments showed that metformin could reduce the promoting effect of ADAMTS12 overexpression on the proliferation and glycolysis of GC cells. In vivo studies confirmed that metformin suppressed the proliferation and glycolysis process via ADAMTS12 in GC cells. CONCLUSION Metformin can repress the proliferation and glycolysis of GC cells via ADAMTS12. The results suggest the potential of ADAMTS12 being a target for the metformin therapy of GC.
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Affiliation(s)
- Rui Chen
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, 317000, Taizhou, Zhejiang, PR China
| | - Jianhui Chen
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, 317000, Taizhou, Zhejiang, PR China
| | - Miaoliang Chen
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, 317000, Taizhou, Zhejiang, PR China
| | - Shenkang Zhou
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, 317000, Taizhou, Zhejiang, PR China
| | - Pinlu Jiang
- Department of Emergency, Taizhou Hospital of Zhejiang Province, 150# Ximen Street, 317000, Taizhou, Zhejiang, PR China.
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Zhang WJ, Yue KL, Wang JZ, Zhang Y. Association between heat shock factor protein 4 methylation and colorectal cancer risk and potential molecular mechanisms: A bioinformatics study. World J Gastrointest Oncol 2023; 15:2150-2168. [PMID: 38173437 PMCID: PMC10758642 DOI: 10.4251/wjgo.v15.i12.2150] [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: 07/28/2023] [Revised: 10/16/2023] [Accepted: 11/17/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND We previously demonstrated that heat shock factor protein 4 (HSF4) facilitates colorectal cancer (CRC) progression. DNA methylation, a major modifier of gene expression and stability, is involved in CRC development and outcome. AIM To investigate the correlation between HSF4 methylation and CRC risk, and to uncover the underlying molecular mechanisms. METHODS Differences in β values of HSF4 methylation loci in multiple malignancies and their correlation with HSF4 mRNA expression were analyzed based on Shiny Methylation Analysis Resource Tool. HSF4 methylation-related genes were identified by LinkedOmics in CRC, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. Protein-protein interaction network of HSF4 methylation-related genes was constructed by String database and MCODE algorithm. RESULTS A total of 19 CpG methylation loci were identified in HSF4, and their β values were significantly increased in CRC tissues and exhibited a positive correlation with HSF4 mRNA expression. Unfortunately, the prognostic and diagnostic performance of these CpG loci in CRC patients was mediocre. In CRC, there were 1694 HSF4 methylation-related genes; 1468 of which displayed positive and 226 negative associations, and they were involved in regulating phenotypes such as immune, inflammatory, and metabolic reprogramming. EGFR, RELA, STAT3, FCGR3A, POLR2K, and AXIN1 are hub genes among the HSF4 methylation-related genes. CONCLUSION HSF4 is highly methylated in CRC, but there is no significant correlation between it and the prognosis and diagnosis of CRC. HSF4 methylation may serve as one of the ways in which HSF4 mediates the CRC process.
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Affiliation(s)
- Wen-Jing Zhang
- Department of Medical Oncology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Ke-Lin Yue
- Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Jing-Zhai Wang
- Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Yu Zhang
- Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
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20
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Yuan J, Li X, Wang F, Liu H, Guan W, Xu G. Insulin-like growth factor 2 mRNA-binding protein 2 is a therapeutic target in ovarian cancer. Exp Biol Med (Maywood) 2023; 248:2198-2209. [PMID: 38084732 PMCID: PMC10903241 DOI: 10.1177/15353702231214268] [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: 02/01/2023] [Accepted: 09/03/2023] [Indexed: 01/23/2024] Open
Abstract
Ovarian cancer (OC) is a fatal gynecologic disease. The most common treatment for OC patients is surgery combined with chemotherapy but most patients at advanced stages eventually develop relapse due to chemoresistance. This study examined the role and function of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in OC. We observed that the expression of IGF2BP2 mRNA and protein was up-regulated in OC cells and tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. An increase in IGF2BP2 expression at mRNA and protein levels was verified by the analyses of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC), respectively. Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) databases were applied to analyze the expression and clinical value of IGF2BP2. Gene set enrichment analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) analyses explored biological functions and the involvement of IGF2BP2 in cell growth. Indeed, the knockdown of IGF2BP2 resulted in the inhibition of OC cell proliferation evaluated by the Cell Counting Kit-8 assay. Genomic amplification of IGF2BP2 partly accounted for its overexpression. High expression of IGF2BP2 was associated with signal transducer and activator of transcription 1 (STAT1) and drug sensitivity and was correlated with an unfavorable survival outcome in OC patients. Furthermore, the responsiveness of chemotherapy and immunotherapy were analyzed using the "pRRophetic" R package and The Cancer Immune Atlas (TCIA) database, respectively. The low expression of IGF2BP2 was associated with chemoresistance but with high tumor microenvironment scores and tumor-infiltrating immune cells, suggesting that immunotherapy may apply in chemoresistant patients. The alteration of IGF2BP2 expression may respond to chemotherapy and immunotherapy. Thus, IGF2BP2 shows potential as a therapeutic target and diagnostic biomarker for OC.
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Affiliation(s)
- Jia Yuan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xin Li
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Fanchen Wang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Huiqiang Liu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Wencai Guan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, China
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai 201508, China
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21
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El-Arabey A, Abdel-Hamied H, Awadalla M, Alosaimi B, Almanaa T, Al-Shouli S, Modafer Y, Alhamdi H, Abdalla M. A bioinformatic analysis of the role of TP53 status on the infiltration of CD8+ T cells into the tumor microenvironment. Braz J Med Biol Res 2023; 56:e12970. [PMID: 37878888 PMCID: PMC10591486 DOI: 10.1590/1414-431x2023e12970] [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: 07/05/2023] [Accepted: 08/27/2023] [Indexed: 10/27/2023] Open
Abstract
CD8+ T cells play basic roles in the immune system in a tumor microenvironment (TME) to fight cancer. Several reports have suggested signs of the involvement of tumor protein p53 (TP53) in a complex immune system network. Moreover, our previous research indicated that TP53 orchestrates the polarization and infiltration of macrophages into the TME. In the present study, the clinical function of TP53 status (wild/mutant) in CD8+ T cell infiltration was assessed using more than 10,000 The Cancer Genome Atlas (TCGA) samples from 30 cancer types through Tumor Immune Estimation (TIMER). Our investigation revealed that CD8+ T cell infiltration was higher in head and neck squamous cell carcinoma (HNSC) and uterine corpus endometrial carcinoma (UCEC) patients with wild-type TP53 than in those with mutant TP53. Wild-type TP53 conferred a good prognosis for HNSC and UCEC (P<0.05). In contrast, CD8+ T cell infiltration in lung adenocarcinoma (LUAD) patients with wild-type TP53 was much lower than in those with mutant TP53. Notably, clinical outcomes for LUAD with wild-type TP53 were poor (P<0.05). This study was the first to provide insights into the novel association of TP53 with CD8+ T cells infiltration in the TME in patients with HNSC, LUAD, and UCEC. Therefore, TP53 status acts as a prognostic marker, and this can be used as a basis to further study the effect of targeting TP53 in these patients. Furthermore, our study found that TP53 status was a reliable predictive factor and therapeutic target in patients with HNSC and UCEC.
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Affiliation(s)
- A.A. El-Arabey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - H.E. Abdel-Hamied
- Department of General Pathology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - M.E. Awadalla
- Research Center, King Fahad Medical City, Riyadh Second Health Cluster, Riyadh, Saudi Arabia
| | - B. Alosaimi
- Research Center, King Fahad Medical City, Riyadh Second Health Cluster, Riyadh, Saudi Arabia
| | - T.N. Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - S.T. Al-Shouli
- Immunology Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Y.A. Modafer
- Department of Biology, Faculty of Science, Jazan University, Jazan, Saudi Arabia
| | - H.W. Alhamdi
- Department of Biology, College of Sciences, King Khalid University, Abha, Saudi Arabia
| | - M. Abdalla
- Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, Shandong, China
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22
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Liu Y, Zhang L, Lei X, Yin X, Liu S. Development of an immunogenic cell death prognostic signature for predicting clinical outcome and immune infiltration characterization in stomach adenocarcinoma. Aging (Albany NY) 2023; 15:11389-11411. [PMID: 37862109 PMCID: PMC10637829 DOI: 10.18632/aging.205132] [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: 07/16/2023] [Accepted: 10/03/2023] [Indexed: 10/22/2023]
Abstract
Stomach adenocarcinoma (STAD) is a common gastric histological cancer type with a high mortality rate. Immunogenic cell death (ICD) plays a key factor during carcinogenesis progress, whereas the prognostic value and role of ICD-related genes (ICDRGs) in STAD remain unclear. The MSigDB database collecting ICDRGs were selected by univariate Cox regression analysis and LASSO algorithm to establish a novel risk model. The Kaplan-Meier survival analysis indicated a significant difference of OS rate of patients by risk score stratification. ESTIMATE, CIBERSORT, and single sample gene set enrichment analysis (ssGSEA) algorithms were conducted to estimate the immune infiltration landscape by risk stratification. Subgroup analysis and tumor mutation burden analysis were also analyzed to identify characteristics between groups. Differences in therapeutic responsiveness to chemotherapeutic drugs and targeted drugs were also analyzed between high-risk group and low-risk group. The impact of one ICDRG, GPX1, on the proliferation, migration and invasiveness of was confirmed by in vitro experiments in GC cells to test the reliability of bioinformatics results. This study gives evidence of the involvement of ICD process in STAD and provides a new perspective for further accurate assessment of prognosis and therapeutic efficacy in STAD patients. Stomach adenocarcinoma (STAD) is a common gastric histological cancer type with a high mortality rate. Immunogenic cell death (ICD) plays a key factor during carcinogenesis progress, whereas the prognostic value and role of ICD-related genes (ICDRGs) in STAD remains unclear. The MSigDB database collected ICDRGs were selected by univariate Cox regression analysis and LASSO algorithm to establish a novel risk model. The Kaplan-Meier survival analysis indicated a significant difference of OS rate of patients by risk score stratification. ESTIMATE, CIBERSORT, and single sample gene set enrichment analysis (ssGSEA) algorithms were conducted to estimate the immune infiltration landscape by risk stratification. Subgroup analysis and tumor mutation burden analysis were also analyzed to identify characteristics between groups. Differences in therapeutic responsiveness to chemotherapeutic drugs and targeted drugs were also analyzed between high-risk group and low-risk group. The impact of one ICDRG, GPX1, on the proliferation, migration and invasiveness of was confirmed by in vitro experiments in GC cells to test the reliability of bioinformatics results. This study gives evidence of the involvement of ICD process in STAD and provides a new perspective for further accurate assessment of prognosis and therapeutic efficacy in STAD patients.
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Affiliation(s)
- Ye Liu
- Department of Intensive Care Unit, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Lijia Zhang
- Ethics Committee Office, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Xue Lei
- Department of Clinical Specialty of Integrated Traditional Chinese and Western Medicine, Graduate School, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Xinyu Yin
- Department of Clinical Specialty of Integrated Traditional Chinese and Western Medicine, Graduate School, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Songjiang Liu
- Department of Oncology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
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23
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Wang J, Luo LZ, Liang DM, Guo C, Huang ZH, Sun GY, Wen J. Progress in the research of cuproptosis and possible targets for cancer therapy. World J Clin Oncol 2023; 14:324-334. [PMID: 37771632 PMCID: PMC10523190 DOI: 10.5306/wjco.v14.i9.324] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/05/2023] [Accepted: 09/04/2023] [Indexed: 09/20/2023] Open
Abstract
Developing novel cancer therapies that exploit programmed cell death pathways holds promise for advancing cancer treatment. According to a recently published study in Science, copper death (cuproptosis) occurs when intracellular copper is overloaded, triggering aggregation of lipidated mitochondrial proteins and Fe-S cluster proteins. This intriguing phenomenon is triggered by the instability of copper ions. Understanding the molecular mechanisms behind cuproptosis and its associated genes, as identified by Tsvetkov, including ferredoxin 1, lipoic acid synthase, lipoyltransferase 1, dihydrolipid amide dehydrogenase, dihydrolipoamide transacetylase, pyruvate dehydrogenase α1, pyruvate dehydrogenase β, metallothionein, glutaminase, and cyclin-dependent kinase inhibitor 2A, may open new avenues for cancer therapy. Here, we provide a new understanding of the role of copper death and related genes in cancer.
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Affiliation(s)
- Jiang Wang
- Children Medical Center, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Lan-Zhu Luo
- Children Medical Center, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Dao-Miao Liang
- Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Chao Guo
- Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Zhi-Hong Huang
- Children Medical Center, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Guo-Ying Sun
- Department of Histology and Embryology, Hunan Normal University School of Medicine, Changsha 410013, Hunan Province, China
| | - Jie Wen
- Department of Pediatric Orthopedics, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha 410013, Hunan Province, China
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24
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Yue H, Wang J, Hou S, Zhang M. As a potential predictor of pan-cancer, UBE2S is related to tumor-associated macrophage infiltration. Future Oncol 2023; 19:1973-1990. [PMID: 37791471 DOI: 10.2217/fon-2023-0086] [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] [Indexed: 10/05/2023] Open
Abstract
Background: At the pan-cancer level, exploring the expression and prognostic significance of a gene, such as UBE2S, will help to gain insight into the role of the gene and its feasibility for cancer screening, prognosis assessment and even gene therapy. Methods: The Cancer Genome Atlas, Human Protein Atlas, Kaplan-Meier, Tumor Immunology Estimation Resource and other databases were used to analyze the expression of UBE2S at the pan-cancer level, its prognosis and the role of the immune microenvironment. Immunohistochemistry samples of tumor tissue collected in our clinic were taken as verification. Results: UBE2S is significantly overexpressed in pan-cancer and is closely associated with malignant clinical features, poor prognosis and tumor-associated macrophages. Conclusion: UBE2S may be a potential diagnostic and prognostic marker for pan-cancer and is associated with tumor-associated macrophages.
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Affiliation(s)
- Haodi Yue
- Department of Center for Clinical Single Cell Biomedicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China
| | - Jialin Wang
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, Beijing, 1000053, China
| | - Siyu Hou
- Department of Gynecology, Shijitan Hospital, Capital Medical University, Beijing, 1000038, China
| | - Mengjun Zhang
- Department of Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
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25
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El-Arabey AA, Zhang H, Abdalla M, Al-Shouli ST, Alkhalil SS, Liu Y. Metformin as a promising target for DPP4 expression: computational modeling and experimental validation. Med Oncol 2023; 40:277. [PMID: 37624423 PMCID: PMC10457412 DOI: 10.1007/s12032-023-02140-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 07/27/2023] [Indexed: 08/26/2023]
Abstract
Metformin is a regularly prescribed and low-cost generic medication. Metformin has been proposed as a target for Dipeptidyl-peptidase 4 (DPP4) expression in various clinical disorders. We provide insilco investigations on molecular docking and dynamic modeling of metformin and DPP4 potential interactions. Moreover, we conducted bioinformatic studies to highlight the clinical significance of DPP4 expression and mutation in various types of malignancies, as well as the invasion of different immune cells into the tumor microenvironment. We believe the present proposal's findings have crucial implications for understanding how metformin may confer health advantages by targeting DPP4 expression in malignancies.
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Affiliation(s)
- Amr Ahmed El-Arabey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751, Egypt.
| | - Haiyan Zhang
- Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, 250022, Shandong, China
| | - Mohnad Abdalla
- Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, 250022, Shandong, China
- Shandong Provincial Clinical Research Center for Children's Health and Disease, Jinan, 250022, Shandong, China
| | - Samia T Al-Shouli
- Immunology Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh, 11461, Saudi Arabia
| | - Samia S Alkhalil
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Alquwayiyah, Riyadh, Saudi Arabia
| | - Yi Liu
- Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, 250022, Shandong, China.
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Lin JC, Liu TP, Chen YB, Huang TS, Chen TY, Yang PM. Inhibition of CDK9 exhibits anticancer activity in hepatocellular carcinoma cells via targeting ribonucleotide reductase. Toxicol Appl Pharmacol 2023; 471:116568. [PMID: 37245555 DOI: 10.1016/j.taap.2023.116568] [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: 02/23/2023] [Revised: 05/12/2023] [Accepted: 05/23/2023] [Indexed: 05/30/2023]
Abstract
Cyclin-dependent kinase 9 (CDK9) inhibitors are a novel category of anticancer treatment for cancers. However, their effects on hepatocellular carcinoma (HCC) are rarely investigated. Human ribonucleotide reductase (RR, which consists of RRM1 and RRM2 subunits) catalyzes the conversion of ribonucleoside diphosphate into 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools, which play essential roles in DNA synthesis and DNA repair. In this study, we identified that CDK9 protein expression in adjacent non-tumor tissues predicted HCC patients' overall and progression-free survivals. The anticancer activity of a CDK9-selective inhibitor, LDC000067, on HCC cells was positively associated with its ability to inhibit the expression of RRM1 and RRM2. LDC000067 downregulated RRM1 and RRM2 expression through post-transcriptional pathway. Specifically, LDC000067 triggered RRM2 protein degradation via multiple pathways, including proteasome-, lysosome-, and calcium-dependent pathways. Furthermore, CDK9 positively correlates with RRM1 or RRM2 expression in HCC patients, and the expressions of these three genes were associated with the higher infiltration of immune cells in HCC. Taken together, this study identified the prognostic relevance of CDK9 in HCC and the molecular mechanism for the anticancer effect of CDK9 inhibitors on HCC.
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Affiliation(s)
- Jiunn-Chang Lin
- Department of Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan; MacKay Junior College of Medicine, Nursing, and Management, New Taipei City 11260, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; Liver Medical Center, MacKay Memorial Hospital, Taipei 10449, Taiwan; PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Tsang-Pai Liu
- Department of Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan; MacKay Junior College of Medicine, Nursing, and Management, New Taipei City 11260, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; Liver Medical Center, MacKay Memorial Hospital, Taipei 10449, Taiwan; PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Yan-Bin Chen
- Department of Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Tun-Sung Huang
- Department of Surgery, MacKay Memorial Hospital, Taipei 10449, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; Liver Medical Center, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Tung-Ying Chen
- Department of Medicine, MacKay Medical College, New Taipei City 25245, Taiwan; Department of Pathology, MacKay Memorial Hospital, Taipei 10449, Taiwan
| | - Pei-Ming Yang
- Liver Medical Center, MacKay Memorial Hospital, Taipei 10449, Taiwan; PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei 11031, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; TMU and Affiliated Hospitals Pancreatic Cancer Groups, Taipei Medical University, Taipei 11031, Taiwan.
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27
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Wen F, Guan X, Qu HX, Jiang XJ. Integrated analysis of single-cell and bulk RNA-seq establishes a novel signature for prediction in gastric cancer. World J Gastrointest Oncol 2023; 15:1215-1226. [PMID: 37546563 PMCID: PMC10401466 DOI: 10.4251/wjgo.v15.i7.1215] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/31/2023] [Accepted: 05/09/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND Single-cell sequencing technology provides the capability to analyze changes in specific cell types during the progression of disease. However, previous single-cell sequencing studies on gastric cancer (GC) have largely focused on immune cells and stromal cells, and further elucidation is required regarding the alterations that occur in gastric epithelial cells during the development of GC.
AIM To create a GC prediction model based on single-cell and bulk RNA sequencing (bulk RNA-seq) data.
METHODS In this study, we conducted a comprehensive analysis by integrating three single-cell RNA sequencing (scRNA-seq) datasets and ten bulk RNA-seq datasets. Our analysis mainly focused on determining cell proportions and identifying differentially expressed genes (DEGs). Specifically, we performed differential expression analysis among epithelial cells in GC tissues and normal gastric tissues (NAGs) and utilized both single-cell and bulk RNA-seq data to establish a prediction model for GC. We further validated the accuracy of the GC prediction model in bulk RNA-seq data. We also used Kaplan–Meier plots to verify the correlation between genes in the prediction model and the prognosis of GC.
RESULTS By analyzing scRNA-seq data from a total of 70707 cells from GC tissue, NAG, and chronic gastric tissue, 10 cell types were identified, and DEGs in GC and normal epithelial cells were screened. After determining the DEGs in GC and normal gastric samples identified by bulk RNA-seq data, a GC predictive classifier was constructed using the Least absolute shrinkage and selection operator (LASSO) and random forest methods. The LASSO classifier showed good performance in both validation and model verification using The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) datasets [area under the curve (AUC)_min = 0.988, AUC_1se = 0.994], and the random forest model also achieved good results with the validation set (AUC = 0.92). Genes TIMP1, PLOD3, CKS2, TYMP, TNFRSF10B, CPNE1, GDF15, BCAP31, and CLDN7 were identified to have high importance values in multiple GC predictive models, and KM-PLOTTER analysis showed their relevance to GC prognosis, suggesting their potential for use in GC diagnosis and treatment.
CONCLUSION A predictive classifier was established based on the analysis of RNA-seq data, and the genes in it are expected to serve as auxiliary markers in the clinical diagnosis of GC.
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Affiliation(s)
- Fei Wen
- Qingdao University, Medical College, Qingdao 266000, Shandong Province, China
| | - Xin Guan
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266071, Shandong Province, China
| | - Hai-Xia Qu
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266071, Shandong Province, China
| | - Xiang-Jun Jiang
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266071, Shandong Province, China
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Liu W, Wang L, Zhang J, Cheng K, Zheng W, Ma Z. CC Chemokine 2 Promotes Ovarian Cancer Progression through the MEK/ERK/MAP3K19 Signaling Pathway. Int J Mol Sci 2023; 24:10652. [PMID: 37445830 DOI: 10.3390/ijms241310652] [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: 05/23/2023] [Revised: 06/02/2023] [Accepted: 06/24/2023] [Indexed: 07/15/2023] Open
Abstract
Ovarian cancer is a gynecological tumor with an incidence rate lower than those of other gynecological tumor types and the second-highest death rate. CC chemokine 2 (CCL2) is a multifunctional factor associated with the progression of numerous cancers. However, the effect of CCL2 on ovarian cancer progression is unclear. Here, we found that exogenous CCL2 and the overexpression of CCL2 promoted the proliferation and metastasis of ovarian cancer cells. On the other hand, CCL2 knockdown via CRISPR/Cas9 inhibited ovarian cancer cell proliferation, migration, and invasion. The present study demonstrated that mitogen-activated protein three kinase 19 (MAP3K19) was the key CCL2 target for regulating ovarian cancer progression through transcriptome sequencing. Additionally, MAP3K19 knockout inhibited ovarian cancer cell proliferation, migration, and invasion. Furthermore, CCL2 increased MAP3K19 expression by activating the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. The present study showed the correlation between CCL2 and ovarian cancer, suggesting that CCL2 may be a novel target for ovarian cancer therapy.
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Affiliation(s)
- Wei Liu
- College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
| | - Lei Wang
- College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
| | - Jiajia Zhang
- College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
| | - Kun Cheng
- College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
| | - Wenming Zheng
- College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
| | - Zhenling Ma
- College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China
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Nasir NM, Alsalim TA, El-Arabey AA, Abdalla M. Anticancer, antioxidant activities and molecular docking study of thiazolidine-4-one and thiadiazol derivatives. J Biomol Struct Dyn 2023; 41:3976-3992. [PMID: 35467480 DOI: 10.1080/07391102.2022.2060306] [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: 01/16/2022] [Accepted: 03/27/2022] [Indexed: 10/18/2022]
Abstract
Liver cancer accounts for a major portion of the global cancer burden. In many nations, the prevalence of this condition has risen in recent decades. New series of thiazolidinones and thiadiazolidine have been designed, synthesized, and evaluated for potential antioxidant and antihepatocarcinogenic activity. The antioxidant activity was evaluated using a DPPH assay. Furthermore, we examined the compounds against Hepg-2 cells using MTT assay, flow cytometry analysis through the cell cycle, reactive oxygen species, and apoptosis. The result showed that compound 6b has the highest antioxidant activity with IC50 = 60.614 ± 0.739 µM. The anticancer activity showed that compounds 5 and 6b have significant toxicity against liver cancer cells Hepg2, IC50 values (9.082 and 4.712) µM, respectively. Flow cytometry experiments revealed that compound 5 arrested Hepg-2 cells in the S process, while compound 6b arrested Hepg-2 cells in the G1. Compound 6b had a greater reduction in reactive oxygen species and late apoptosis than compound 5. Substantially, compound 5 had affinity energies of -7.6 and -8.5 for Akt and CDK4 proteins, respectively, but compound 6b had affinity energies of -7.8 and -10.1 for Akt1 and CDK4 proteins, respectively. Consequently, compound 6b had lower binding energies than compound 5. In this work, we used multiple bioinformatics methods to shed light on the prospective therapeutic use of these series as novel candidates to target immune cells in the tumor microenvironment of hepatocellular carcinomas such as CD8+ T cells, endothelial cells, and hematopoietic stem cells.
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Affiliation(s)
- Noor M Nasir
- Department of Chemistry, Faculty of Education for Pure Sciences, University of Basrah, Basrah, Iraq
| | - Tahseen A Alsalim
- Department of Chemistry, Faculty of Education for Pure Sciences, University of Basrah, Basrah, Iraq
| | - Amr Ahmed El-Arabey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Mohnad Abdalla
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Shandong Province, People's Republic of China
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El-Arabey AA, Alkhalil SS, Al-Shouli ST, Awadalla ME, Alhamdi HW, Almanaa TN, Mohamed SSEM, Abdalla M. Revisiting macrophages in ovarian cancer microenvironment: development, function and interaction. Med Oncol 2023; 40:142. [PMID: 37039909 PMCID: PMC10090027 DOI: 10.1007/s12032-023-01987-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/02/2023] [Indexed: 04/12/2023]
Abstract
Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and have been linked to immunosuppression and poor prognosis. TAMs have been shown to be harmful in ovarian cancer (OC), with a positive correlation between their high levels of tumors and poor overall patient survival. These cells are crucial in the progression and chemoresistance of OC. The primary pro-tumoral role of TAMs is the release of cytokines, chemokines, enzymes, and exosomes that directly enhance the invasion potential and chemoresistance of OC by activating their pro-survival signalling pathways. TAMs play a crucial role in the metastasis of OC in the peritoneum and ascities by assisting in spheroid formation and cancer cell adhesion to the metastatic regions. Furthermore, TAMs interact with tumor protein p53 (TP53), exosomes, and other immune cells, such as stem cells and cancer-associated fibroblasts (CAFs) to support the progression and metastasis of OC. In this review we revisit development, functions and interactions of TAMs in the TME of OC patients to highlight and shed light on challenges and excitement down the road.
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Affiliation(s)
- Amr Ahmed El-Arabey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, 11751 Egypt
| | - Samia S. Alkhalil
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Alquwayiyah, Riyadh, Saudi Arabia
| | - Samia T. Al-Shouli
- Immunology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | | | - Heba W. Alhamdi
- Department of Biology, College of Sciences, King Khalid University, Abha, 61413 Saudi Arabia
| | - Taghreed N. Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Samah Saif Eldin M. Mohamed
- Department of Clinical Laboratory science, College of Applied Sciences, Shaqra University, Alquwayiyah, Riyadh, Saudi Arabia
| | - Mohnad Abdalla
- Pediatric Research Institute, Children’s Hospital Affiliated to Shandong University, Jinan, 250022 Shandong China
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Al-Shawi AAA, El-Arabey AA, Mutlaq DZ, Eltayb WA, Iriti M, Abdalla M. Study on Molecular Anti-tumor Mechanism of 2-Thiohydantoin Derivative based on Molecular Docking and Bioinformatic Analyses. Curr Top Med Chem 2023; 23:440-452. [PMID: 36617706 DOI: 10.2174/1568026623666230106121527] [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: 08/17/2022] [Revised: 11/27/2022] [Accepted: 11/28/2022] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Several methods for synthesizing 2-thiohydantoin derivatives have been devised and exploited, and they have found widespread application as antioxidants, antimicrobials, antivirals, and anticancer agents. As a result, we tried to understand the underlying processes of the 2- thiohydantoin derivative's anti-LIHC activity. METHODS We predicted the anticancer mechanism of N-(4-oxo-5-(2-oxo-2-(p-tolylamino)ethyl)-3- phenyl-2-thioxoimidazolidin-1-yl)benzamide as a derivative of 2-thiohydantoin by utilizing molecular docking and molecular dynamic simulation. Furthermore, based on the results of molecular dynamic modelling, we employed bioinformatics to anticipate the immunotherapy of this molecule in the tumor microenvironment (TME) of Liver Hepatocellular Carcinoma (LIHC) patients. Next, we examined how this derivative affected proliferation, cell cycle progression, reactive oxygen species production, and apoptosis in HepG2 cancer cells. RESULTS Substantially, our investigation revealed that the IC50 value was 2.448 μM and that it arrested the cell cycle of HepG2 in the S phase. Furthermore, molecular docking and dynamics studies revealed a worthy interaction of this compound with AKT1 and CDK2 proteins. Considerably, AKT1 and CDK2 have negative affinity energies of -10.4 kcal/mol and -9.6 kcal/mol, respectively. Several bioinformatic tools were used in this investigation to provide insight into the future clinical application of this derivative as a novel candidate to target immune cells such as macrophages, neutrophils, eosinophils, and CD8+ T cells. CONCLUSION The relevance of this 2-thiohydantoin derivative was demonstrated by our experimental tests, docking studies, and bioinformatics analysis, and it may be investigated as a lead molecule for anticancer medicines, notably as AKT1 and CKD2 inhibitors.
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Affiliation(s)
| | - Amr Ahmed El-Arabey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Dakhil Zughayir Mutlaq
- Department of Chemistry, College of Education for Pure Sciences, University of Basrah, Basrah, Iraq
| | - Wafa Ali Eltayb
- Biotechnology Department, Faculty of Science and Technology, Shendi University, Shendi, Nher Anile, Sudan
| | - Marcello Iriti
- Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milano, Italy
- National Interuniversity Consortium of Materials Science and Technology (INSTM), 50121 Firenze, Italy
| | - Mohnad Abdalla
- Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, Shandong, 250022, China
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Badve SS, Gökmen-Polar Y. Targeting the Tumor-Tumor Microenvironment Crosstalk. Expert Opin Ther Targets 2023; 27:447-457. [PMID: 37395003 DOI: 10.1080/14728222.2023.2230362] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/23/2023] [Indexed: 07/04/2023]
Abstract
INTRODUCTION Cancer development and progression is a complex process influenced by co-evolution of the cancer cells and their microenvironment. However, traditional anti-cancer therapy is mostly targeted toward cancer cells. To improve the efficacy of cancer drugs, the complex interactions between the tumor (T) and the tumor microenvironment (TME) should be considered while developing therapeutics. AREAS COVERED The present review article will discuss the components of T-TME as well as the potential to co-target these two distinct elements. We document that these approaches have resulted in success in preventing tumor progression and metastasis, albeit in animal models in some cases. Lastly, it is important to consider the tissue context and tumor type as these could significantly modify the role of these molecules/pathways and hence the overall likelihood of response. Furthermore, we discuss the potential strategies to target the components of tumor microenvironment in anti-cancer therapy. PubMed and ClinicalTrials.gov was searched through May 2023. EXPERT OPINION The tumor-tumor microenvironment cross talk and heterogeneity are major mechanisms conferring resistance to standard of care. Better understanding of the tissue specific T-TME interactions and dual targeting has the promise of improving cancer control and clinical outcomes.
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Affiliation(s)
- Sunil S Badve
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
| | - Yesim Gökmen-Polar
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA
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Qi YH, Yang LZ, Zhou L, Gao LJ, Hou JY, Yan Z, Bi XG, Yan CP, Wang DP, Cao JM. Sympathetic nerve infiltration promotes stomach adenocarcinoma progression via norepinephrine/β2-adrenoceptor/YKL-40 signaling pathway. Heliyon 2022; 8:e12468. [PMID: 36593854 PMCID: PMC9803717 DOI: 10.1016/j.heliyon.2022.e12468] [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: 05/12/2022] [Revised: 08/13/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
Objective This study aimed to address the status, role, and mechanism of sympathetic nerve infiltration in the progression of stomach adenocarcinoma (STAD). Methods Sympathetic nerve and its neurotransmitter NE, β-ARs, and associated signaling molecules in the STAD tissues and the adjacent tissues from 46 STAD patients were examined using immunostaining, HPLC, and western blotting. The effects and mechanisms of β2-AR activation on the proliferation, migration and invasion of AGS and SGC-7901 gastric cancer (GC) cell lines were examined using CCK-8, transwell, and western blotting assays. Correlations between genes and STAD survival were analyzed using bioinformatics. Results Striking sympathetic nerve infiltration, elevations of NGF, TrkA, GAP43, TH, S100, NE, β2-AR, YKL-40, syndecan-1, MMP9, CD206, and CD31 were observed in the STAD tissues compared to the adjacent tissues. Activation of β2-AR in the two GC cell lines significantly amplified the expressions of NGF, YKL-40, MMP9, syndecan-1, p-STAT3 and p-ERK, and increased GC cell proliferation, migration and invasion. Bioinformatic analyses revealed positive correlations of NGF, β2-AR, syndecan-1, and macrophage infiltration, respectively, with low survival of STAD, of β2-AR respectively with STAT3, ERK1/2 (MAPK1/3), YKL-40, MMP9, and syndecan-1, and of YKL-40 with MMP9. Conclusion Sympathetic nerves significantly infiltrated into human STAD tissues as a result of high NGF and TrkA expressions; elevated NE led to overactivation of β2-AR-STAT3/ERK-YKL-40 signaling pathway, and finally caused cancer cell growth and invasion, M2 macrophage infiltration, angiogenesis, matrix degradation and STAD metastasis and progression.
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Affiliation(s)
- Yue-Hong Qi
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China,Department of Anesthesiology, Shanxi Provincial Peoples Hospital, Taiyuan, China
| | - Lu-Zi Yang
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
| | - Lan Zhou
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
| | - Li-Juan Gao
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
| | - Jia-Yi Hou
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
| | - Zi Yan
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China
| | - Xiao-Gang Bi
- Department of Anesthesiology, Shanxi Provincial Peoples Hospital, Taiyuan, China
| | - Cai-Ping Yan
- Center of Translational Medicine, Shanxi Medical University, Taiyuan, China
| | - De-Ping Wang
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China,Corresponding author.
| | - Ji-Min Cao
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, And the Department of Physiology, Shanxi Medical University, Taiyuan, China,Corresponding author.
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Vandna, Ahlawat S, Sharma KK, Mohan H. Proteomic, biochemical, histopathological, and elevated plus maze analysis reveals the gut damaging role of ketoprofen with Yersinia enterocolitica and altered behavior in Wistar rats. Toxicol Appl Pharmacol 2022; 457:116315. [PMID: 36372189 DOI: 10.1016/j.taap.2022.116315] [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: 07/14/2022] [Revised: 10/20/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is known to damage the intestinal epithelial cells (IECs) that play numerous important roles, including nutrient absorption and barrier protection. In the current study, we determined the effect of ketoprofen on the rat gut when administered with Yersinia enterocolitica. On performing the label-free quantitation of the rat gut proteins, the expression of 494 proteins out of 1628 proteins was altered, which has a profound effect on NF-kB signaling pathway, immune system, dysbiosis, and gut injury. Further, the biochemical [enhanced malondialdehyde (MDA) & hepatic enzyme activities and reduced serotonin & antioxidants levels i.e., catalase (CAT) and superoxide dismutase (SOD)] and histopathological analysis suggested the significant damage in treated rats, compared to control rats. Lastly, the elevated plus maze (EPM) study confirmed high levels of anxiety in treated rats in comparison to the control group. Altogether, results suggest that the co-administration of ketoprofen with Y. enterocolitica damages gut, alters hepatic enzyme activities, and affects behavioral responses in the treated rats.
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Affiliation(s)
- Vandna
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak 124001, Haryana, India
| | - Shruti Ahlawat
- Department of Microbiology, Maharshi Dayanand University, Rohtak 124001, Haryana, India
| | - Krishna Kant Sharma
- Department of Microbiology, Maharshi Dayanand University, Rohtak 124001, Haryana, India.
| | - Hari Mohan
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak 124001, Haryana, India.
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El-Arabey AA, Abdalla M. GATA3 as an immunomodulator in obesity-related metabolic dysfunction associated with fatty liver disease, insulin resistance, and type 2 diabetes. Chem Biol Interact 2022; 366:110141. [PMID: 36058260 DOI: 10.1016/j.cbi.2022.110141] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/20/2022] [Accepted: 08/27/2022] [Indexed: 11/03/2022]
Abstract
Obesity is the leading risk factor associated with Metabolic dysfunction Associated with Fatty Liver Disease (MAFLD), Insulin Resistance (IR), and type 2 diabetes (T2DM). Notably, MAFLD affects 25% of the world's adult population, ranging from 13.5% in Africa to 31.8% in the Middle East. The prevalence of MAFLD is 80-90% in obese adults and 30-50% in patients with diabetes. According to the recent WHO update, more than 400 million people will experience T2DM by 2025. Furthermore, the worldwide obesity incidence rate has risen in the preceding years. Adipogenesis deterioration is a critical step in the induction of obesity correlated with MAFLD, IR and T2DM. The well-known transcription factor GATA3 is highly expressed in the preadipocytes-adipocytes transition of embryonic stem cells and obese people with IR. In this regard, the reduction of GATA3 improves the differentiation of adipocytes. Omental adipose tissue inflammation by upregulation of macrophages infiltration is strongly linked with body mass index in insulin tolerance of obese people. In particular, the dynamic interaction between macrophages and adipocytes significantly regulates obese adipose tissue's inflammatory status and influences IR by reducing the differentiation of adipocytes, macrophage function, and glucose transport. Emerging evidence demonstrated that GATA3 is a master regulator for macrophage polarization and infiltration. Hence, we will shed light on GATA3 as an emerging target for immunomodulation in human obesity associated with MAFLD, IR, and T2DM by reducing macrophages' recruitment and inflammation of muscles and liver.
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Affiliation(s)
- Amr Ahmed El-Arabey
- Department of Pharmacology and Toxicology, Al-Azhar University, Faculty of Pharmacy, Cairo, Egypt.
| | - Mohnad Abdalla
- Research Institute of Pediatrics, Children's Hospital Affiliated to Shandong University (Jinan Children's Hospital), Jinan, China
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Pyroptosis: a novel signature to predict prognosis and immunotherapy response in gliomas. Hum Cell 2022; 35:1976-1992. [PMID: 36129672 DOI: 10.1007/s13577-022-00791-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 09/06/2022] [Indexed: 11/04/2022]
Abstract
Gliomas are the most common primary brain tumors and are highly malignant with a poor prognosis. Pyroptosis, an inflammatory form of programmed cell death, promotes the inflammatory cell death of cancer. Studies have demonstrated that pyroptosis can promote the inflammatory cell death (ICD) of cancer, thus affecting the prognosis of cancer patients. Therefore, genes that control pyroptosis could be a promising candidate bio-indicator in tumor therapy. The function of pyroptosis-related genes (PRGs) in gliomas was investigated based on the Chinese Glioma Genome Atlas (CGGA), the Cancer Genome Atlas (TCGA) and the Repository of Molecular Brain Neoplasia Data (Rembrandt) databases. In this study, using the non-negative matrix factorization (NMF) clustering method, 26 PRGs from the RNA sequencing data were divided into two subgroups. The LASSO and Cox regression was used to develop a 4-gene (BAX, Caspase-4, Caspase-8, PLCG1) risk signature, and all glioma patients in the CGGA, TCGA and Rembrandt cohorts were divided into low- and high-risk groups. The results demonstrate that the gene risk signature related to clinical features can be used as an independent prognostic indicator in glioma patients. Moreover, the high-risk subtype had rich immune infiltration and high expression of immune checkpoint genes in the tumor immune microenvironment (TIME). The analysis of the Submap algorithm shows that patients in the high-risk group could benefit more from anti-PD1 treatment. The risk characteristics associated with pyroptosis proposed in this study play an essential role in TIME and can potentially predict the prognosis and immunotherapeutic response of glioma patients.
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Zeng C, Liu Y, He R, Lu X, Dai Y, Qi G, Liu J, Deng J, Lu W, Jin J, Liu Q. Identification and validation of a novel cellular senescence-related lncRNA prognostic signature for predicting immunotherapy response in stomach adenocarcinoma. Front Genet 2022; 13:935056. [PMID: 36092903 PMCID: PMC9453157 DOI: 10.3389/fgene.2022.935056] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/03/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Cellular senescence is a novel hallmark of cancer associated with patient outcomes and tumor immunotherapy. However, the value of cellular senescence-related long non-coding RNAs (lncRNAs) in predicting prognosis and immunotherapy response for stomach adenocarcinoma (STAD) patients needs further investigation.Methods: The transcriptome and corresponding clinical information of STAD and cellular senescence-related genes were, respectively, downloaded from the Cancer Genome Atlas (TCGA) and CellAge databases. Differential expression analysis and coexpression analysis were performed to obtain cellular senescence-related lncRNAs. Univariate regression analysis and least absolute shrinkage and selection operator (LASSO) Cox analysis were conducted to establish the cellular senescence-related lncRNA prognostic signature (CSLPS). Next, the survival curve, ROC curve, and nomogram were developed to assess the capacity of predictive models. Moreover, principal component analysis (PCA), gene set enrichment analysis (GSEA), tumor microenvironment (TME), tumor mutation burden (TMB), microsatellite instability (MSI), and tumor immune dysfunction and exclusion (TIDE) score analysis were performed between high- and low-risk groups.Results: A novel CSLPS involving fifteen lncRNAs (REPIN1-AS1, AL355574.1, AC104695.3, AL033527.2, AC083902.1, TYMSOS, LINC00460, AC005165.1, AL136115.1, AC007405.2, AL391152.1, SCAT1, AC129507.1, AL121748.1, and ADAMTS9-AS1) was developed. According to the nomogram, the risk model based on the CSLPS was an independent prognostic factor and could predict 1-, 3-, and 5-year overall survival for STAD patients. GSEA suggested that the high-risk group was mainly associated with Toll-like receptor, JAK/STAT, NOD-like receptor, and chemokine signaling pathways. Further analysis revealed that STAD patients in the low-risk group with better clinical outcomes had a higher TMB, higher proportion of high microsatellite instability (MSI-H), better immune infiltration, and lower TIDE scores.Conclusion: A fifteen-CSlncRNA prognostic signature could predict survival outcomes, and patients in the low-risk group may be more sensitive to immunotherapy.
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Affiliation(s)
- Cheng Zeng
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Oncology, Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Yu Liu
- Department of Internal Medicine, School of Medicine, Dalian Medical University, Dalian, Liaoning, China
| | - Rong He
- Cancer Institute, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiaohuan Lu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuyang Dai
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Guoping Qi
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Jingsong Liu
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
| | - Jianzhong Deng
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Oncology, Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Wenbin Lu
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Oncology, Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
| | - Jianhua Jin
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Oncology, Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
- *Correspondence: Jianhua Jin, ; Qian Liu,
| | - Qian Liu
- Department of Oncology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China
- Department of Oncology, Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China
- *Correspondence: Jianhua Jin, ; Qian Liu,
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Yan LD, Yang L, Li N, Wang M, Zhang YH, Zhou W, Yu ZQ, Peng XC, Cai J. Prognostic role of multiple abnormal genes in non-small-cell lung cancer. World J Clin Cases 2022; 10:7772-7784. [PMID: 36158484 PMCID: PMC9372825 DOI: 10.12998/wjcc.v10.i22.7772] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/19/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-small-cell lung cancer (NSCLC) has the highest morbidity and mortality rates among all malignant tumor types. Although therapies targeting the mutated genes such as KRAS have been used in the clinic for many years, the prognosis remains poor. Therefore, it is necessary to further study the aberrant expression or mutation of non-target genes affecting the survival and prognosis. AIM To explore the impact of simultaneous abnormalities of multiple genes on the prognosis and survival of patients. METHODS We used R packages to analyze gene expression data and clinical data downloaded from The Cancer Genome Atlas (TCGA) database. We also collected samples from 85 NSCLC patients from the First People's Hospital of Jingzhou City and retrospectively followed the patients. Multivariate Cox regression analysis and survival analysis were performed. RESULTS Analysis of gene expression data from TCGA revealed that the overexpression of the following single genes affected overall survival: TP53 (P = 0.79), PTEN (P = 0.94), RB1 (P = 0.49), CTNNB1 (P = 0.24), STK11 (P = 0.32), and PIK3CA (P = 0.013). However, the probability of multiple genes (TP53, PTEN, RB1, and STK11) affecting survival was 0.025. Retrospective analysis of clinical data revealed that sex (hazard ratio [HR] = 1.29; [95%CI: 0.64-2.62]), age (HR = 1.05; [95%CI: 1.02-1.07]), smoking status (HR = 2.26; [95%CI: 1.16-4.39]), tumor histology (HR = 0.58; [95%CI: 0.30-1.11]), cancer stage (HR = 16.63; [95%CI: 4.8-57.63]), epidermal growth factor receptor (EGFR) mutation (HR = 1.82; [95%CI: 1.05-3.16]), abundance (HR = 4.95; [95%CI: 0.78-31.36]), and treatment with tyrosine kinase inhibitors (TKIs) (HR = 0.58; [95%CI: 0.43-0.78]) affected patient survival. Co-occurring mutations of TP53, PTEN, RB1, and STK11 did not significantly affect the overall survival of patients receiving chemotherapy (P = 0.96) but significantly affected the overall survival of patients receiving TKIs (P = 0.045). CONCLUSION Co-occurring mutation or overexpression of different genes has different effects on the overall survival and prognosis of NSCLC patients. Combined with TKI treatment, the co-occurring mutation of some genes may have a synergistic effect on the survival and prognosis of NSCLC patients.
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Affiliation(s)
- Lu-Da Yan
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Liu Yang
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Na Li
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Meng Wang
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Yan-Hua Zhang
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Wen Zhou
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Zhi-Qiong Yu
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Xiao-Chun Peng
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Jun Cai
- Department of Oncology, The First Affiliated Hospital of Yangtze University, Jingzhou 434023, Hubei Province, China
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You W, Ouyang J, Cai Z, Chen Y, Wu X. Comprehensive Analyses of Immune Subtypes of Stomach Adenocarcinoma for mRNA Vaccination. Front Immunol 2022; 13:827506. [PMID: 35874675 PMCID: PMC9300892 DOI: 10.3389/fimmu.2022.827506] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 06/13/2022] [Indexed: 11/25/2022] Open
Abstract
Background Although messenger RNA (mRNA) vaccines have unique advantages against multiple tumors, mRNA vaccine targets in stomach adenocarcinoma (STAD) remain unknown. The potential effectiveness of mRNA vaccines is closely associated with the tumor immune infiltration microenvironment. The present study aimed to identify tumor antigens of STAD as mRNA vaccine targets and systematically determine immune subtypes (ISs) of STAD that might be suitable for immunotherapy. Methods Gene expression profiles and clinical data of patients with gastric cancer were downloaded from The Cancer Genome Atlas (TCGA; n = 409) and the Gene Expression Omnibus (GEO; n = 433), and genomic data were extracted from cBioPortal. Differential gene expression was analyzed using the limma package, genetic alterations were visualized using maftools, and prognosis was analyzed using ToPP. Correlations between gene expression and immune infiltration were calculated using TIMER software, and potential ISs were identified using ConsensusClusterPlus. Functional enrichment was analyzed in clusterProfiler, and r co-expression networks were analyzed using the weighted gene co-expression network analysis (WGCNA) package in R. Results Overexpression of the prognostic and highly mutated antigens ADAMTS18, COL10A1, PPEF1, and STRA6 was associated with infiltration by antigen-presenting cells in STAD. Five ISs (IS1–IS5) in STAD with distinct prognoses were developed and validated in TCGA and GEO databases. The tumor mutational burden and molecular and clinical characteristics significantly differed among IS1–IS5. Both IS1 and IS2 were associated with a high mutational burden, massive infiltration by immune cells, especially antigen-presenting cells, and better survival compared with the other subtypes. Both IS4 and IS5 were associated with cold immune infiltration and correlated with advanced pathological stages. We analyzed the immune microenvironments of five subtypes of immune modulators and biomarkers to select suitable populations for mRNA vaccination and established four co-expressed key modules to validate the characteristics of the ISs. Finally, the correlation of these four mRNA vaccine targets with the transcription factors of DC cells, including BATF3, IRF4, IRF8, ZEB2, ID2, KLF4, E2-2, and IKZF1, were explored to reveal the underlying mechanisms. Conclusions ADAMTS18, COL10A1, PPEF1, and STRA6 are potential mRNA vaccine candidates for STAD. Patients with IS1 and IS2 are suitable populations for mRNA vaccination immunotherapy.
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Affiliation(s)
- Weiqiang You
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jian Ouyang
- The Center for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, Institute for Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Zerong Cai
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yufeng Chen
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaojian Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Xiaojian Wu,
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Javed S, Benoist S, Devos P, Truant S, Guimbaud R, Lièvre A, Sefrioui D, Cohen R, Artru P, Dupré A, Bachet JB, de la Fouchardière C, Ploquin A, Turpin A. Prognostic factors of BRAF V600E colorectal cancer with liver metastases: a retrospective multicentric study. World J Surg Oncol 2022; 20:131. [PMID: 35461290 PMCID: PMC9034502 DOI: 10.1186/s12957-022-02594-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 04/07/2022] [Indexed: 12/21/2022] Open
Abstract
Background BRAF V600E-mutant colorectal cancers (CRCs) are associated with shorter survival than BRAF wild-type tumors. Therapeutic decision-making for colorectal liver metastases (CRLM) harboring this mutation remains difficult due to the scarce literature. The aim was to study a large cohort of BRAF V600E-mutant CRLM patients in order to see if surgery extend overall survival among others prognostic factors. Methods BRAF V600E-mutant CRCs diagnosed with liver-only metastases, resected or not, were retrospectively identified between April 2008 and December 2017, in 25 French centers. Clinical, molecular, pathological characteristics and treatment features were collected. Overall survival (OS) was defined as the time from CRLM diagnosis to death from any cause. Cox proportional hazard models were used for statistical analysis. Results Among the 105 patients included, 79 (75%) received chemotherapy, 18 (17%) underwent upfront CRLM surgery, and 8 (8%) received exclusive best supportive care. CRLM surgery was performed in 49 (46.7%) patients. CRLM were mainly synchronous (90%) with bilobar presentation (61%). The median OS was 34 months (range, 28.9–67.3 months) for resected patients and 10.6 (6.7–12.5) months for unresected patients (P < 0.0001). In multivariate analysis, primary tumor surgery (hazard ratio (HR) = 0.349; 95% confidence interval (CI) 0.164–0.744, P = 0.0064) and CRLM resection (HR = 0.169; 95% CI 0.082–0.348, P < 0.0001) were associated with significantly better OS. Conclusions In the era of systemic cytotoxic chemotherapies, liver surgery seems to extend OS in BRAF V600E-mutant CRCs with liver only metastases historical cohort.
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Affiliation(s)
- Sahir Javed
- Department of Medical Oncology, Centre Oscar Lambret, F-59000, Lille, France.,Department of Medical Oncology, Centre Hospitalier de Valenciennes, F-59300, Valenciennes, France
| | - Stéphane Benoist
- Department of Digestive Surgery and Surgical Oncology, Bicêtre Hospital, AP-HP, Paris-Sud University, Paris, France
| | - Patrick Devos
- University of Lille, CHU Lille, F-59000, Lille, France
| | - Stéphanie Truant
- Department of Digestive Surgery and Transplantation, CHU Lille, F-59000, Lille, France
| | - Rosine Guimbaud
- Department of Medical Oncology, Claudius Regaud Institute, Toulouse, France
| | - Astrid Lièvre
- Department of Gastroenterology, CHU Pontchaillou, Rennes 1 University, Rennes, France
| | - David Sefrioui
- Digestive Oncology Unit, Department of Hepatogastroenterology, Rouen University Hospital, Normandie Université, UNIROUEN, Inserm 1245, IRON group, Rouen, France
| | - Romain Cohen
- Medical Oncology Department, Saint-Antoine Hospital, Sorbonne University, AP-HP, F-75012, Paris, France
| | - Pascal Artru
- Department of Gastroenterology, Jean Mermoz Hospital, Lyon, France
| | - Aurélien Dupré
- Department of Surgical Oncology, Leon Berard Cancer Center, UNICANCER, Lyon, France
| | - Jean-Baptiste Bachet
- Department of Hepato-Gastroenterology, Hôpital Pitié Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
| | | | - Anne Ploquin
- Department of Oncology, CHU Lille, F-59000, Lille, France
| | - Anthony Turpin
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France.
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Tan D, Zhang Y. Silencing of Nudix type 5 represses proliferation and invasion and enhances chemosensitivity of gastric carcinoma cells by affecting the AKT/GSK-3β/β-catenin pathway. Toxicol Appl Pharmacol 2022; 441:115968. [PMID: 35247377 DOI: 10.1016/j.taap.2022.115968] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/22/2022] [Accepted: 02/27/2022] [Indexed: 01/01/2023]
Abstract
Nudix type 5 (NUDT5) has been recently identified as a new cancer-associated protein that is involved in numerous cancers. To date, the relationship between NUDT5 and gastric carcinoma has not been addressed. In the current research, we focused on exploring the potential relevance of NUDT5 in gastric carcinoma. The initial analysis of NUDT5 expression in gastric carcinoma by TCGA data revealed a clear increase in NUDT5 expression in tumor versus normal tissue. The increased expression of NUDT5 was also validated in the clinical specimens of gastric carcinoma by immunoblotting detection. Moreover, high NUDT5 levels predicted a poorer overall survival in gastric carcinoma patients. A series of cellular functional assays demonstrated that gastric carcinoma cells with silenced NUDT5 exhibited decreased proliferative and invasive ability, increased cell cycle arrest at the G0/G1 phase, and enhanced chemosensitivity. In-depth research showed that the silencing of NUDT5 led to a reduction in the activation of AKT and β-catenin. The reactivation of AKT blocked the repressive effect of NUDT5 silencing on β-catenin activation. The forced expression of β-catenin also reversed NUDT5-silencing-mediated anticancer effects. A Xenograft tumor assay confirmed the anticancer role of NUDT5 in gastric carcinoma in vivo. In short, these findings reveal elevated NUDT5 levels in gastric carcinoma and demonstrate that the inhibition of NUDT5 displays promising anticancer effects by affecting the AKT/β-catenin pathway. Thus, our work unveils a vital role of NUDT5 in gastric carcinoma and indicates it as a viable candidate target for anticancer drug discovery.
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Affiliation(s)
- Dong Tan
- Department of General Surgery, No. 215 Hospital of Shaanxi Nuclear Industry, No. 52 Weiyang West Road, Xianyang, Shaanxi 712000, PR China
| | - Yafei Zhang
- Department of Endoscopy, No. 215 Hospital of Shaanxi Nuclear Industry, No. 52 Weiyang West Road, Xianyang, Shaanxi 712000, China.
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Chen J, Liu W, Du J, Wang P, Wang J, Ye K. Comprehensive Genomic and Epigenomic Analyses on Transcriptomic Regulation in Stomach Adenocarcinoma. Front Genet 2022; 12:778095. [PMID: 35222516 PMCID: PMC8873582 DOI: 10.3389/fgene.2021.778095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/28/2021] [Indexed: 12/24/2022] Open
Abstract
Background: DNA methylation (MET)–mediated transcriptomic disturbance and copy number variations (CNVs) exert a significant influence in stimulating the heterogeneous progression of stomach adenocarcinoma (STAD). Nevertheless, the relation of DNA MET with CNVs, together with its impact on tumor occurrence, is still unclear.Methods: The messenger RNA (mRNA) expression (EXP) profiles, DNA MET, and DNA copy numbers, together with STAD mutation data, were collected from the TCGA official data portal. We employed circular binary segmentation algorithm in “DNAcopy.” library of R package for mapping DNA CNV data at genetic level for all samples based on the segmented CNV data. Stable clusters of samples were recognized using negative matrix factorization cluster analysis based on 50 iterations and the “brunet” method using the MET-correlated (METcor) and CNV-correlated (CNVcor) genes. The R package “iCluster” method was utilized to comprehensively analyze the EXP, MET, and DNA CNV profiles.Results: A total of 313 STAD samples were isolated for checking DNA copy numbers and MET and for measuring EXP. In accordance with our results, we discovered obvious co-regulation of CNVcor genes and METcor counterparts. Apart from that, these genes were subject to multi-omics integration. Meanwhile, three subtypes of STAD were detected and confirmed based on independent data. Among them, the subtype with increased aggressiveness was related to decreased mutation frequencies of ARID1A, PIK3CA, ZFHX3, SPECC1, OBSCN, KMT2D, FSIP2, ZBTB20, TTN, and RANBP2, together with the abnormal levels of JPH3, KCNB1, and PLCXD3.Conclusion: According to the results, these aforementioned genes exerted crucial roles in the development of invasive STAD. Our findings on transcriptomic regulation genomically and epigenetically facilitate the understanding of the STAD pathology from different aspects, which help to develop efficient anti-STAD therapy.
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de Bakker T, Journe F, Descamps G, Saussez S, Dragan T, Ghanem G, Krayem M, Van Gestel D. Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments. Front Oncol 2022; 11:799993. [PMID: 35071005 PMCID: PMC8770810 DOI: 10.3389/fonc.2021.799993] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 12/15/2021] [Indexed: 01/10/2023] Open
Abstract
TP53 mutation is one of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC) and results in an accumulation of p53 protein in tumor cells. This makes p53 an attractive target to improve HNSCC therapy by restoring the tumor suppressor activity of this protein. Therapeutic strategies targeting p53 in HNSCC can be divided into three categories related to three subtypes encompassing WT p53, mutated p53 and HPV-positive HNSCC. First, compounds targeting degradation or direct inhibition of WT p53, such as PM2, RITA, nutlin-3 and CH1iB, achieve p53 reactivation by affecting p53 inhibitors such as MDM2 and MDMX/4 or by preventing the breakdown of p53 by inhibiting the proteasomal complex. Second, compounds that directly affect mutated p53 by binding it and restoring the WT conformation and transcriptional activity (PRIMA-1, APR-246, COTI-2, CP-31398). Third, treatments that specifically affect HPV+ cancer cells by targeting the viral enzymes E6/E7 which are responsible for the breakdown of p53 such as Ad-E6/E7-As and bortezomib. In this review, we describe and discuss p53 regulation and its targeting in combination with existing therapies for HNSCC through a new classification of such cancers based on p53 mutation status and HPV infection.
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Affiliation(s)
- Tycho de Bakker
- Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Fabrice Journe
- Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons, Mons, Belgium
| | - Géraldine Descamps
- Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons, Mons, Belgium
| | - Sven Saussez
- Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons, Mons, Belgium
| | - Tatiana Dragan
- Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Ghanem Ghanem
- Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Mohammad Krayem
- Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Dirk Van Gestel
- Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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Guo Y, Jiang F, Yang W, Shi W, Wan J, Li J, Pan J, Wang P, Qiu J, Zhang Z, Li B. Effect of 1α,25(OH) 2D 3-Treated M1 and M2 Macrophages on Cell Proliferation and Migration Ability in Ovarian Cancer. Nutr Cancer 2021; 74:2632-2643. [PMID: 34894920 DOI: 10.1080/01635581.2021.2014903] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The biological active form of vitamin D3, 1α,25-dehydroxyvitamin D3 [1α,25(OH)2D3], exerts pleiotropic effects including bone mineralization, anti-tumor, as well as immunomodulator. This study aimed to explore the potential impact of 1α,25(OH)2D3 on tumor-associated macrophages (TAMs) infiltration in ovarian cancer. Firstly, human monocytic THP-1 cells were differentiated into macrophages (M0) in the presence of phorbol 12-myristate 13-acetate (PMA). In Vivo, 1α,25(OH)2D3 not only reversed the polarization of M2 macrophages, but also decreased the proliferation and migration abilities of ovarian cancer cells induced by M2 macrophages supernatant. Furthermore, 1α,25(OH)2D3 dramatically decreased the secretion of TGF-β1 and MMP-9 in M2 macrophages. However, no significant effect was observed in 1α,25(OH)2D3 treated M1 macrophages. In Vivo, vitamin D3 had an inhibitive effect of 1α,25(OH)2D3-treated M2 macrophages on tumorigenesis. In addition, we conducted the association of TAMs with the poor prognosis of patients with ovarian cancer by meta-analysis, which suggested the higher proportion of M2 macrophages was related to the poorer prognosis in ovarian cancer. Collectively, these results identified distinct roles of 1α,25(OH)2D3 treated M1 and M2 macrophages on cell proliferation and migration abilities in ovarian cancer.
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Affiliation(s)
- Yi Guo
- Medical College of Soochow University, Suzhou, China.,Jiangpu Community Healthcare Service, Suzhou, Kunshan, China
| | - Fei Jiang
- Medical College of Soochow University, Suzhou, China
| | - Wenqing Yang
- Medical College of Soochow University, Suzhou, China
| | - Weiqiang Shi
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianmei Wan
- Medical College of Soochow University, Suzhou, China
| | - Jie Li
- Medical College of Soochow University, Suzhou, China
| | - Jinjing Pan
- Medical College of Soochow University, Suzhou, China
| | - Ping Wang
- Medical College of Soochow University, Suzhou, China
| | - Junlan Qiu
- Medical College of Soochow University, Suzhou, China.,Department of Oncology and Hematology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Zengli Zhang
- Medical College of Soochow University, Suzhou, China
| | - Bingyan Li
- Medical College of Soochow University, Suzhou, China
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Deng M, Peng L, Li J, Liu X, Xia X, Li G. PPP1R14B Is a Prognostic and Immunological Biomarker in Pan-Cancer. Front Genet 2021; 12:763561. [PMID: 34858479 PMCID: PMC8631915 DOI: 10.3389/fgene.2021.763561] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/18/2021] [Indexed: 12/24/2022] Open
Abstract
Recent studies have shown that PPP1R14B was highly expressed in tumor tissues and patients with high expression of PPP1R14B had poor survival rates. However, the function and mechanisms of PPP1R14B in tumor progression remain ill defined. There was also lack of pan-cancer evidence for the relationship between PPP1R14B and various tumor types based on abundant clinical data. We used the TCGA project and GEO databases to perform pan-cancer analysis of PPP1R14B, including expression differences, correlations between expression levels and survival, genetic alteration, immune infiltration, and relevant cellular pathways, to investigate the functions and potential mechanisms of PPP1R14B in the pathogenesis or clinical prognosis of different cancers. Herein, we found that PPP1R14B was involved in the prognosis of pan-cancer and closely related to immune infiltration. Increased PPP1R14B expression correlated with poor prognosis and increased immune infiltration levels in myeloid-derived suppressor cells (MDSCs). Our studies suggest that PPP1R14B can be used as a prognostic biomarker for pan-cancer. Our findings may provide an antitumor strategy targeting PPP1R14B, including manipulation of tumor cell growth or the tumor microenvironment, especially myeloid-derived suppressor cell infiltration.
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Affiliation(s)
- Mingxia Deng
- Biomedical Translational Research Institute, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Long Peng
- Department of Cardiovascular Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiamin Li
- Department of General Surgery, Dongguan Tungwah Hospital, Dongguan, China
| | - Xiong Liu
- Biomedical Translational Research Institute, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Xichun Xia
- Biomedical Translational Research Institute, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Guangqiang Li
- Biomedical Translational Research Institute, The First Affiliated Hospital, Jinan University, Guangzhou, China
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Zhang J, Liu W, Feng S, Zhong B. The possible role of SRMS in colorectal cancer by bioinformatics analysis. World J Surg Oncol 2021; 19:326. [PMID: 34781983 PMCID: PMC8594183 DOI: 10.1186/s12957-021-02431-y] [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: 04/13/2021] [Accepted: 10/24/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) is a non-receptor tyrosine kinase that has been found to be overexpressed in various tumors. However, the role of SRMS in colorectal cancer (CRC) has not been well established. METHODS We evaluated the expression levels of SRMS in CRC using GEPIA, Oncomine, and HPA datasets. Survival information and gene expression data of CRC were obtained from The Cancer Genome Atlas (TCGA). Then, the association between SRMS and clinicopathological features was analyzed using UALCAN dataset. LinkedOmics was used to determine co-expression and functional networks associated with SRMS. Besides, we used TISIDB to assess the correlation between SRMS and immune signatures, including tumor-infiltrating immune cells and immunomodulators. Lastly, protein-protein interaction network (PPI) was established and the function enrichment analysis of the SRMS-associated immunomodulators and immune cell marker genes were performed using the STRING portal. RESULTS Compared to normal colorectal tissues, SRMS was found to be overexpressed in CRC tissues, which was correlated with a poor prognosis. In colon adenocarcinoma (COAD), the expression levels of SRMS are significantly correlated with pathological stages and nodal metastasis status. Functional network analysis suggested that SRMS regulates intermediate filament-based processes, protein autophosphorylation, translational initiation, and elongation signaling through pathways involving ribosomes, proteasomes, oxidative phosphorylation, and DNA replication. In addition, SRMS expression was correlated with infiltrating levels of CD4+ T cells, CD56dim, MEM B, Neutrophils, Th2, Th17, and Act DC. The gene ontology (GO) analysis of SRMS-associated immunomodulators and immune cell marker genes showed that they were mainly enriched in the immune microenvironment molecule-related signals. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of these genes indicated that they are involved in multiple cancer-related pathways. CONCLUSIONS SRMS is a promising prognostic biomarker and potential therapeutic target for CRC patients. In particular, SRMS regulates CRC progression by modulating cytokine-cytokine receptor interaction, chemokines, IL-17, and intestinal immune networks for IgA production signaling pathways among others. However, more studies are needed to validate these findings.
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Affiliation(s)
- Jie Zhang
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Kaifu District, Changsha, 410008, China
| | - Weidong Liu
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Kaifu District, Changsha, 410008, China
| | - Sisi Feng
- Department of Essential Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Baiyun Zhong
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Kaifu District, Changsha, 410008, China.
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El-Arabey AA, Abdalla M. GATA3 as a regulator for naughty cancer-associated fibroblasts in the microenvironment of high-grade serous ovarian cancer. Hum Cell 2021; 34:1934-1936. [PMID: 34432264 DOI: 10.1007/s13577-021-00598-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 08/17/2021] [Indexed: 12/20/2022]
Affiliation(s)
- Amr Ahmed El-Arabey
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
| | - Mohnad Abdalla
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Cultural West Road, Jinan, Shandong Province, 250012, People's Republic of China
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48
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Luo X, Xu J, Yu J, Yi P. Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer. Front Immunol 2021; 12:692360. [PMID: 34248988 PMCID: PMC8261131 DOI: 10.3389/fimmu.2021.692360] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/02/2021] [Indexed: 12/21/2022] Open
Abstract
Reciprocal signaling between immune cells and ovarian cancer cells in the tumor microenvironment can alter immune responses and regulate disease progression. These signaling events are regulated by multiple factors, including genetic and epigenetic alterations in both the ovarian cancer cells and immune cells, as well as cytokine pathways. Multiple immune cell types are recruited to the ovarian cancer tumor microenvironment, and new insights about the complexity of their interactions have emerged in recent years. The growing understanding of immune cell function in the ovarian cancer tumor microenvironment has important implications for biomarker discovery and therapeutic development. This review aims to describe the factors that shape the phenotypes of immune cells in the tumor microenvironment of ovarian cancer and how these changes impact disease progression and therapy.
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Affiliation(s)
- Xin Luo
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States.,Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Ping Yi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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49
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Yuan X, Liu K, Li Y, Zhang AZ, Wang XL, Jiang CH, Liang WH, Zhang HJ, Pang LJ, Li M, Yang L, Qi Y, Zheng Q, Li F, Hu JM. HPV16 infection promotes an M2 macrophage phenotype to promote the invasion and metastasis of esophageal squamous cell carcinoma. Clin Transl Oncol 2021; 23:2382-2393. [PMID: 34075547 DOI: 10.1007/s12094-021-02642-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 05/07/2021] [Indexed: 12/30/2022]
Abstract
OBJECTIVES High-risk human papillomavirus (HR-HPV) is an important risk factor for esophageal cancer. Macrophages constitute a crucial immune medium for regulating HPV-related tumors; however, the specific regulatory mechanisms remain unknown. Therefore, the purpose of our current study was to investigate the mechanism by which HPV16E6 regulates macrophages to promote the invasion and metastasis of esophageal cancer. METHODS HPV16E6 infection was detected by polymerase chain reaction. Immunohistochemistry was used to verify the distribution of tumor-associated macrophages (TAMs) and MMP-9 expression in esophageal squamous cell carcinoma tissues (ESCCs), and cancer adjacent normal tissues (CANs) from Kazakh patients. ESCC cells were transfected with a plasmid over-expressing HPV16E6 and non-contact cocultured with macrophages. RESULTS The infection rate of HPV16E6 in Kazakh ESCCs was clearly higher than that in CANs (P < 0.05). The density of CD163-positive TAMs was significantly positively correlated with HPV16E6 infection in ESCCs (P < 0.05). After coculturing macrophages and EC9706 cells transfected with the HPV16E6 plasmid, the phenotype of macrophages transformed into M2 macrophages. The migration and invasion ability of ESCC cells were higher in the HPV16E6-transfected and coculture group than in the HPV16E6 empty vector-transfected and non-cocultured HPV16E6-transfected groups (all P < 0.05). The density of M2-like TAMs in ESCCs was positively correlated with the level of MMP-9 expression. MMP-9 expression in the HPV16E6-ESCC coculture macrophages group was substantially higher than that in controls (all P < 0.05). CONCLUSIONS HPV16 infection mediates tumor-associated macrophages to promote ESCC invasion and migration.
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Affiliation(s)
- X Yuan
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - K Liu
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - Y Li
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - A Z Zhang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - X L Wang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - C H Jiang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - W H Liang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - H J Zhang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - L J Pang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - M Li
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - L Yang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - Y Qi
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China
| | - Q Zheng
- 69245 Military Hospital, Urumqi, Xinjiang, 831500, China
| | - F Li
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China.,Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 10020, China
| | - J M Hu
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases (Ministry of Education), The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi , Xinjiang , 832000, China.
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50
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El-Arabey AA, Abdalla M, Abd-Allah AR. Ovarian cancer immunotherapy of NF-κB may have a dark side. Hum Cell 2021; 34:1019-1020. [PMID: 33515361 DOI: 10.1007/s13577-021-00490-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 01/14/2023]
Affiliation(s)
- Amr Ahmed El-Arabey
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt.
| | - Mohnad Abdalla
- Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 Cultural West Road, Jinan, 250012, Shandong Province, People's Republic of China
| | - Adel Rashad Abd-Allah
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
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