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Sharen G, Meng H, Zhang L, Liu K, Wang Y, Zhao D. LncRNA XIST enhances gastric cancer cell function by regulating STAT3/PD-L1 axis as a competing endogenous RNA for miR-124. Am J Cancer Res 2025; 15:1597-1613. [PMID: 40371130 PMCID: PMC12070116 DOI: 10.62347/jbhh9597] [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: 09/24/2024] [Accepted: 01/02/2025] [Indexed: 05/16/2025] Open
Abstract
OBJECTIVE To investigate the role and underlying mechanisms of the long non-coding RNA (lncRNA) X inactive-specific transcript (XIST) in gastric cancer (GC). METHODS Real-time quantitative PCR (RT-qPCR), CCK-8, colony formation, flow cytometry, Transwell, and scratch assays were used to evaluate the biological effects of XIST and miR-124 in GC cells. Bioinformatics analysis and dual-luciferase reporter (DLR) assays identified interactions between XIST, miR-124, and STAT3. Western blotting and RT-qPCR assessed changes in downstream targets, while a xenograft tumor model evaluated the in vivo effects of XIST knockdown. RESULTS XIST was significantly upregulated, and miR-124 was downregulated in GC tissues and cell lines, with the strongest effects observed in MGC803 cells. Knockdown of XIST or overexpression of miR-124 suppressed GC cell proliferation, colony formation, migration, invasion, and promoted apoptosis, effects that were reversed by miR-124 inhibitors. Bioinformatics and DLR assays confirmed that XIST directly targeted miR-124 and regulated STAT3 expression. XIST knockdown increased miR-124 levels, reducing STAT3, PD-1, PD-L1, N-cadherin, and MMP9 expression, while elevating E-cadherin levels; these effects were reversed by miR-124 inhibitors. Additionally, sh-STAT3 mitigated the pro-tumorigenic effects of pcDNA-XIST, confirming the regulatory relationship. In vivo, XIST knockdown suppressed tumor growth by increasing miR-124 expression. CONCLUSION XIST promotes STAT3 expression by competitively binding to miR-124, thereby promoting GC progression. Targeting the XIST/miR-124/STAT3 axis may represent a potential therapeutic strategy for GC.
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Affiliation(s)
- Gaowa Sharen
- Department of Pathology, The Affiliated Hospital of Inner Mongolia Medical UniversityHohhot, Inner Mongolia, P. R. China
- Department of Pathological Anatomy, College of Basic Medicine of Inner Mongolia Medical UniversityHohhot, Inner Mongolia, P. R. China
| | - Haoyu Meng
- The Second Affiliated Hospital of Inner Mongolia Medical UniversityHohhot, Inner Mongolia, P. R. China
- Inner Mongolia Baogang HospitalBaotou, Inner Mongolia, P. R. China
| | - Lei Zhang
- Department of General Surgery, The Affiliated Hospital of Inner Mongolia Medical UniversityHohhot, Inner Mongolia, P. R. China
| | - Kejian Liu
- Department of General Surgery, The Affiliated Hospital of Inner Mongolia Medical UniversityHohhot, Inner Mongolia, P. R. China
| | - Yu Wang
- Department of General Surgery, The Affiliated Hospital of Inner Mongolia Medical UniversityHohhot, Inner Mongolia, P. R. China
| | - Defang Zhao
- Department of General Surgery, The Affiliated Hospital of Inner Mongolia Medical UniversityHohhot, Inner Mongolia, P. R. China
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Luo D, Liu Y, Lu Z, Huang L. Targeted therapy and immunotherapy for gastric cancer: rational strategies, novel advancements, challenges, and future perspectives. Mol Med 2025; 31:52. [PMID: 39923010 PMCID: PMC11806620 DOI: 10.1186/s10020-025-01075-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: 07/16/2024] [Accepted: 01/10/2025] [Indexed: 02/10/2025] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors worldwide, and its treatment has been a focus of medical research. Herein we systematically review the current status of and advancements in targeted therapy and immunotherapy for GC, which have emerged as important treatment strategies in recent years with great potential, and summarize the efficacy and safety of such treatments. Targeted therapies against key targets in GC, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), have shown remarkable therapeutic efficacies by inhibiting tumor progression and/or blood supply. In particular, markable breakthroughs have been made in HER2-targeting drugs for HER2-positive GC patients. To address intrinsic and acquired resistances to HER2-targeting drugs, novel therapeutic agents including bispecific antibodies and antibody-drug conjugates (ADC) targeting HER2 have been developed. Immunotherapy enhances the recognition and elimination of cancer cells by activating body anticancer immune system. Programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies are the most commonly used immunotherapeutic agents and have been used with some success in GC treatment. Innovative immunotherapy modalities, including adoptive immune cell therapy, tumor vaccines, and non-specific immunomodulators therapy, and oncolytic viruses have shown promise in early-stage clinical trials for GC. Clinical trials have supported that targeted therapy and immunotherapy can significantly improve the survival and quality of life of GC patients. However, the effects of such therapies need to be further improved and more personalized, with advancement in researches on tumor immune microenvironment. Further studies remain needed to address the issues of drug resistance and adverse events pertaining to such therapies for GC. The combined application of such therapies and individualized treatment strategies should be further explored with novel drugs developed, to provide more effective treatments for GC patients.
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Affiliation(s)
- Dong Luo
- Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China
- Center of Structural Heart Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yunmei Liu
- School of Cultural Heritage and Information Management, Shanghai University, Shanghai, 200444, China.
| | - Zhengmao Lu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
| | - Lei Huang
- Department of Gastroenterology, National Clinical Research Center for Digestive Diseases, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
- National Key Laboratory of Immunity and Inflammation, Changhai Clinical Research Unit, The First Affiliated Hospital of Naval Medical University/Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
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Nishiyama M, Miki Y, Tanaka H, Yoshii M, Kuroda K, Kasashima H, Fukuoka T, Tamura T, Shibutani M, Toyokawa T, Lee S, Maeda K. Immunological Analysis of Prognostic Factors in Conversion Surgery Cases for Gastric Cancer. J Surg Res 2025; 306:533-542. [PMID: 39889314 DOI: 10.1016/j.jss.2024.12.053] [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: 06/03/2024] [Revised: 12/04/2024] [Accepted: 12/30/2024] [Indexed: 02/02/2025]
Abstract
INTRODUCTION In order to clarify the optimal strategy regarding conversion surgery (CS) for gastric cancer (GC) patients, we focused on clinicopathological findings, including immunological factors, related to the favorable prognosis in patients with stage IV GC who underwent CS. MATERIALS AND METHODS A total of 25 patients with Stage IV GC who underwent induction chemotherapy (IC) and CS at our hospital between 2010 and 2021 were enrolled in this study. Biopsy specimens before IC and surgical specimens were collected. Immunohistochemical staining was performed using programmed death-ligand 1 (PD-L1) antibody, translationally controlled tumor protein (TCTP) antibody, and CD20 antibody. Prognostic factors were investigated using clinicopathological factors as well as immunological factors such as PD-L1, TCTP, and CD20 expression. RESULTS cN0, ycStage1-2, R0-1 surgery, D2 lymph node dissection, ypN0, and ypStage1-2 were significantly associated with favorable overall survival. Among patients who underwent R0/1 surgery, only histological type was a significant prognostic factor for recurrence-free survival. Low PD-L1 expression before IC and high TCTP expression after IC were significantly associated with favorable recurrence-free survival. CONCLUSIONS In addition to clinical factors, high TCTP expression after IC was identified as a significant favorable prognostic factor, which could help in identifying candidates for CS in the future.
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Affiliation(s)
- Masaki Nishiyama
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yuichiro Miki
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
| | | | - Mami Yoshii
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kenji Kuroda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Kasashima
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Tatsunari Fukuoka
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Tatsuro Tamura
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masatsune Shibutani
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Toyokawa
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shigeru Lee
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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Hu M, Zhang Y, Zhang P, Liu K, Zhang M, Li L, Yu Z, Zhang X, Zhang W, Xu Y. Targeting APE1: Advancements in the Diagnosis and Treatment of Tumors. Protein Pept Lett 2025; 32:18-33. [PMID: 39648425 DOI: 10.2174/0109298665338519241114103223] [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: 07/11/2024] [Revised: 10/07/2024] [Accepted: 10/16/2024] [Indexed: 12/10/2024]
Abstract
With the emergence of the precision medicine era, targeting specific proteins has emerged as a pivotal breakthrough in tumor diagnosis and treatment. Apurinic/apyrimidinic Endonuclease 1 (APE1) is a multifunctional protein that plays a crucial role in DNA repair and cellular redox regulation. This article comprehensively explores the fundamental mechanisms of APE1 as a multifunctional enzyme in biology, with particular emphasis on its potential significance in disease diagnosis and strategies for tumor treatment. Firstly, this article meticulously analyzes the intricate biological functions of APE1 at a molecular level, establishing a solid theoretical foundation for subsequent research endeavors. In terms of diagnostic applications, the presence of APE1 can be detected in patient serum samples, biopsy tissues, and through cellular in situ testing. The precise detection methods enable changes in APE1 levels to serve as reliable biomarkers for predicting tumor occurrence, progression, and patient prognosis. Moreover, this article focuses on elucidating the potential role of APE1 in tumor treatment by exploring various inhibitors, including nucleic acid-based inhibitors and small molecule drug inhibitors categories, and revealing their unique advantages in disrupting DNA repair function and modulating oxidative-reduction activity. Finally, the article provides an outlook on future research directions for APE1 while acknowledging major technical difficulties and clinical challenges that need to be overcome despite its immense potential as a target for tumor therapy.
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Affiliation(s)
- Minghui Hu
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Yingyu Zhang
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Pin Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Kangbo Liu
- Henan Institute for Drug and Medical Device Inspection (Henan Vaccine Issuance Center), Zhengzhou, 450018, China
| | - Mengxin Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Lifeng Li
- Henan International Joint Laboratory for Prevention and Treatment of Pediatric Disease, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Zhidan Yu
- Henan International Joint Laboratory for Prevention and Treatment of Pediatric Disease, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Xianwei Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Wancun Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
- Henan International Joint Laboratory for Prevention and Treatment of Pediatric Disease, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Ying Xu
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
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Lee SM, Oh H. Association of PD-L1 positivity with Epstein Barr virus infection and microsatellite instability in gastric carcinomas with lymphoid stroma. Sci Rep 2024; 14:30932. [PMID: 39730741 DOI: 10.1038/s41598-024-81764-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 11/28/2024] [Indexed: 12/29/2024] Open
Abstract
Gastric carcinoma with lymphoid stroma (GCLS) is characterized by dense intra-and peritumoral lymphocytic infiltration and a high rate of Epstein Barr Virus (EBV) infection, suggesting being a promising candidate for immunotherapy. We investigated correlations between PD-L1 expression and clinicopathologic factors, including EBV positivity and microsatellite instability (MSI) status in GCLSs. The study included resected 214 GCLSs and 300 gastric adenocarcinomas (GACs) for control. Epstein Barr Virus encoding region in situ hybridization (EBER ISH), immunohistochemistry for PD-L1 and HER2, dual-colored in situ hybridization for HER2, and MSI analysis were performed. EBV positivity was found in 181 (85%) of 214 GCLSs. MSI analysis demonstrated that 0.6% of EBV + GCLSs and 54.5% of EBV-GCLSs were MSI-high compared to 7% of EBV-GACs. Approximately 3% and 3.9% of HER2 amplifications were found in EBV- and EBV + GCLSs compared to 13% of EBV-GACs. PD-L1 expression with ≥ 1, ≥ 5, and ≥ 10 combined positive scores (CPS) were observed in 81.8%, 70.2%, and 55.3% of EBV + GCLSs. PD-L1 expression with ≥ 10 CPS was observed in 21.2% of EBV-GCLSs, predominantly in MSI-H tumors (85.7%). EBV positivity and MSI are associated with PD-L1 positivity rates in patients with GCLS who may respond better to PD-1/PD-L1 inhibitors but not anti-HER2 inhibitors.
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Affiliation(s)
- Sun Mi Lee
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 W. 11th street, Indianapolis, IN, 46202, USA.
- Department of Pathology, Jeju National University Hospital, Jeju-si, South Korea.
| | - Hyunjoo Oh
- Department of Internal Medicine, Jeju National University Hospital, Jeju-si, South Korea
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Mangiapane G, D'Agostino VG, Tell G. Emerging roles of bases modifications and DNA repair proteins in onco-miRNA processing: novel insights in cancer biology. Cancer Gene Ther 2024; 31:1765-1772. [PMID: 39322751 DOI: 10.1038/s41417-024-00836-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/13/2024] [Accepted: 09/16/2024] [Indexed: 09/27/2024]
Abstract
Onco-microRNAs (onco-miRNAs) are essential players in the post-transcriptional regulation of gene expression and exert a crucial role in tumorigenesis. Novel information about the epitranscriptomic modifications, involved in onco-miRNAs biogenesis, and in the modulation of their interplay with regulatory factors responsible for their processing and sorting are emerging. In this review, we highlight the contribution of bases modifications, sequence motifs, and secondary structures on miRNAs processing and sorting. We focus on several modes of action of RNA binding proteins (RBPs) on these processes. Moreover, we describe the new emerging scenario that shows an unexpected though essential role of selected DNA repair proteins in actively participating in these events, highlighting the original intervention represented by the non-canonical functions of Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), a central player in Base Excision Repair (BER) pathway of DNA lesions. Taking advantage of this new knowledge will help in prospecting new cancer diagnostic and therapeutic strategies.
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Affiliation(s)
- Giovanna Mangiapane
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DMED), University of Udine, Udine, Italy
| | - Vito Giuseppe D'Agostino
- Laboratory of Biotechnology and Nanomedicine, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Gianluca Tell
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DMED), University of Udine, Udine, Italy.
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Wang J, Han X, Yu H, Xie G. AND Logic-Gate-Based Dual-Locking Probe System for the Sensitive Detection of microRNA and APE1. Anal Chem 2024; 96:9570-9575. [PMID: 38822787 DOI: 10.1021/acs.analchem.4c01080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2024]
Abstract
MicroRNA (miRNA) and apurinic/apyrimidinic endonuclease 1 (APE1) have been reported to be closely associated with cancers, making them potential crucial biomarkers and therapeutic targets. However, focusing on the detection of a single target is not conducive to the diagnosis and prognosis assessment of diseases. In this study, an AND logic-gate-based dual-locking hairpin-mediated catalytic hairpin assembly (DL-CHA) was developed for sensitive and specific detection of microRNA and APE1. By addition of a lock to each of the hairpins, with APE1 and microRNA serving as keys, fluorescence signals could only be detected in the presence of simultaneous stimulation by APE1 and miRNA-224. This indicated that the biosensor could operate as an AND logic gate. DL-CHA exhibited advantages such as a low background, rapid response, and high logic capability. Therefore, the biosensor serves as a novel approach to cancer diagnosis with significant potential applications.
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Affiliation(s)
- Jiani Wang
- Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
- Sichuan Nursing Vocational College,Chengdu 610100, People's Republic of China
| | - Xiaole Han
- Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Hongyan Yu
- Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
| | - Guoming Xie
- Key Laboratory of Clinical Laboratory Diagnostics (Chinese Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, People's Republic of China
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Rahmat JN, Liu J, Chen T, Li Z, Zhang Y. Engineered biological nanoparticles as nanotherapeutics for tumor immunomodulation. Chem Soc Rev 2024; 53:5862-5903. [PMID: 38716589 DOI: 10.1039/d3cs00602f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
Biological nanoparticles, or bionanoparticles, are small molecules manufactured in living systems with complex production and assembly machinery. The products of the assembly systems can be further engineered to generate functionalities for specific purposes. These bionanoparticles have demonstrated advantages such as immune system evasion, minimal toxicity, biocompatibility, and biological clearance. Hence, bionanoparticles are considered the new paradigm in nanoscience research for fabricating safe and effective nanoformulations for therapeutic purposes. Harnessing the power of the immune system to recognize and eradicate malignancies is a viable strategy to achieve better therapeutic outcomes with long-term protection from disease recurrence. However, cancerous tissues have evolved to become invisible to immune recognition and to transform the tumor microenvironment into an immunosuppressive dwelling, thwarting the immune defense systems and creating a hospitable atmosphere for cancer growth and progression. Thus, it is pertinent that efforts in fabricating nanoformulations for immunomodulation are mindful of the tumor-induced immune aberrations that could render cancer nanotherapy inoperable. This review systematically categorizes the immunosuppression mechanisms, the regulatory immunosuppressive cellular players, and critical suppressive molecules currently targeted as breakthrough therapies in the clinic. Finally, this review will summarize the engineering strategies for affording immune moderating functions to bionanoparticles that tip the tumor microenvironment (TME) balance toward cancer elimination, a field still in the nascent stage.
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Affiliation(s)
- Juwita N Rahmat
- Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore 117585, Singapore
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
| | - Jiayi Liu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Taili Chen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - ZhiHong Li
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Yong Zhang
- Department of Biomedical Engineering, College of Engineering, The City University of Hong Kong, Hong Kong SAR.
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Xu M, Ren T, Deng J, Yang J, Lu T, Xi H, Yuan L, Zhang W, Zhou J. Correlation of CT parameters and PD-L1 expression status in gastric cancer. Abdom Radiol (NY) 2024; 49:1320-1329. [PMID: 38436699 DOI: 10.1007/s00261-024-04200-3] [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] [Received: 10/26/2023] [Revised: 01/02/2024] [Accepted: 01/12/2024] [Indexed: 03/05/2024]
Abstract
OBJECTIVE We aimed to explore the correlation between routine computed tomography (CT) imaging features and programmed cell death ligand-1(PD-L1) expression status in gastric cancer and evaluate the predictive value of imaging parameters for this immunotherapy biomarker. MATERIALS AND METHODS Patients with gastric adenocarcinoma who underwent abdominal CT three-stage enhanced scan and PD-L1 immunohistochemical testing before treatment were retrospectively examined. All diagnoses were confirmed through pathology. According to the expression status of PD-L1, they were divided into the positive (CPS ≥ 5) or negative group (CPS < 5). Baseline CT imaging features were collected. Diagnostic performances of the different variables were evaluated using receiver operating characteristic (ROC) curve. RESULTS In total, 67 patients (17 women and 50 men; mean age: 59.55 ± 10.22 years) with gastric adenocarcinoma were included in the study. The overall stages, probability of maximum lymph node short diameter > 1 cm and peak of lesion enhancement occurring in the arterial phase were statistically significant between the two groups (p < 0.05). Moreover, the arterial enhancement fraction (AEF) was significantly higher in the positive group than that in the negative group (p < 0.05), and ROC curve analysis showed that the AEF exhibited a high evaluation efficacy (area under the curve [AUC] = 0.724 [95% confidence interval (CI): 0.602-0.826]). The combined parameters had the best diagnostic efficacy (AUC = 0.825 [95%CI: 0.716-0.933]), sensitivity (75.00%), and specificity (81.40%). CONCLUSIONS These findings confirm a correlation between CT imaging features and PD-L1 expression status in gastric cancer, and AEF may help evaluate high PD-L1 expression and select patients suitable for immunotherapy.
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Affiliation(s)
- Min Xu
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou, 730030, China
- Second Clinical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Tiezhu Ren
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou, 730030, China
- Second Clinical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Juan Deng
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou, 730030, China
- Second Clinical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Jingjing Yang
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou, 730030, China
- Second Clinical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Ting Lu
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou, 730030, China
- Second Clinical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Huaze Xi
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou, 730030, China
- Second Clinical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Long Yuan
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou, 730030, China
- Second Clinical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Wenjuan Zhang
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou, 730030, China.
- Second Clinical School, Lanzhou University, Lanzhou, China.
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China.
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China.
| | - Junlin Zhou
- Department of Radiology, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou, 730030, China.
- Second Clinical School, Lanzhou University, Lanzhou, China.
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China.
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China.
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Zhang X, Zhang Y, Zhang Q, Lu M, Chen Y, Zhang X, Zhang P. Role of AT-rich interaction domain 1A in gastric cancer immunotherapy: Preclinical and clinical perspectives. J Cell Mol Med 2024; 28:e18063. [PMID: 38041544 PMCID: PMC10902580 DOI: 10.1111/jcmm.18063] [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: 09/13/2023] [Revised: 10/31/2023] [Accepted: 11/14/2023] [Indexed: 12/03/2023] Open
Abstract
The application of immune checkpoint inhibitor (ICI) using monoclonal antibodies has brought about a profound transformation in the clinical outcomes for patients grappling with advanced gastric cancer (GC). Nonetheless, despite these achievements, the quest for effective functional biomarkers for ICI therapy remains constrained. Recent research endeavours have shed light on the critical involvement of modified epigenetic regulators in the pathogenesis of gastric tumorigenesis, thus providing a glimpse into potential biomarkers. Among these regulatory factors, AT-rich interaction domain 1A (ARID1A), a pivotal constituent of the switch/sucrose non-fermentable (SWI/SNF) complex, has emerged as a promising candidate. Investigations have unveiled the pivotal role of ARID1A in bridging the gap between genome instability and the reconfiguration of the tumour immune microenvironment, culminating in an enhanced response to ICI within the landscape of gastric cancer treatment. This all-encompassing review aims to dissect the potential of ARID1A as a valuable biomarker for immunotherapeutic approaches in gastric cancer, drawing from insights garnered from both preclinical experimentation and clinical observations.
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Affiliation(s)
- Xuemei Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Youzhi Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- School of PharmacyHubei University of Science and TechnologyXianningChina
| | - Qiaoyun Zhang
- School of PharmacyHubei University of Science and TechnologyXianningChina
| | - Mengyao Lu
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yuan Chen
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoyu Zhang
- Division of Gastrointestinal Surgery, Department of General Surgery, Huai'an Second People's Hospitalthe Affiliated Huai'an Hospital of Xuzhou Medical UniversityHuaianChina
| | - Peng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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11
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Liu KH, Yang W, Tian HP. Relationships between intravoxel incoherent motion parameters and expressions of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) in patients with cervical cancer. Clin Radiol 2024; 79:e264-e272. [PMID: 37926648 DOI: 10.1016/j.crad.2023.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 06/27/2023] [Accepted: 10/05/2023] [Indexed: 11/07/2023]
Abstract
AIM To determine the associations of intravoxel incoherent motion (IVIM) parameters with expression of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), and evaluate the performance of the combined model established based on IVIM and clinicopathological parameters in predicting PD-L1and PD-1 status of cervical cancer (CC) patients. MATERIALS AND METHODS Seventy-eight consecutive CC patients were enrolled prospectively and underwent magnetic resonance imaging (MRI) including IVIM. IVIM quantitative parameters were measured, compared, and correlated with PD-L1 and PD-1 expression. Independent factors related to PD-L1 and PD-1 positivity were identified and were used to establish the combined model. The combined model's diagnostic performance was evaluated using the receiver operating characteristic (ROC) analysis. The Shapley additive explanation (SHAP) algorithm was used to explain the contribution of each parameter in the combined model. RESULTS The real diffusion coefficient (D) value was significantly lower in the PD-L1-positive group than in the PD-L1-negative group (0.64 ± 0.12 versus 0.72 ± 0.11, p=0.021). The PD-1-positive and PD-1-negative groups showed similar trends (0.63 ± 0.13 versus 0.73 ± 0.09, p=0.003). Parametrial invasion, lymph node status, pathological grade, FIGO (International Federation of Gynecology and Obstetrics) staging, and D values were independently associated with PD-L1 and PD-1expression. A combined model incorporating these parameters showed good discrimination with the sensitivity, specificity of 90.9%, 82.6% for PD-L1, and 93.5%, 72% for PD-1. According to the SHAP value, FIGO staging and pathological grade were the most influential features of the prediction model. CONCLUSION IVIM parameters were found to correlate with PD-L1 and PD-1 expression. The combined model, incorporating parametrial invasion, lymph node status, pathological grade, FIGO staging, and D values, showed good discrimination in predicting PD-L1 and PD-1 status, providing the basis for CC immunotherapy.
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Affiliation(s)
- K H Liu
- College of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, PR China
| | - W Yang
- Department of Radiology, General Hospital of Ningxia Medical University, 804 Shengli Road, Yinchuan, 750004, PR China.
| | - H P Tian
- Department of Pathology, General Hospital of Ningxia Medical University, Yinchuan, PR China
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12
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Akkanapally V, Bai XF, Basu S. Therapeutic Immunomodulation in Gastric Cancer. Cancers (Basel) 2024; 16:560. [PMID: 38339311 PMCID: PMC10854796 DOI: 10.3390/cancers16030560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/21/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Gastric carcinoma, being one of the most prevalent types of solid tumors, has emerged as the third leading cause of death worldwide. The symptoms of gastric cancer (GC) are typically complex, which makes early detection challenging. Immune checkpoint inhibition has become the new standard targeted therapy for advanced or metastatic GC. It is currently being explored in various combinations, both with and without chemotherapy, across multiple therapies in clinical trials. Immunotherapy can stimulate immune responses in GC patients, leading to the destruction of cancer cells. Compared with traditional therapies, immunotherapy has shown strong effectiveness with tolerable toxicity levels. Hence, this innovative approach to the treatment of advanced GC has gained popularity. In this review, we have outlined the recent advancements in immunotherapy for advanced GC, including immune checkpoint inhibitors, cancer vaccines, vascular endothelial growth factor-A inhibitors, and chimeric antigen receptor T-cell therapy. Our current emphasis is on examining the immunotherapies presently employed in clinical settings, addressing the existing challenges associated with these therapeutic approaches, and exploring promising strategies to overcome their limitations.
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Affiliation(s)
- Venu Akkanapally
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (V.A.); (X.-F.B.)
| | - Xue-Feng Bai
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (V.A.); (X.-F.B.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Sujit Basu
- Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; (V.A.); (X.-F.B.)
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
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13
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Siqueira PB, de Sousa Rodrigues MM, de Amorim ÍSS, da Silva TG, da Silva Oliveira M, Rodrigues JA, de Souza da Fonseca A, Mencalha AL. The APE1/REF-1 and the hallmarks of cancer. Mol Biol Rep 2024; 51:47. [PMID: 38165468 DOI: 10.1007/s11033-023-08946-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 10/10/2023] [Indexed: 01/03/2024]
Abstract
APE1/REF-1 (apurinic/apyrimidinic endonuclease 1 / redox factor-1) is a protein with two domains, with endonuclease function and redox activity. Its main activity described is acting in DNA repair by base excision repair (BER) pathway, which restores DNA damage caused by oxidation, alkylation, and single-strand breaks. In contrast, the APE1 redox domain is responsible for regulating transcription factors, such as AP-1 (activating protein-1), NF-κB (Nuclear Factor kappa B), HIF-1α (Hypoxia-inducible factor 1-alpha), and STAT3 (Signal Transducers and Activators of Transcription 3). These factors are involved in physiological cellular processes, such as cell growth, inflammation, and angiogenesis, as well as in cancer. In human malignant tumors, APE1 overexpression is associated with lung, colon, ovaries, prostate, and breast cancer progression, more aggressive tumor phenotypes, and worse prognosis. In this review, we explore APE1 and its domain's role in cancer development processes, highlighting the role of APE1 in the hallmarks of cancer. We reviewed original articles and reviews from Pubmed related to APE1 and cancer and found that both domains of APE1/REF-1, but mainly its redox activity, are essential to cancer cells. This protein is often overexpressed in cancer, and its expression and activity are correlated to processes such as proliferation, invasion, inflammation, angiogenesis, and resistance to cell death. Therefore, APE1 participates in essential processes of cancer development. Then, the activity of APE1/REF-1 in these hallmarks suggests that targeting this protein could be a good therapeutic approach.
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Affiliation(s)
- Priscyanne Barreto Siqueira
- Departamento de Biofísica e Biometria, Laboratório de Biologia do Câncer, Universidade do Estado do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro, Brasil.
| | - Mariana Moreno de Sousa Rodrigues
- Departamento de Biofísica e Biometria, Laboratório de Biologia do Câncer, Universidade do Estado do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro, Brasil.
| | - Ísis Salviano Soares de Amorim
- Departamento de Biofísica e Biometria, Laboratório de Biologia do Câncer, Universidade do Estado do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro, Brasil
- Laboratório de Alimentos Funcionais, Universidade Federal do Rio de Janeiro, Instituto de Nutrição Josué de Castro, Rio de Janeiro, Brasil
| | - Thayssa Gomes da Silva
- Departamento de Biofísica e Biometria, Laboratório de Biofotônica, Universidade do Estado do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro, Brasil
| | - Matheus da Silva Oliveira
- Departamento de Biofísica e Biometria, Laboratório de Biologia do Câncer, Universidade do Estado do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro, Brasil
| | - Juliana Alves Rodrigues
- Departamento de Biofísica e Biometria, Laboratório de Biologia do Câncer, Universidade do Estado do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro, Brasil
| | - Adenilson de Souza da Fonseca
- Departamento de Biofísica e Biometria, Laboratório de Biofotônica, Universidade do Estado do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro, Brasil
| | - Andre Luiz Mencalha
- Departamento de Biofísica e Biometria, Laboratório de Biologia do Câncer, Universidade do Estado do Rio de Janeiro, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro, Brasil
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14
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Han Z, Wang N, Qiao Q, He X, Wang N. Association of PD-L1 Expression with Clinicopathologic Characters in Gastric Cancer: A Comprehensive Meta-analysis. Curr Med Chem 2024; 31:3198-3216. [PMID: 37921182 DOI: 10.2174/0109298673263784230922060257] [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: 05/24/2023] [Revised: 07/18/2023] [Accepted: 08/16/2023] [Indexed: 11/04/2023]
Abstract
PURPOSE The expression level of programmed death ligand-1(PD-L1) in patients with gastric cancer is the key to determining the use of immune drugs. The relationship between PD-L1 expression level and clinical characteristics is worth exploring. METHODS By setting the search terms correlated to PD-L1 and gastric cancer, a nearly comprehensive search was carried out in four major databases, and the deadline for searching was September 1, 2022. The retrieved documents were further screened by strict inclusion and exclusion criteria after removing the duplication. Next, the quality of the included studies was evaluated with the Newcastle-Ottawa Scale (NOS) scale. Finally, the STATA15.1 software was used to process data and draw plots, and the odds ratios (ORs) were adopted to assess the pooled effect size. RESULTS A total of 85 works of literature were included in this study through screening strictly, and detailed data were extracted after evaluating the quality of the literature. The process of analysis was conducted in the whole population, Asia-Africa population, European and American population, and Asian population with CPS≥1, amd all found that the expression of PD-L1 in gastric cancer was correlated with age, tumor size, EBV infection, Her-2 expression and microsatellite status. However, the subgroup of the region also found some differences in Asian and Western regions, which was interesting and worth studying further. The included research of this study did not have significant publish bias. CONCLUSION After careful analysis, this study found that age (>60 years), tumor size (>5cm), EBV infection (+), Her-2 expression (+), microsatellite status (MSI), and mismatch repair status (dMMR) were risk factors for positive expression of PD-L1 in gastric cancer.
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Affiliation(s)
- Zhuo Han
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Qing Qiao
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Air Force Medical University, Xi'an, 710038, China
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15
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Sharma S, Rana R, Prakash P, Ganguly NK. Drug target therapy and emerging clinical relevance of exosomes in meningeal tumors. Mol Cell Biochem 2024; 479:127-170. [PMID: 37016182 PMCID: PMC10072821 DOI: 10.1007/s11010-023-04715-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 03/17/2023] [Indexed: 04/06/2023]
Abstract
Meningioma is the most common central nervous system (CNS) tumor. In recent decades, several efforts have been made to eradicate this disease. Surgery and radiotherapy remain the standard treatment options for these tumors. Drug therapy comes to play its role when both surgery and radiotherapy fail to treat the tumor. This mostly happens when the tumors are close to vital brain structures and are nonbenign. Although a wide variety of chemotherapeutic drugs and molecular targeted drugs such as tyrosine kinase inhibitors, alkylating agents, endocrine drugs, interferon, and targeted molecular pathway inhibitors have been studied, the roles of numerous drugs remain unexplored. Recent interest is growing toward studying and engineering exosomes for the treatment of different types of cancer including meningioma. The latest studies have shown the involvement of exosomes in the theragnostic of various cancers such as the lung and pancreas in the form of biomarkers, drug delivery vehicles, and vaccines. Proper attention to this new emerging technology can be a boon in finding the consistent treatment of meningioma.
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Affiliation(s)
- Swati Sharma
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060 India
| | - Rashmi Rana
- Department of Research, Sir Ganga Ram Hospital, New Delhi, 110060 India
| | - Prem Prakash
- Department of Molecular Medicine, Jamia Hamdard, New Delhi, 110062 India
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16
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Zou Y, Wang J, Zhang J, Guo Q, Song Z, Tang H. Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer. Oncol Lett 2024; 27:20. [PMID: 38058467 PMCID: PMC10696633 DOI: 10.3892/ol.2023.14153] [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: 05/11/2023] [Accepted: 10/11/2023] [Indexed: 12/08/2023] Open
Abstract
The programmed death receptor 1/programmed death receptor ligand 1 axis (PD-1/PD-L1) is involved in tumor immune escape and is a potential prognostic biomarker and anti-tumor immunotherapy target in patients with gastric cancer (GC). However, the results of studies obtained in recent years have been inconsistent. The present study aimed to determine the possible predictive significance of PD-L1 in conjunction with three proteins linked with PD-L1 regulation in patients with primary GC. In the present study, the PD-L1, human epidermal growth factor receptor 2 (HER2), cluster of differentiation (CD)133 and microphage-associated CD68 expression levels were identified by multiplexed immunohistochemistry and assessed by automated pathological analysis system in 93 GC tumors and neighboring normal tissues arrayed on the same tissue microarray. All four proteins were statistically analyzed in relation to the clinicopathological characteristics. The expression levels of HER2, CD133 and CD68 were considerably higher in cancer tissues compared with neighboring normal tissues (P<0.05), however, the reverse trend was detected for PD-L1 expression (P=0.0577), particularly in tumor nest (TN; P<0.05). There was no significant correlation between the HER2 and CD133 expression levels and clinicopathological factors. However, significant relationships were found between PD-L1 expression and the TNM stage, pathological differentiation and survival status of patients (P<0.05). Moreover, survival time was prolonged in individuals with elevated PD-L1 expression in TN and GC tissues, but no significant correlation was identified (P=0.0881). The CD68 expression level in tumor stroma, but not in TN, was significantly correlated with poor pathological differentiation in patients with GC (P<0.05). However, PD-L1+CD68+ macrophages were strongly related to lower tumor size (diameter <5 cm), early TNM stage (stage I+II), good pathological differentiation and overall survival in TN (P<0.05). In conclusion, PD-L1+CD68+ macrophage infiltration in TN might be a potential indicator of prognosis in patients with primary GC and merits further investigation.
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Affiliation(s)
- Yunlian Zou
- Department of Hematology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
| | - Jinli Wang
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Jinping Zhang
- Department of Hematology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
| | - Qiang Guo
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Zhengji Song
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
| | - Hui Tang
- Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan 650504, P.R. China
- Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, P.R. China
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17
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Koerner AS, Moy RH, Ryeom SW, Yoon SS. The Present and Future of Neoadjuvant and Adjuvant Therapy for Locally Advanced Gastric Cancer. Cancers (Basel) 2023; 15:4114. [PMID: 37627142 PMCID: PMC10452310 DOI: 10.3390/cancers15164114] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Gastric cancer is a highly prevalent and lethal disease worldwide. Given the insidious nature of the presenting symptoms, patients are frequently diagnosed with advanced, unresectable disease. However, many patients will present with locally advanced gastric cancer (LAGC), which is often defined as the primary tumor extending beyond the muscularis propria (cT3-T4) or having nodal metastases (cN+) disease and without distant metastases (cM0). LAGC is typically treated with surgical resection and perioperative chemotherapy. The treatment of LAGC remains a challenge, given the heterogeneity of this disease, and the optimal multimodal treatment regimen may be different for different LAGC subtypes. However, many promising treatments are on the horizon based on knowledge of molecular subtypes and key biomarkers of LAGC, such as microsatellite instability, HER2, Claudin 18.2, FGFR2, and PD-L1. This review will expand upon the discussion of current standard neoadjuvant and adjuvant therapies for LAGC and explore the ongoing and future clinical trials for novel therapies, with information obtained from searches in PubMed and ClinicalTrials.gov.
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Affiliation(s)
- Anna S. Koerner
- Division of Surgical Oncology, Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Ryan H. Moy
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Sandra W. Ryeom
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Sam S. Yoon
- Division of Surgical Oncology, Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
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18
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Malfatti MC, Bellina A, Antoniali G, Tell G. Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons. Cells 2023; 12:1895. [PMID: 37508559 PMCID: PMC10378182 DOI: 10.3390/cells12141895] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/06/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.
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Affiliation(s)
- Matilde Clarissa Malfatti
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Alessia Bellina
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Giulia Antoniali
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Gianluca Tell
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
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19
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Ridgley LA, Falci Finardi N, Gengenbach BB, Opdensteinen P, Croxford Z, Ma JKC, Bodman-Smith M, Buyel JF, Teh AYH. Killer to cure: Expression and production costs calculation of tobacco plant-made cancer-immune checkpoint inhibitors. PLANT BIOTECHNOLOGY JOURNAL 2023; 21:1254-1269. [PMID: 36811226 DOI: 10.1111/pbi.14034] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 01/18/2023] [Accepted: 02/11/2023] [Indexed: 05/27/2023]
Abstract
Immune checkpoint inhibitors (ICIs) have achieved huge clinical success. However, many still have limited response rates, and are prohibitively costly. There is a need for effective and affordable ICIs, as well as local manufacturing capacity to improve accessibility, especially to low-to-middle income countries (LMICs). Here, we have successfully expressed three key ICIs (anti-PD-1 Nivolumab, anti-NKG2A Monalizumab, and anti-LAG-3 Relatimab) transiently in Nicotiana benthamiana and Nicotiana tabacum plants. The ICIs were expressed with a combination of different Fc regions and glycosylation profiles. They were characterized in terms of protein accumulation levels, target cell binding, binding to human neonatal Fc receptors (hFcRn), human complement component C1q (hC1q) and various Fcγ receptors, as well as protein recovery during purification at 100 mg- and kg-scale. It was found that all ICIs bound to the expected target cells. Furthermore, the recovery during purification, as well as Fcγ receptor binding, can be altered depending on the Fc region used and the glycosylation profiles. This opens the possibility of using these two parameters to fine-tune the ICIs for desired effector functions. A scenario-based production cost model was also generated based on two production scenarios in hypothetical high- and low-income countries. We have shown that the product accumulation and recovery of plant production platforms were as competitive as mammalian cell-based platforms. This highlights the potential of plants to deliver ICIs that are more affordable and accessible to a widespread market, including LMICs.
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Affiliation(s)
- Laura A Ridgley
- Institute for Infection and Immunity, St. George's, University of London, London, UK
- Institute for Cancer Vaccines and Immunotherapy, London, UK
| | - Nicole Falci Finardi
- Institute for Infection and Immunity, St. George's, University of London, London, UK
| | | | - Patrick Opdensteinen
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany
| | - Zack Croxford
- Institute for Infection and Immunity, St. George's, University of London, London, UK
| | - Julian K-C Ma
- Institute for Infection and Immunity, St. George's, University of London, London, UK
| | - Mark Bodman-Smith
- Institute for Infection and Immunity, St. George's, University of London, London, UK
- Institute for Cancer Vaccines and Immunotherapy, London, UK
| | - Johannes F Buyel
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany
- Institute for Molecular Biotechnology, RWTH Aachen University, Aachen, Germany
- Department of Biotechnology (DBT), Institute of Bioprocess Science and Engineering (IBSE), University of Natural Resources and Life Sciences, Vienna (BOKU), Vienna, Austria
| | - Audrey Y-H Teh
- Institute for Infection and Immunity, St. George's, University of London, London, UK
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Lu P, Cao X, Zheng J, Sun Y, Tang Z, Zhao M. Visualization and Comparison of the Level of Apurinic/Apyrimidinic Endonuclease 1 in Live Normal/Cancerous and Neuron Cells with a Fluorescent Nanoprobe. Molecules 2023; 28:molecules28093935. [PMID: 37175345 PMCID: PMC10179877 DOI: 10.3390/molecules28093935] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/24/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
As a major apurinic/apyrimidinic endonuclease and a redox signaling protein in human cells, APE1 plays a crucial role in cellular function and survival. The relationship between alterations of APE1 expression and subcellular localization and the initiation, development and treatment of various cancers has received extensive attention. However, comparing the in-vivo activity of APE1 in normal and cancerous breast live cells remains challenging due to the low efficiency of commonly used liposome transfection methods in delivering DNA substrate probes into human normal breast epithelial cells (MCF-10A). In this work, we develop a DNA/RNA hybrid-based small magnetic fluorescent nanoprobe (25 ± 3 nm) that can be taken up by various live cells under magnetic transfection. The D0/R-nanoprobe demonstrates an outstanding specificity toward APE1 and strong resistance to the cellular background interference. Using this nanoprobe, we are not only able to visualize the intracellular activity of APE1 in breast ductal carcinoma (MCF-7) live cells, but also demonstrate the APE1 activity in MCF-10A live cells for the first time. The method is then extended to observe the changes in APE1 levels in highly metabolically active neuroendocrine cells under normal conditions and severe attacks by reactive oxygen species in real-time. The fluorescent nanoprobe provides a useful tool for studying the dynamic changes of intracellular APE1 in normal or cancerous live cells. It also displays the potential for visible and controllable release of miRNA drugs within live cells for therapeutic purposes.
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Affiliation(s)
- Peng Lu
- Beijing National Laboratory for Molecular Sciences and MOE Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Xiangjian Cao
- Beijing National Laboratory for Molecular Sciences and MOE Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Jinghui Zheng
- Beijing National Laboratory for Molecular Sciences and MOE Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Ying Sun
- Beijing National Laboratory for Molecular Sciences and MOE Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Ziyu Tang
- Beijing National Laboratory for Molecular Sciences and MOE Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Meiping Zhao
- Beijing National Laboratory for Molecular Sciences and MOE Key Laboratory of Bioorganic Chemistry and Molecular Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
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21
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Chitapanarux T, Gumrai P, Kongkarnka S, Wannasai K, Lertprasertsuke N. Programmed death-ligand 1 expression and overall survival in Thai patients with gastric cancer. Sci Rep 2023; 13:7241. [PMID: 37142693 PMCID: PMC10160126 DOI: 10.1038/s41598-023-34434-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/29/2023] [Indexed: 05/06/2023] Open
Abstract
Programmed death-ligand 1 (PD-L1) expression has now been implicated in gastric cancer (GC). This study was conducted to determine the impact of clinicopathological characteristics on PD-L1 expression and its association with survival in GC patients receiving standard-of-care. In total, 268 GC patients receiving upfront surgery were enrolled at Chiang Mai University Hospital. PD-L1 expression was assayed by immunohistochemistry staining using the Dako 22C3 pharmDx. The rates of PD-L1 positivity by combined positive score (CPS) at a cutoff value of 1 and 5 were 22% and 7%. PD-L1 positivity was significantly higher in patients younger than 55 than those older than 55 (32.6% vs. 16.5%, p = 0.003; 11.6% vs. 4.4%, p = 0.027). PD-L1 positivity was observed more frequently in GC with metastases than without (25.2% vs. 17.1%, p = 0.112; 7.2% vs. 6.7%, p = 0.673). Patients with PD-L1 positive had a significantly shorter median overall survival than those with PD-L1 negative (32.7 vs. 41.6 months, p = 0.042, 27.6 vs. 40.8 months, p = 0.038). In conclusion, PD-L1 expression has been associated with young age, short survival, and metastases, although unrelated to the tumor stage. For GC patients, PD-L1 testing is recommended, especially among young patients with metastases.
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Affiliation(s)
- Taned Chitapanarux
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Northern Thai Research Group of Radiation Oncology (NTRG-RO), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
| | - Pawut Gumrai
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Sarawut Kongkarnka
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Komson Wannasai
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nirush Lertprasertsuke
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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22
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Shimozaki K, Nakayama I, Hirota T, Yamaguchi K. Current Strategy to Treat Immunogenic Gastrointestinal Cancers: Perspectives for a New Era. Cells 2023; 12:1049. [PMID: 37048122 PMCID: PMC10093684 DOI: 10.3390/cells12071049] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/15/2023] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
Since pembrolizumab, an anti-programmed death-1 (PD-1) antibody, showed a dramatic response to immunogenic cancers with microsatellite instability-high (MSI-H) and/or deficient mismatch repair (dMMR) in the pilot clinical trial KEYNOTE-016, subsequent studies have confirmed durable responses of anti-PD-1 inhibitors for MSI-H/dMMR solid tumors. As immunotherapy is described as a "game changer," the therapeutic landscape for MSI-H/dMMR solid tumors including gastrointestinal cancers has changed considerably in the last decade. An MSI/MMR status has been established as the predictive biomarker for immune checkpoint blockades, playing an indispensable role in the clinical practice of patients with MSI-H/dMMR tumors. Immunotherapy is also now investigated for locally advanced MSI-H/dMMR gastrointestinal cancers. Despite this great success, a few populations with MSI-H/dMMR gastrointestinal cancers do not respond to immunotherapy, possibly due to the existence of intrinsic or acquired resistance mechanisms. Clarifying the underlying mechanisms of resistance remains a future task, whereas attempts to overcome resistance and improve the efficacy of immunotherapy are currently ongoing. Herein, we review recent clinical trials with special attention to MSI-H/dMMR gastrointestinal cancers together with basic/translational findings, which provide their rationale, and discuss perspectives for the further therapeutic development of treatment in this field.
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Affiliation(s)
- Keitaro Shimozaki
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Izuma Nakayama
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan
| | - Toru Hirota
- Department of Experimental Pathology, Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastrointestinal Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo 135-0063, Japan
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23
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Zhao H, Ding Y, Zhang L. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis. Open Med (Wars) 2023; 18:20220620. [PMID: 36820068 PMCID: PMC9938643 DOI: 10.1515/med-2022-0620] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 02/16/2023] Open
Abstract
Gastric cancer (GC) is a common cancer worldwide with high mortality. Sirtuin 1 (SIRT1) and apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) are abnormally expressed in GC cells and related to p53, which is involved in ferroptosis. Thus, we explore the mechanism via which SIRT1, APE1, and p53 impact ferroptosis in GC cells. Specifically, GC cells were transfected with small-interfering RNA for SIRT1 (SiSIRT1) or small-interfering RNA for APE1 (SiAPE1) or with short-hairpin RNA for p53, and the cell viability, Fe2+, malondialdehyde (MDA), and glutathione (GSH) contents were detected by cell counting kit-8 assay and enzyme-linked immunosorbent assay. Western blot, immunofluorescence, and quantitative real-time polymerase chain reaction were conducted to quantify SIRT1, APE1, p53, solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) levels in GC cells. Silencing of SIRT1 decreased viability, GSH content, and expressions of GPX4 and SLC7A11, while increased Fe2+, MDA content, and p53 expression in GC cells. Such aforementioned effects were reversed by APE1 overexpression. Also, SiAPE1 generated the same effects as SiSIRT1 on the above aspects, which was offset by p53 silencing. In short, SIRT1/APE1 promotes the growth of GC cells by targeting p53 to inhibit ferroptosis.
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Affiliation(s)
- Huijin Zhao
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, China
| | - Yuanyi Ding
- Department of No. 2 General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, China
| | - Lan Zhang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, China
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24
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Si L, Pan X, He K, Sun L, Wang Y, Xu X, Lu J. PD‐L1
expression by different scoring methods and different cutoff values and correlation with clinicopathological characteristics in gastric cancer: A retrospective study. PRECISION MEDICAL SCIENCES 2023. [DOI: 10.1002/prm2.12094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- Lixiang Si
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - XiaoHua Pan
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Kang He
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Ling Sun
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Yajing Wang
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Xinyu Xu
- The Department of Pathology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
| | - Jianwei Lu
- The Department of Oncology The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research Nanjing China
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25
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Keshavjee SH, Moy RH, Reiner SL, Ryeom SW, Yoon SS. Gastric Cancer and the Immune System: The Key to Improving Outcomes? Cancers (Basel) 2022; 14:cancers14235940. [PMID: 36497422 PMCID: PMC9739366 DOI: 10.3390/cancers14235940] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022] Open
Abstract
Gastric adenocarcinoma is by far the most common form of gastric cancer (GC) and is a highly lethal form of cancer arising from the gastric epithelium. GC is an important area of focus of the medical community, given its often late-stage of diagnosis and associated high mortality rate. While surgery and chemotherapy remain the primary treatments, attention has been drawn to the use of immunologic therapies, which have shown promise in the treatment of other malignancies. The role for immune-based therapies has become clearer as we obtain a greater understanding of the role of the immune system in gastric cancer formation and growth. A variety treatment to augment the immune system are under evaluation in clinical trials, and these include immune checkpoint inhibitors, antibody-drug conjugates, and immune cell-based therapies. Here, we review the immune landscape and immune-based therapies for GC.
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Affiliation(s)
- Sara H. Keshavjee
- Division of Surgical Oncology, Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Ryan H. Moy
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Steven L. Reiner
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Sandra W. Ryeom
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Division of Surgical Sciences, Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Sam S. Yoon
- Division of Surgical Oncology, Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
- Correspondence:
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26
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Explore and Analyze the Composition and Characteristics of Intestinal Microbiota between Gastric Cancer Patients and Healthy People. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5834293. [PMID: 36118097 PMCID: PMC9477631 DOI: 10.1155/2022/5834293] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/30/2022] [Accepted: 07/20/2022] [Indexed: 11/25/2022]
Abstract
Gastric cancer is one of the most common malignant tumors in the world. As the intestine is downstream of the digestive tract, the occurrence of gastric cancer may have a certain significant impact on it. Therefore, it is particularly important to find out the intestinal bacteria closely related to gastric cancer, to identify the specific flora related to gastric cancer, and to maintain the stability of the core structure of intestinal microecology in patients with gastric cancer. Based on this, the fecal samples of gastric cancer patients and healthy people were collected, and the diversity and composition of intestinal flora in patients with gastric cancer were analyzed by 16S rRNA sequencing technology. We found that there was no significant difference in the diversity and abundance of intestinal flora between gastric cancer patients and healthy people. The relative abundance of Faecalibacterium, Bifidobacterium, and Subdoligranulum in the intestinal tract of patients with gastric cancer was significantly lower than that in healthy people, while the relative abundance of Enterococcus, Streptococcus, and Bacteroides was increased. This study found that there were six kinds of intestinal microflora closely related to the occurrence of gastric cancer, which provided a theoretical basis for further exploring the pathogenesis of gastric cancer.
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27
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Deng Y, Tan Y, Zhang Y, Zhang L, Zhang C, Ke Y, Su X. Design of Uracil-Modified DNA Nanotubes for Targeted Drug Release via DNA-Modifying Enzyme Reactions. ACS APPLIED MATERIALS & INTERFACES 2022; 14:34470-34479. [PMID: 35867518 DOI: 10.1021/acsami.2c09488] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
DNA nanostructure-based responsive drug delivery has become an increasingly potent method in cancer therapy. However, a variety of important cancer biomarkers have not been explored in searching of new and efficient targeted delivery systems. Uracil degradation glycosylase and human apurinic/apyrimidinic endonuclease are significantly more active in cancer cells. Here, we developed uracil-modified DNA nanotubes that can deliver drugs to tumor cells through an enzyme-induced disassembly process. Although the reaction of these enzymes on their natural DNA substrates has been established, their reactivity on self-assembled nanostructures of nucleic acids is not well understood. We leveraged molecular dynamic simulation based on coarse-grained model to forecast the enzyme reactivity on different DNA designs. The experimental data are highly consistent with the simulation results. It is the first example of molecule simulation being used to guide the design of enzyme-responsive DNA nano-delivery systems. Importantly, we found that the efficiency of drug release from the nanotubes can be regulated by tuning the positions of uracil modification. The DNA nanotubes equipped with cancer-specific aptamer AS1411 are used to deliver doxorubicin to tumor-bearing mice not only effectively inhibiting tumor growth but also protecting major organs from drug-caused damage. We believe that this work provides new knowledge on and insights into future design of enzyme-responsive DNA-based nanocarriers for drug delivery.
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Affiliation(s)
- Yingnan Deng
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Yuanhang Tan
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - YingWei Zhang
- College of Material Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Linghao Zhang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - ChunYi Zhang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
| | - Yonggang Ke
- Wallance H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, United States
| | - Xin Su
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
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28
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Relationship between Yes-Associated Protein 1 and Prognosis of Digestive System Neoplasm: Quantitative Analysis and Bioinformatics Analysis Based on 4023 Patients. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3798694. [PMID: 35911146 PMCID: PMC9325623 DOI: 10.1155/2022/3798694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/07/2022] [Accepted: 06/14/2022] [Indexed: 11/18/2022]
Abstract
Yes-associated protein 1 (YAP1) is involved in the development of a variety of malignancies. However, the prognosis of malignant digestive tumors with YAP1 expression is still controversial. This study searched 31 articles with 36 data sets of 4023 patients to explore the role of YAP1 expression on the prognosis of digestive malignant tumors by searching the PubMed, Embase, Web of Science, Google Scholar, and Cochrane Library databases. Specifically, relevant cancer expression matrix data were downloaded from The Cancer Genome Atlas (TCGA) database. In this meta-analysis, quantitative analysis showed that the overexpression of YAP1 was not conducive to OS (1.62, 95% CI (1.38, 1.90), P=0.001) and DFS (1.59, 95% CI (1.31, 1.93), P=0.001) in patients with digestive malignant tumors. In addition, TCGA database analysis showed that YAP1 was overexpressed in gastric cancer, cholangiocarcinoma, and colorectal cancer. Survival analysis showed that the patients with high expression of YAP1 in pancreatic cancer have a poor OS (MST: 394 vs. 691 days, P < 0.0001) and DFS (MST: 371 vs. 542 days, P=0.026) prognosis. YAP1 may be a molecular marker that effectively predicts the survival of malignant digestive tumors, especially pancreatic cancer, and is a potential therapeutic target for malignant digestive tumors.
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29
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Ribeiro HSC, Menezes JN, da Costa WL, F. de Jesus VH, Diniz AL, Godoy AL, de Farias IC, Torres SM, Neotti T, Mello CAL, Begnami MDFS, Dias‐Neto E, Riechelmann RP, Fernandez Coimbra FJ. PD‐L1 expression in gastric and gastroesophageal junction cancer patients treated with perioperative chemotherapy. J Surg Oncol 2022; 126:150-160. [DOI: 10.1002/jso.26929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 04/27/2022] [Accepted: 05/08/2022] [Indexed: 01/27/2023]
Affiliation(s)
- Héber S. C. Ribeiro
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | | | - Wilson L. da Costa
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
- Department of Medicine/Epidemiology and Population Sciences Baylor College of Medicine Houston Texas USA
| | | | - Alessandro L. Diniz
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | - André L. Godoy
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | | | - Silvio M. Torres
- Department of Abdominal Surgery A. C. Camargo Cancer Center São Paulo Brazil
| | - Tatiane Neotti
- Department of Pathology A. C. Camargo Cancer Center São Paulo Brazil
| | - Celso A. L. Mello
- Department of Clinical Oncology A. C. Camargo Cancer Center São Paulo Brazil
| | | | - Emmanuel Dias‐Neto
- Laboratory of Medical Genomics A. C. Camargo Cancer Center São Paulo Brazil
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30
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Lu X, Li D, Luo Z, Duan Y. A dual-functional fluorescent biosensor based on enzyme-involved catalytic hairpin assembly for the detection of APE1 and miRNA-21. Analyst 2022; 147:2834-2842. [PMID: 35621039 DOI: 10.1039/d2an00108j] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Both apurinic/apyrimidinic endonuclease 1 (APE1) and microRNA-21 (miRNA-21) have been reported to be related to tumors, enabling them to be the biomarkers of several cancers. This has led to the development of various biosensors to detect APE1 or miRNA-21. However, biosensors that focus on single target detection are subject to low accuracy. In this work, a fluorescent biosensor based on enzyme-involved catalytic hairpin assembly (CHA) for the detection of APE1 and miRNA-21 was developed, aimed at improving the accuracy of early-phase diagnosis of cancers. Two hairpin structured DNA probes (H1 and H2) were utilized to concatenate the enzyme-assisted circuit and CHA circuit in the system. The stem of H1 with a blunt end was modified with an AP site, while H2 was modified with 6-FAM at the 5' terminal and Dabcyl at the 3' terminal. In the presence of APE1, H1 was cleaved from the AP site to expose the toehold sequence. Then, miRNA-21 bound with the toehold sequence to initiate the CHA reaction between H1 and H2. The assembled product of CHA triggered the 6-FAM of H2 at a distance from Dabcyl, which recovered the fluorescence signal. It is worth noting that only under the co-stimulation of APE1 and miRNA-21 can the fluorescence signal be detected, indicating that the biosensor could work as an AND logic gate. The proposed dual-functional biosensor achieved a limit of detection (LOD) of 0.016 U mL-1 for APE1 and 0.25 nM for miRNA-21 and APE1, respectively, and also exhibits good selectivity and stability for the two biomarkers. Thus, the biosensor has great potential to be applied as a new platform for cancer diagnosis.
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Affiliation(s)
- Xiaoyong Lu
- Research Center of Analytical Instrumentation, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, P.R. China.
| | - Dan Li
- Research Center of Analytical Instrumentation, Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710069, Shaanxi, P.R. China.
| | - Zewei Luo
- Research Center of Analytical Instrumentation, Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710069, Shaanxi, P.R. China.
| | - Yixiang Duan
- Research Center of Analytical Instrumentation, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, P.R. China.
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31
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Janjigian YY, Van Cutsem E, Muro K, Wainberg Z, Al-Batran SE, Hyung WJ, Molena D, Marcovitz M, Ruscica D, Robbins SH, Negro A, Tabernero J. MATTERHORN: phase III study of durvalumab plus FLOT chemotherapy in resectable gastric/gastroesophageal junction cancer. Future Oncol 2022; 18:2465-2473. [PMID: 35535555 DOI: 10.2217/fon-2022-0093] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Standard-of-care for resectable gastric/gastroesophageal junction cancer includes surgery and neoadjuvant-adjuvant 5-fluorouracil-leucovorin-oxaliplatin-docetaxel (FLOT) chemotherapy. Early-phase clinical studies support further clinical development of the immune checkpoint inhibitor (ICI); durvalumab, an anti-PD-L1 antibody, in patients with gastric/gastroesophageal junction cancer. Accumulating evidence indicates that ICIs combined with FLOT chemotherapy improve clinical outcomes in patients with advanced or metastatic cancer. We describe the rationale for and the design of MATTERHORN, a randomized, double-blind, placebo-controlled, phase III study investigating the efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy followed by adjuvant durvalumab monotherapy in patients with resectable gastric/gastroesophageal junction cancer. The planned sample size is 900 patients, the primary end point is event-free survival and safety and tolerability will be evaluated. Clinical trial registration: NCT04592913 (ClinicalTrials.gov).
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Affiliation(s)
- Yelena Y Janjigian
- Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Eric Van Cutsem
- Department of Gastroenterology/Digestive Oncology, University Hospitals Leuven & KU Leuven, Leuven, 3000, Belgium
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan
| | - Zev Wainberg
- Department of Gastrointestinal Medical Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90404, USA
| | - Salah-Eddin Al-Batran
- Institute of Clinical Cancer Research, Krankenhaus Nordwest, University Cancer Center, Frankfurt, 60488, Germany
| | - Woo Jin Hyung
- Department of Surgery, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Daniela Molena
- Esophageal Surgery Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | | | - Dario Ruscica
- Global Clinical Development, AstraZeneca, Cambridge, CB2 8PA, UK
| | - Scott H Robbins
- Global Clinical Development, AstraZeneca, Gaithersburg, MD 20878, USA
| | - Alejandra Negro
- Global Clinical Development, AstraZeneca, Gaithersburg, MD 20878, USA
| | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron Hospital Campus & Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, 08035, Spain
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Saleh RR, Scott JL, Meti N, Perlon D, Fazelzad R, Ocana A, Amir E. Prognostic Value of Programmed Death Ligand-1 Expression in Solid Tumors Irrespective of Immunotherapy Exposure: A Systematic Review and Meta-Analysis. Mol Diagn Ther 2022; 26:153-168. [PMID: 35106739 DOI: 10.1007/s40291-022-00576-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND The programmed cell death-1/programmed cell death ligand-1 (PD-L1) pathway, which plays a crucial role in cancer immune surveillance, is the target of several approved immunotherapeutic agents and is used as a predictive biomarker in some solid tumors. However, its use as a prognostic marker (i.e., regardless of therapy used) is not established clearly with available data demonstrating inconsistent prognostic impact of PD-L1 expression in solid tumors. METHODS We conducted a systematic literature search of electronic databases and identified publications exploring the effect of PD-L1 expression on overall survival and/or disease-free survival. Hazard ratios were pooled in a meta-analysis using generic inverse-variance and random-effects modeling. We used the Deeks method to explore subgroup differences based on disease site, stage of disease, and method of PD-L1 quantification. RESULTS One hundred and eighty-six studies met the inclusion criteria. Programmed cell death ligand-1 expression was associated with worse overall survival (hazard ratio 1.33, 95% confidence interval 1.26-1.39; p < 0.001). There was significant heterogeneity between disease sites (subgroup p = 0.002) with pancreatic, hepatocellular, and genitourinary cancers associated with the highest magnitude of adverse outcomes. Programmed cell death ligand-1 was also associated with worse overall disease-free survival (hazard ratio 1.19, 95% confidence interval 1.09-1.30; p < 0.001). Stage of disease did not significantly affect the results (subgroup p = 0.52), nor did the method of quantification via immunohistochemistry or messenger RNA (subgroup p = 0.70). CONCLUSIONS High expression of PD-L1 is associated with worse survival in solid tumors albeit with significant heterogeneity among tumor types. The effect is consistent in early-stage and metastatic disease and is not sensitive to method of PD-L1 quantification. These data can provide additional information for the counseling of patients with cancer about prognosis.
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Affiliation(s)
- Ramy R Saleh
- Department of Medical Oncology, McGill University, Montreal, QC, Canada
| | - Jordan L Scott
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada
| | - Nicholas Meti
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada
| | - Danielle Perlon
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada
| | - Rouhi Fazelzad
- Information Specialist, Library and Information Services, Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Alberto Ocana
- Hospital Clinico San Carlos and Instituto de Investigación Sanitaria San Carlos (IdISSC), and Centro Regional de Investigaciones Biomedicas (CRIB), Centro de Investigación Biomédica en Red Cáncerci (CIBERONC), Universidad Castilla La Mancha (UCLM), Madrid, Spain
| | - Eitan Amir
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada.
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Oliveira TT, Coutinho LG, de Oliveira LOA, Timoteo ARDS, Farias GC, Agnez-Lima LF. APE1/Ref-1 Role in Inflammation and Immune Response. Front Immunol 2022; 13:793096. [PMID: 35296074 PMCID: PMC8918667 DOI: 10.3389/fimmu.2022.793096] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 02/07/2022] [Indexed: 12/12/2022] Open
Abstract
Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional enzyme that is essential for maintaining cellular homeostasis. APE1 is the major apurinic/apyrimidinic endonuclease in the base excision repair pathway and acts as a redox-dependent regulator of several transcription factors, including NF-κB, AP-1, HIF-1α, and STAT3. These functions render APE1 vital to regulating cell signaling, senescence, and inflammatory pathways. In addition to regulating cytokine and chemokine expression through activation of redox sensitive transcription factors, APE1 participates in other critical processes in the immune response, including production of reactive oxygen species and class switch recombination. Furthermore, through participation in active chromatin demethylation, the repair function of APE1 also regulates transcription of some genes, including cytokines such as TNFα. The multiple functions of APE1 make it an essential regulator of the pathogenesis of several diseases, including cancer and neurological disorders. Therefore, APE1 inhibitors have therapeutic potential. APE1 is highly expressed in the central nervous system (CNS) and participates in tissue homeostasis, and its roles in neurodegenerative and neuroinflammatory diseases have been elucidated. This review discusses known roles of APE1 in innate and adaptive immunity, especially in the CNS, recent evidence of a role in the extracellular environment, and the therapeutic potential of APE1 inhibitors in infectious/immune diseases.
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Affiliation(s)
- Thais Teixeira Oliveira
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte (UFRN), Natal, Brazil
| | - Leonam Gomes Coutinho
- Instituto Federal de Educação, Ciência e Tecnologia do Rio Grande do Norte (IFRN), São Paulo do Potengi, Brazil
| | | | | | - Guilherme Cavalcanti Farias
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte (UFRN), Natal, Brazil
| | - Lucymara Fassarella Agnez-Lima
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte (UFRN), Natal, Brazil
- *Correspondence: Lucymara Fassarella Agnez-Lima,
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Optimising Multimodality Treatment of Resectable Oesophago-Gastric Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14030586. [PMID: 35158854 PMCID: PMC8833621 DOI: 10.3390/cancers14030586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/15/2022] [Accepted: 01/20/2022] [Indexed: 12/23/2022] Open
Abstract
Simple Summary Oesophageal (food pipe) and stomach cancers are amongst the hard-to-treat cancers that result in significant illness and deaths around the globe. Over the last few decades, there has been remarkable progress in the treatment of these cancers as a result of advances in diagnosis, surgical techniques, systemic therapy and radiotherapy. However, even if caught in the early stages, most patients with these cancers will unfortunately have their cancers come back, usually becoming widespread and difficult to treat. Therefore, optimising the early treatment strategy of these cancers is essential to improve the outcome and reduce the risk of recurrence. There are currently various geographically influenced standard of care management practices of early stomach and oesophageal cancers, ranging from using chemotherapy before and after surgery to the use of combined chemoradiotherapy before surgery and more recently the use of immunotherapy after surgery. However, it is not very clear if one strategy is significantly better than the others and there are some ongoing studies aiming to directly compare these treatment options. In addition, our understanding of the molecular and genetic features of these cancers can help improve our clinical practice and inform our choice of the best treatment strategy for the individual patient. Abstract Oesophago–gastric adenocarcinoma remains a leading cause of cancer-related morbidity and mortality worldwide. Although there has been an enormous progress in the multimodality management of resectable oesophago–gastric adenocarcinoma, most patients still develop a recurrent disease that eventually becomes resistant to systemic therapy. Currently, there is no global consensus on the optimal multimodality approach and there are variations in accepted standards of care, ranging from preoperative chemoradiation to perioperative chemotherapy and, more recently, adjuvant immune checkpoint inhibitors. Ongoing clinical trials are aimed to directly compare multimodal treatment options as well as the additional benefit of targeted therapies and immunotherapies. Furthermore, our understanding of the molecular and genetic features of oesophago–gastric cancer has improved significantly over the last decade and these data may help inform the best approach for the individual patient, utilising biomarker selection and precision medicine.
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Immunotherapy in Gastrointestinal Malignancies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1342:259-272. [PMID: 34972968 DOI: 10.1007/978-3-030-79308-1_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Gastrointestinal (GI) cancers represent a heterogeneous group of malignancies, each with a unique tumor biology that in turn affects response to treatment and subsequent prognosis. The interplay between tumor cells and the local immune microenvironment also varies within each GI malignancy and can portend prognosis and response to therapy. Treatment with immune checkpoint inhibitors has changed the treatment landscape of various solid tumors including (but not limited to) renal cell carcinoma, melanoma, and lung cancer. Advances in the understanding between the interplay between the immune system and tumors cells have led to the integration of immunotherapy as standard of care in various GI malignancies. For example, immunotherapy is now a mainstay of treatment for tumors harboring defects in DNA mismatch repair proteins and tumors harboring a high mutational load, regardless of primary site of origin. Data from recent clinical trials have led to the integration of immunotherapy as standard of care for a subset of gastroesophageal cancers and hepatocellular carcinoma. Here, we outline the current landscape of immunotherapy in GI malignancies and highlight ongoing clinical trials that will likely help to further our understanding of how and when to integrate immunotherapy into the treatment of various GI malignancies.
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Lee D, Oh S, Cho H, Yoo J, Lee G. OUP accepted manuscript. Nucleic Acids Res 2022; 50:2211-2222. [PMID: 35137198 PMCID: PMC8887469 DOI: 10.1093/nar/gkac043] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 12/20/2021] [Accepted: 01/13/2022] [Indexed: 11/13/2022] Open
Affiliation(s)
- Donghun Lee
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
- Single-Molecule Biology Laboratory, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
- Cell Mechanobiology Laboratory, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
| | - Sanghoon Oh
- Single-Molecule Biology Laboratory, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
| | - HyeokJin Cho
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
- Single-Molecule Biology Laboratory, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
- Cell Mechanobiology Laboratory, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
| | - Jungmin Yoo
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
- Single-Molecule Biology Laboratory, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
- Cell Mechanobiology Laboratory, Gwangju Institute of Science and Technology, Gwangju 61005, Korea
| | - Gwangrog Lee
- To whom correspondence should be addressed. Tel: +82 62 715 3558;
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Basile D, Simionato F, Calvetti L, Cappetta A, Pesavento A, Mongillo M, Roviello G, Rosati G, Rossi G, Aprile G. Comparing immunotherapies to other frequently used treatments of gastric cancer. Expert Rev Clin Pharmacol 2021; 14:1221-1232. [PMID: 34114518 DOI: 10.1080/17512433.2021.1938546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 06/01/2021] [Indexed: 12/07/2022]
Abstract
Introduction: Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option.Areas covered: A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled. In our short review, we offer the current available data regarding immunotherapies in gastric cancers, discuss potential limits of the reported trials, compare outcomes of checkpoints inhibitor to those of standard chemotherapy or other novel treatments, and present basic principles of immune surveillance and immune escape that may be embraced in the near future with novel drug combinations.Expert opinion: Gastric cancer patients may benefit from immunotherapy, both given alone in advanced lines and upfront in combination with chemotherapy. We believe that appropriate patients' and tumor's selection are crucial issues to maximize its potential efficacy. In addition, we think that assay standardization, biomarker agreement, and translational studies will improve the benefit-to-risk ratio of these agents in the clinical practice.
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Affiliation(s)
- Debora Basile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | | | - Lorenzo Calvetti
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | | | - Annalisa Pesavento
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
- Oncology Unit, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | - Marta Mongillo
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
- Oncology Unit, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | | | - Gerardo Rosati
- Medical Oncology, San Carlo General Hospital, Potenza, Italy
| | - Gemma Rossi
- Medical Oncology, San Carlo General Hospital, Potenza, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
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Panza S, Malivindi R, Caruso A, Russo U, Giordano F, Győrffy B, Gelsomino L, De Amicis F, Barone I, Conforti FL, Giordano C, Bonofiglio D, Catalano S, Andò S. Novel Insights into the Antagonistic Effects of Losartan against Angiotensin II/AGTR1 Signaling in Glioblastoma Cells. Cancers (Basel) 2021; 13:cancers13184555. [PMID: 34572782 PMCID: PMC8469998 DOI: 10.3390/cancers13184555] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/03/2021] [Accepted: 09/08/2021] [Indexed: 11/23/2022] Open
Abstract
Simple Summary Patients with high-grade glioma (HGG) such as glioblastoma (GBM) who undergo surgical resection with adjuvant therapy have a mean overall survival of 14.6 months and 100% of recurrence. Thus, these disappointing outcomes in terms of glioblastoma life expectancy require seeking novel pharmacological tools, including drug repurposing. In the present study, we identify a novel molecular mechanism through which Losartan antagonizes Angiotensin II (Ang II)/Angiotensin II type I receptor (AGTR1) signaling, overexpressed in GBM cells. For instance, we demonstrate how Losartan drastically inhibits the stimulatory effects of Ang II on aromatase activity and consequently reduces local estrogen production, sustaining cancer progression. Thus, it is reasonable to repurpose Losartan as an adjuvant pharmacological tool to be implemented prospectively in the novel therapeutic strategies adopted in GBM patients. Abstract New avenues for glioblastoma therapy are required due to the limited mortality benefit of the current treatments. The renin-angiotensin system (RAS) exhibits local actions and works as a paracrine system in different tissues and tumors, including glioma. The glioblastoma cell lines U-87 MG and T98G overexpresses Angiotensin II (Ang II)/Angiotensin II type I receptor (AGTR1) signaling, which enhances in vitro and in vivo local estrogen production through a direct up-regulation of the aromatase gene promoters p I.f and p I.4. In addition, Ang II/AGTR1 signaling transactivates estrogen receptor-α in a ligand-independent manner through mitogen-activated protein kinase (MAPK) activation. The higher aromatase mRNA expression in patients with glioblastoma was associated with the worst survival prognostic, according to The Cancer Genome Atlas (TCGA). An intrinsic immunosuppressive glioblastoma tumor milieu has been previously documented. We demonstrate how Ang II treatment in glioblastoma cells increases programmed death-ligand 1 (PD-L1) expression reversed by combined exposure to Losartan (LOS) in vitro and in vivo. Our findings highlight how LOS, in addition, antagonizes the previously documented neoangiogenetic, profibrotic, and immunosuppressive effects of Ang II and drastically inhibits its stimulatory effects on local estrogen production, sustaining glioblastoma cell growth. Thus, Losartan may represent an adjuvant pharmacological tool to be repurposed prospectively for glioblastoma treatment.
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Affiliation(s)
- Salvatore Panza
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende, CS, Italy
| | - Rocco Malivindi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
| | - Amanda Caruso
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende, CS, Italy
| | - Umberto Russo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary;
- Cancer Biomarker Research Group, Research Centre for Natural Sciences, 1117 Budapest, Hungary
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
| | - Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
| | - Francesca Luisa Conforti
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende, CS, Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende, CS, Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende, CS, Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy; (S.P.); (R.M.); (A.C.); (U.R.); (F.G.); (L.G.); (F.D.A.); (I.B.); (F.L.C.); (C.G.); (D.B.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende, CS, Italy
- Correspondence: ; Tel.: +39-0984-496201; Fax: +39-0984-496203
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Mixed and nonvaccine high risk HPV types are associated with higher mortality in Black women with cervical cancer. Sci Rep 2021; 11:14064. [PMID: 34234252 PMCID: PMC8263581 DOI: 10.1038/s41598-021-93485-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 06/24/2021] [Indexed: 12/26/2022] Open
Abstract
We studied the incidence of HPV genotypes in mostly Black women with cervical carcinoma and correlated histopathologic tumor characteristics, immune markers and clinical data with survival. Disease-free survival (DFS) and overall survival (OS) were recorded for 60 months post-diagnosis. Fifty four of the 60 (90%) patients were Black and 36 (60%) were < 55 years of age. Of the 40 patients with typeable HPV genotypes, 10 (25%) had 16/18 HPV genotypes, 30 (75%) had one of the non-16/18 HPV genotypes, and 20 (50%) had one of the 7 genotypes (35, 39, 51, 53, 56, 59 and 68) that are not included in the nonavalent vaccine. Mixed HPV infections (≥ 2 types) were found in 11/40 (27.5%) patients. Patients infected with non-16/18 genotypes, including the most common genotype, HPV 35, had significantly shorter DFS and OS. PD-L1 (p = 0.003), MMR expression (p = 0.01), clinical stage (p = 0.048), histologic grade (p = 0.015) and mixed HPV infection (p = 0.026) were independent predictors of DFS. A remarkably high proportion of cervical cancer cells in our patients expressed PD-L1 which opens the possibility of the use of immune checkpoint inhibitors to treat these cancers. Exclusion of the common HPV genotypes from the vaccine exacerbates mortality from cervical cancer in underserved Black patients.
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Zhang Y, Ding L, Ni Q, Tao R, Qin J. Transcription factor PAX4 facilitates gastric cancer progression through interacting with miR-27b-3p/Grb2 axis. Aging (Albany NY) 2021; 13:16786-16803. [PMID: 34162761 PMCID: PMC8266315 DOI: 10.18632/aging.203214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 05/24/2021] [Indexed: 12/26/2022]
Abstract
Gastric cancer (GC) is one of the most common aggressive cancers. The discovery of an effective biomarker is necessary for GC diagnosis. In this study, we confirmed that Paired box gene 4 (PAX4) is up-regulated in GC tissues and cells via quantitative real time polymerase chain reaction (qRT-PCR), western blot and immunohistochemical staining. It was also identified that PAX4 contributed to GC cell proliferation, migration and invasion through Cell Counting Kit-8, BrdU, flow cytometry assay, colony formation assay, transwell assays, and wound healing assay. miR-27b-3p was confirmed with the binding site with PAX4 using ChIP assay and served as a tumor suppressor that inhibiting GC cell growth and metastasis, and reversed the effect of PAX4. Bioinformatics prediction and dual luciferase assay results demonstrated that miR-27b-3p targeted Grb2, which could alter the function of miR-27b-3p. Furthermore, the transcriptional control of PAX4-regulated miR-27b-3p activated the Ras-ERK pathway. Taken together, the PAX4/miR-27b-3p/Grb2 loop is known to be involved in GC cell promotion, and can be seen as a promising target for GC therapy.
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Affiliation(s)
- Yan Zhang
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
| | - Li Ding
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
| | - Qingfeng Ni
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
| | - Ran Tao
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
| | - Jun Qin
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China
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Liu W, Chen H, Wang D. Protective role of astragaloside IV in gastric cancer through regulation of microRNA-195-5p-mediated PD-L1. Immunopharmacol Immunotoxicol 2021; 43:443-451. [PMID: 34124983 DOI: 10.1080/08923973.2021.1936013] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
AIM Astragaloside IV (AS-IV) was reported to exert anti-cancer function in many cancers, but its actions in gastric cancer (GC) remain unclear. In the present study, we tried to elaborate the underlying mechanism by which AS-IV regulated the epithelial-mesenchymal transition (EMT) and angiogenesis of GC cells. METHODS The expressions of hsa-miR-15b-5p, hsa-miR-15a-5p, hsa-miR-195-5p, hsa-miR-424-5p and hsa-miR-497-5p in GC tissues and adjacent normal tissues were predicted by TCGA database. SGC7901 or MGC803 cells were treated with AS-IV, or transfected with miR-195-5p inhibitor/mimic or pcDNA3.1-PD-L1 followed by detection of cell proliferation, EMT and angiogenesis. The target relation between miR-195-5p and PD-L1 was confirmed by dual luciferase reporter gene assay. RESULTS Elevated hsa-miR-15b-5p, hsa-miR-15a-5p and hsa-miR-424-5p expressions were found in GC tissues, while decreased hsa-miR-195-5p and hsa-miR-497-5p expressions were observed in GC tissues. AS-IV inhibits EMT and angiogenesis in GC. PD-L1 was a potential target of miR-195-5p. Down-regulation of miR-195-5p or elevated PD-L1 expression reverses the inhibitory effect of AS-IV on EMT and angiogenesis of GC cells. CONCLUSION The present study demonstrated that AS-IV inhibited EMT and angiogenesis in GC through upregulation of miR-195-5p, highlighting the potential therapeutic effect of AS-IV on GC via miR-195-5p-regulated PD-L1.
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Affiliation(s)
- Wei Liu
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital Central South University, Changsha, P.R. China
| | - Han Chen
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital Central South University, Changsha, P.R. China
| | - Dongsheng Wang
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital Central South University, Changsha, P.R. China
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Wang J, Lun L, Jiang X, Wang Y, Li X, Du G, Wang J. APE1 facilitates PD-L1-mediated progression of laryngeal and hypopharyngeal squamous cell carcinoma. Int Immunopharmacol 2021; 97:107675. [PMID: 33964809 DOI: 10.1016/j.intimp.2021.107675] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/18/2021] [Accepted: 04/11/2021] [Indexed: 02/06/2023]
Abstract
Laryngeal squamous cell carcinoma (LSCC) and hypopharyngeal squamous cell carcinoma (HSCC) seriously affect the life quality of patients. Nowadays, immunotherapy is widely used in the treatment of cancer. Tumor-infiltrating lymphocytes (TILs), programmed cell death 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1) play key roles in the immunotherapy of cancer. Moreover, study has reported that the upregulation of PD-L1 and apurinic/apyrimidinic endonuclase 1 (APE1) are associated with tumorigenesis and poor prognosis of gastric cancer. In the present study, the number of CD3+ T lymphocytes and the expressions of PD-1 and PD-L1 in LSCC and HSCC were detected in clinical samples. In addition, the expressions of PD-L1 and APE1 and their correlation were explored. The results showed that PD-1+ T lymphocytes were wildly infiltrated and PD-L1 was overexpressed in LSCC and HSCC tissues. PD-1 had a positive correlation with cancer progression, and glottic and subglottic LSCC tissues might have a more active immune microenvironment. Moreover, the results showed that upregulated co-expression of PD-L1 and APE1 was a biomarker of LSCC, and APE1 could regulate the expression of PD-L1 through NF-κB signaling pathway. In conclusion, the combine detection of the expressions of PD-1, PD-L1 and APE1 will provide predictive value for the treatment of LSCC and HSCC via immune checkpoint inhibitors, which will help us to identify the patient population more likely to benefit from the immune checkpoint inhibitors based on the tumor immune microenvironment.
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Affiliation(s)
- Juan Wang
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266061, Shandong, China
| | - Limin Lun
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266061, Shandong, China
| | - Xin Jiang
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China
| | - Yi Wang
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266061, Shandong, China
| | - Xiaopeng Li
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266061, Shandong, China
| | - Guoqiang Du
- Department of Otolaryngology Head and Neck Surgery, Qingdao Municipal Hospital (Group), Qingdao 266071, Shandong, China.
| | - Jin Wang
- Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China.
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Isvoranu G, Surcel M, Munteanu AN, Bratu OG, Ionita-Radu F, Neagu MT, Chiritoiu-Butnaru M. Therapeutic potential of interleukin-15 in cancer (Review). Exp Ther Med 2021; 22:675. [PMID: 33986840 PMCID: PMC8112152 DOI: 10.3892/etm.2021.10107] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 02/24/2021] [Indexed: 12/21/2022] Open
Abstract
The immune system is dysfunctional in cancer, and therapeutic approaches designated to restore immunity and increase long-term overall survival are desirable. The role of immunotherapy is to trigger the immune system to recognize and destroy tumor cells. Interleukin-15 (IL-15) is a member of the common gamma-chain (γc) cytokines that promote the differentiation and expansion of T cells, B cells and natural killer (NK) cells, leading to enhanced antitumor responses. This suggests that IL-15 is a promising candidate for anticancer therapy. Renewed interest in cancer immunotherapy has led to an increased number of preclinical studies and clinical trials that have investigated the reliability and potency of IL-15-based agents, not only as single therapy, but also in combination with others. This review provides a description of these studies which show the advantages and disadvantages of IL-15 as an immunotherapeutic agent. We present here the role of IL-15 and pharmacologically improved IL-15 superagonists as a single treatment or in combination with other therapeutic agents.
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Affiliation(s)
- Gheorghita Isvoranu
- Department of Animal Husbandry, 'Victor Babes' National Institute of Pathology, 050096 Bucharest, Romania
| | - Mihaela Surcel
- Department of Immunology, 'Victor Babes' National Institute of Pathology, 050096 Bucharest, Romania
| | - Adriana Narcisa Munteanu
- Department of Immunology, 'Victor Babes' National Institute of Pathology, 050096 Bucharest, Romania.,Department of Doctoral School of Biology, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania
| | - Ovidiu Gabriel Bratu
- Department of Clinical Department III, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.,Department of Clinic of Urology, 'Dr. Carol Davila' University Emergency Central Military Hospital, 010825 Bucharest, Romania.,Academy of Romanian Scientists, 050094 Bucharest, Romania
| | - Florentina Ionita-Radu
- Department of Gastroenterology, 'Dr. Carol Davila' University Emergency Central Military Hospital, 010825 Bucharest, Romania
| | - Monica Teodora Neagu
- Department of Immunology, 'Victor Babes' National Institute of Pathology, 050096 Bucharest, Romania.,Department of Doctoral School of Biology, Faculty of Biology, University of Bucharest, 050095 Bucharest, Romania
| | - Marioara Chiritoiu-Butnaru
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy (IBAR), 060031 Bucharest, Romania
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Khoshghamat N, Jafari N, Moetamani-Ahmadi M, Khalili-Tanha G, Khajavi Rad MH, Sahebdel S, Khalili-Tanha N, Soleimanpour S, Khazaei M, Hassanian SM, Ferns GA, Avan A. Programmed cell death 1 as prognostic marker and therapeutic target in upper gastrointestinal cancers. Pathol Res Pract 2021; 220:153390. [PMID: 33640713 DOI: 10.1016/j.prp.2021.153390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/14/2021] [Accepted: 02/15/2021] [Indexed: 12/28/2022]
Abstract
Gastrointestinal (GIs) cancers are among the most common causes of cancer related death, and hence the importance for the identification of novel prognostic/predictive biomarkers for detection of patients at an early stage, and for using these to identify novel targeted therapies to improve the efficacy of existing chemotherapeutic regimens. Programmed cell death 1 has been reported as a potential target in several malignancies, and targeting agents are being developed, some already approved by FDA, such as: pembrolizumab, Atezolizumab, Nivolumab. Pembrolizumab that have been approved for the treatment of metastatic non-small cell lung cancer. Here we provide an overview of the mechanism of action PD-1/PD-L1, prognostic value and current progress in clinical trials using PD-1/PD-L1 inhibitors, and the resistant mechanisms at underlie the inhibitory effect of these agents in the treatment of gastrointestinal cancers.
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Affiliation(s)
- Negar Khoshghamat
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91387-35499, Iran
| | - Niloufar Jafari
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Ghazaleh Khalili-Tanha
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Saeed Sahebdel
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Nima Khalili-Tanha
- Veterinary Medicine Student, Faculty of Veterinary Medicine, Ferdowsi University Mashhad, Iran
| | - Saman Soleimanpour
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex, UK
| | - Amir Avan
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Malfatti MC, Antoniali G, Codrich M, Burra S, Mangiapane G, Dalla E, Tell G. New perspectives in cancer biology from a study of canonical and non-canonical functions of base excision repair proteins with a focus on early steps. Mutagenesis 2021; 35:129-149. [PMID: 31858150 DOI: 10.1093/mutage/gez051] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 12/05/2019] [Indexed: 12/15/2022] Open
Abstract
Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (DDR) pathways are thought to play a pivotal role in genomic instabilities associated with cancer development, and are further thought to be important predictive biomarkers for therapy using the synthetic lethality paradigm. However, novel unpredicted perspectives are emerging from the identification of several non-canonical roles of DNA repair enzymes, particularly in gene expression regulation, by different molecular mechanisms, such as (i) non-coding RNA regulation of tumour suppressors, (ii) epigenetic and transcriptional regulation of genes involved in genotoxic responses and (iii) paracrine effects of secreted DNA repair enzymes triggering the cell senescence phenotype. The base excision repair (BER) pathway, canonically involved in the repair of non-distorting DNA lesions generated by oxidative stress, ionising radiation, alkylation damage and spontaneous or enzymatic deamination of nucleotide bases, represents a paradigm for the multifaceted roles of complex DDR in human cells. This review will focus on what is known about the canonical and non-canonical functions of BER enzymes related to cancer development, highlighting novel opportunities to understand the biology of cancer and representing future perspectives for designing new anticancer strategies. We will specifically focus on APE1 as an example of a pleiotropic and multifunctional BER protein.
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Affiliation(s)
- Matilde Clarissa Malfatti
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Giulia Antoniali
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Marta Codrich
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Silvia Burra
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Giovanna Mangiapane
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Emiliano Dalla
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Gianluca Tell
- Laboratory of Molecular Biology and DNA repair, Department of Medicine (DAME), University of Udine, Udine, Italy
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Caffrey PJ, Delaney S. Chromatin and other obstacles to base excision repair: potential roles in carcinogenesis. Mutagenesis 2021; 35:39-50. [PMID: 31612219 DOI: 10.1093/mutage/gez029] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 09/13/2019] [Indexed: 12/29/2022] Open
Abstract
DNA is comprised of chemically reactive nucleobases that exist under a constant barrage from damaging agents. Failure to repair chemical modifications to these nucleobases can result in mutations that can cause various diseases, including cancer. Fortunately, the base excision repair (BER) pathway can repair modified nucleobases and prevent these deleterious mutations. However, this pathway can be hindered through several mechanisms. For instance, mutations to the enzymes in the BER pathway have been identified in cancers. Biochemical characterisation of these mutants has elucidated various mechanisms that inhibit their activity. Furthermore, the packaging of DNA into chromatin poses another obstacle to the ability of BER enzymes to function properly. Investigations of BER in the base unit of chromatin, the nucleosome core particle (NCP), have revealed that the NCP acts as a complex substrate for BER enzymes. The constituent proteins of the NCP, the histones, also have variants that can further impact the structure of the NCP and may modulate access of enzymes to the packaged DNA. These histone variants have also displayed significant clinical effects both in carcinogenesis and patient prognosis. This review focuses on the underlying molecular mechanisms that present obstacles to BER and the relationship of these obstacles to cancer. In addition, several chemotherapeutics induce DNA damage that can be repaired by the BER pathway and understanding obstacles to BER can inform how resistance and/or sensitivity to these therapies may occur. With the understanding of these molecular mechanisms, current chemotherapeutic treatment regiments may be improved, and future therapies developed.
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Affiliation(s)
- Paul J Caffrey
- Department of Chemistry, Brown University, Providence, RI
| | - Sarah Delaney
- Department of Chemistry, Brown University, Providence, RI
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Qiu Z, Du Y. Clinicopathological and prognostic significance of programmed death ligant-1 expression in gastric cancer: a meta-analysis. J Gastrointest Oncol 2021; 12:112-120. [PMID: 33708429 DOI: 10.21037/jgo-20-568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Gastric cancer (GC) is a common malignant tumor with a high incidence in China. The use of immune checkpoint inhibitors has become the focus of tumor immunotherapy in recent years. This study was to investigate the clinicopathological and prognostic significance of programmed death ligant-1 (PD-L1) expression in GC. Methods We searched the PubMed, ScienceNet, EMbase, CNKI, and Wanfang databases for retrospective cohort studies on the clinicopathology and prognosis of PD-L1 expression in GC published between January 2010 and April 2020. The literature was first selected to extract data according to the inclusion and exclusion criteria, then a meta-analysis performed using Stata15.0 software. Publication bias and sensitivity analysis were carried out for the included studies. Results A total of 3,218 patients in 15 studies were included in the meta-analysis. The positive expression of PD-L1 was related to a decrease in the 3-year survival rate (HR =1.32, 95% CI: 1.02-1.49, P=0.028) and 5-year survival rate (HR =1.39, 95% CI: 1.14-1.69, P=0.001). The difference in PD-L1 expression was related to lymph node metastasis (OR =1.73, 95% CI: 1.18-2.54, P<0.001), but not to tumor stage (OR =1.28, 95% CI: 0.81-2.02, P=0.292). Conclusions The results show that PD-L1 is related to the prognosis of GC. Its high expression decreases the 3- and 5-year survival rates and promotes lymph node metastasis, but does not reflect tumor stage. The results may provide a theoretical basis for the choice of clinical immunotherapy in GC patients.
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Affiliation(s)
- Zhebing Qiu
- Department of Gastrointestinal Tumor Surgery, Shengzhou People's Hospital (the First Affiliated Hospital of Zhejiang University Shengzhou Branch), Shengzhou, China
| | - Yinguo Du
- Department of Gastrointestinal Tumor Surgery, Shengzhou People's Hospital (the First Affiliated Hospital of Zhejiang University Shengzhou Branch), Shengzhou, China
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Lu X, Zhao H, Yuan H, Chu Y, Zhu X. High nuclear expression of APE1 correlates with unfavorable prognosis and promotes tumor growth in hepatocellular carcinoma. J Mol Histol 2021; 52:219-231. [PMID: 33392892 DOI: 10.1007/s10735-020-09939-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023]
Abstract
APE1 is a multifunctional protein that plays important roles in cancer development. However, the association between APE1 expression and the clinicopathological parameters of HCC patients has not been fully characterized. In this study, bioinformatics analysis of APE1 was performed in several databases, including the TCGA, GeneCard, Human Protein Atlas and Ualcan databases. The relationship between APE1 mRNA expression and several attributes of liver cancer patients in TCGA was investigated. Then, the protein expression of APE1 was detected by IHC analysis in 95 HCC samples and the association between APE1 expression and the clinicopathological parameters of HCC patients was explored. GSEA-KEGG analysis was performed to predict the potential signaling pathways that associated with APE1 expression. Then the siRNA-mediated knockdown model of APE1 was constructed in HCC cell line to further detect the detailed function of APE1 in HCC development in vitro and in vivo. The results of the bioinformatics analysis showed that APE1 expression was primarily located in the cell nucleus. APE1 mRNA expression was substantially correlated with pathological grade and T status in TCGA database. Elevated APE1 expression was observed in HCC samples and was associated with unfavorable survival time in liver cancer patients. IHC data demonstrated that the nuclear expression of APE1 in HCC tissues was significantly higher than that in noncancerous tissues. The expression level of the APE1 protein in HCC was strongly associated with tumor diameter and overall survival. Survival analysis indicated that APE1 nuclear expression is an independent prognostic marker for the overall survival of HCC patients. GSEA-KEGG results confirmed that APE1 associated with the base excision repair signaling pathway. The data of phenotypic experiments indicated that APE1 remarkably promoted tumor growth both in HCC cells and xenografts. The findings firstly imply that nuclear expression of APE1 is a valuable prognostic marker for HCC. APE1 significantly facilitate HCC development and targeting APE1 may be a promising strategy for HCC treatment.
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Affiliation(s)
- Xiaohua Lu
- Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Hui Zhao
- Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Hongxin Yuan
- Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Yushan Chu
- Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Xiaoqing Zhu
- Department of Interventional Radiology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
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Amini M, Hejazi M, Ghorban K, Mokhtarzadeh A, Baradaran B. Identification of functional methylated CpG loci in PD-L1 promoter as the novel epigenetic biomarkers for primary gastric cancer. Gene 2020; 772:145376. [PMID: 33359128 DOI: 10.1016/j.gene.2020.145376] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 02/08/2023]
Abstract
Gastric cancer (GC) is considered one of the most lethal malignancies worldwide due to poor prognosis. Aberrant methylation has been demonstrated to be involved in PD-L1 dysregulated expression in human cancers and possesses a great value as a diagnostic biomarker. Given that, in this study, we investigated the methylation status of PD-L1 as a promising biomarker in primary gastric tumors and identified functional CpG loci undergoing aberrant methylation through tumorigenesis of GC. PD-L1 methylation was initially evaluated in-silico using TCGA-STAD dataset. Pearson's correlation analysis was further employed to identify the most significant functional methylated CpG loci of PD-L1 gene in TCGA-STAD patient cohort. Methylation status and its correlation with PD-L1 expression were also validated using q-MSP and qRT-PCR in a set of internal samples, including 25 paired primary gastric tumors and adjacent normal tissues. The obtained results from TCGA-STAD showed that PD-L1 is significantly hypermethylated through gastric tumorigenesis, mostly in two CpG loci overlapping with cg19724470 and cg15837913 probes. Besides, PD-L1 DNA methylation was negatively correlated with PD-L1 expression in tumor samples. Furthermore, hypermethylation of cg19724470 and cg15837913 regions was validated in primary gastric tumors compared to adjacent normal samples. Also, ROC curve analysis illustrated the high diagnostic value of PD-L1 methylation for early detection of GC (AUC = 0.8110). In conclusion, the findings of this study suggested that PD-L1 expression is regulated by methylation in functional CpG loci and its methylation could be considered as a valuable diagnostic target for GC.
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Affiliation(s)
- Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Hejazi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khodayar Ghorban
- Department of Immunology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Ahad Mokhtarzadeh
- Immunology 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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50
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Hydrogen peroxide and Helicobacter pylori extract treatment combined with APE1 knockdown induce DNA damage, G2/M arrest and cell death in gastric cancer cell line. DNA Repair (Amst) 2020; 96:102976. [DOI: 10.1016/j.dnarep.2020.102976] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 08/28/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023]
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