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1
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Zhong B, Du J, Liu F, Sun S. The Role of Yes-Associated Protein in Inflammatory Diseases and Cancer. MedComm (Beijing) 2025; 6:e70128. [PMID: 40066231 PMCID: PMC11892025 DOI: 10.1002/mco2.70128] [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: 04/17/2024] [Revised: 02/02/2025] [Accepted: 02/11/2025] [Indexed: 03/17/2025] Open
Abstract
Yes-associated protein (YAP) plays a central role in the Hippo pathway, primarily governing cell proliferation, differentiation, and apoptosis. Its significance extends to tumorigenesis and inflammatory conditions, impacting disease initiation and progression. Given the increasing relevance of YAP in inflammatory disorders and cancer, this study aims to elucidate its pathological regulatory functions in these contexts. Specifically, we aim to investigate the involvement and molecular mechanisms of YAP in various inflammatory diseases and cancers. We particularly focus on how YAP activation, whether through Hippo-dependent or independent pathways, triggers the release of inflammation and inflammatory mediators in respiratory, cardiovascular, and digestive inflammatory conditions. In cancer, YAP not only promotes tumor cell proliferation and differentiation but also modulates the tumor immune microenvironment, thereby fostering tumor metastasis and progression. Additionally, we provide an overview of current YAP-targeted therapies. By emphasizing YAP's role in inflammatory diseases and cancer, this study aims to enhance our understanding of the protein's pivotal involvement in disease processes, elucidate the intricate pathological mechanisms of related diseases, and contribute to future drug development strategies targeting YAP.
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Affiliation(s)
- Bing Zhong
- Department of Otolaryngology‐Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuanChina
| | - Jintao Du
- Department of Otolaryngology‐Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuanChina
| | - Feng Liu
- Department of Otolaryngology‐Head and Neck SurgeryWest China HospitalSichuan UniversityChengduSichuanChina
| | - Silu Sun
- State Key Laboratory of Oral DiseasesNational Clinical Research Center for Oral DiseasesChinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and ManagementWest China Hospital of StomatologySichuan UniversityChengduSichuanChina
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2
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Wang S, Mu Y, Zhang J, Wang C. Prognostic and clinicopathological significance of mucin family members expression in gastric cancer: a meta-analysis. Front Oncol 2025; 14:1512971. [PMID: 39886661 PMCID: PMC11779608 DOI: 10.3389/fonc.2024.1512971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 12/13/2024] [Indexed: 02/01/2025] Open
Abstract
Background Mucin family members have been reported to be widely expressed in gastric carcinoma with diverse functions. Several important mucins exert the function of tumorigenesis or progression in gastric cancer (GC). Here, we conduct this meta-analysis to evaluate the association between mucin expression and clinicopathological features in GC. Methods Literature searches were performed in PubMed, Embase, The Cochrane Library, and ISI Web of Science, and, finally, 28 studies met our criteria. Odds ratios or hazard ratios with 95% confidence intervals were calculated to evaluate the effect quantity. We analyzed the expression of MUC1, MUC2, MUC5AC, and MUC6 and their clinicopathological characteristics separately at the same time. Results Twenty-eight studies that contain 4,603 patients were included in our meta-analysis. MUC1 was associated with gender, Lauren classification, depth of tumor invasion, TNM, vascular invasion, lymph metastasis, and lymphatic invasion, WHO grade, as well as the 5-year survival rate. MUC2 was significantly correlated with lymphatic invasion and WHO grade. MUC5AC was highly positive in gender, depth of tumor invasion, WHO grade, TNM, lymph metastasis, and lymphatic invasion. Moreover, cases with decreased MUC5AC expression were correlated with less 5-year survival. MUC6 was only related with lymphatic invasion. Conclusion Our meta-analysis showed that MUC1 and MUC5AC had prognostic value in GC detected by immunohistochemistry. MUC1 and MUC5AC were also associated with some other significant clinicopathological parameters. Moreover, MUC2 and MUC6 also exert their influence in lymphatic invasion. However, further enlarged study awaits to verify our conclusion to deeply explore the role of mucin family members in GC.
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Affiliation(s)
| | | | | | - Chengfeng Wang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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3
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Estaji F, Zibaee S, Torabi M, Moghim S. Epstein-Barr Virus and gastric carcinoma pathogenesis with emphasis on underlying epigenetic mechanisms. Discov Oncol 2024; 15:719. [PMID: 39601901 PMCID: PMC11602878 DOI: 10.1007/s12672-024-01619-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024] Open
Abstract
Gastric cancer (GC) remains one of the top causes of cancer-related mortality around the world. The pathogenesis of GC is attributed to lifestyle, family history, genetic mutations, epigenetic alterations, as well as infectious agents such as Epstein-Barr Virus (EBV). EBV, a ubiquitous human gamma herpes virus, with latent asymptomatic infection in more than 95% of the world's population, is able to infect through the oral epithelium. EBV is described as the first virus found in human neoplastic, when it was detected in Burkitt lymphoma tumor biopsy. Nowadays this virus is considered to be involved in various human malignancies such as GC. Despite comprehensive efforts and immense studies, the main underlying mechanism is not well described as there are crucial contradictions regarding the presence of this virus and the prognosis of the disease. Immunological alterations, genetic mutations, and epigenetic modifications are among the most important criteria presented in EBV- associated gastric cancer (EBVaGC), leading to its consideration as a separate subtype with unique clinical, histological, biochemical, and genetic characteristics. The current study aimed to review the association between EBV and GC with an emphasis on the role of epigenetic modifications in the suppression or progression of carcinogenesis. To put all findings in a nutshell, several genes and chromatin mutations, promoter hypermethylation and subsequent silencing of related genes, and histone modifications and aberrant micro RNAs (miRNAs) expression were considered as the major altered mechanisms in the pathogenesis of EBVaGC, most of which able to be suggested as therapeutic targets. However, the current knowledge appeared to be imperfect, hence further studies are encouraged.
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Affiliation(s)
- Fatemeh Estaji
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Saeed Zibaee
- Department of Research and Development of Biological Products, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization, Mashhad, Iran
| | - Maryam Torabi
- Department of Biotechnology, Molecular Biology Laboratory of Khorasan Razavi Veterinary Head Office, Mashhad, Iran
| | - Sharareh Moghim
- Department of Bacteriology & Virology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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4
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Zhao Q, Miao C, Lu Q, Wu W, He Y, Wang M, Liu H, Zhao J, Lian C. A nomogram for predicting overall survival in patients with gastric cancer based on tumor suppressor RCAN1.4 expression and clinical risk factors. Medicine (Baltimore) 2024; 103:e40601. [PMID: 39809174 PMCID: PMC11596420 DOI: 10.1097/md.0000000000040601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 10/31/2024] [Indexed: 01/16/2025] Open
Abstract
Gastric cancer (GC) is one of the most prevalent malignant tumors in the world and has an extremely poor prognosis. Regulator of calcineurin 1 (RCAN1), a known tumor suppressor in various cancers, has an undefined role in the proliferation and metastasis of GC. Primary tumor and paired normal gastric tissues were collected from 77 patients with GC for evaluating the mRNA levels of 3 RCAN1 transcripts. Kaplan-Meier survival curves and Cox regression analysis were used to assess the prognostic value of 3 RCAN1 transcripts, and to select variables for nomogram. The mRNA levels of RCAN1 isoform 1 (RCAN1.1, P = .0312) and isoform 2 (RCAN1.2, P = .007) were significantly diminished in GC tissues compared with normal tissues, whereas isoform 4 (RCAN1.4) expression level showed no significant differences. GC patients with lower RCAN1.4 mRNA levels had shorter overall survival time than patients whose tumors had high RCAN1.4 levels (P = .04). Downregulated expression of RCAN1.4 was found to be an independent prognostic factor of overall survival in GC patients, with a hazard ratio of 2.485 and a significant P-value of .023 in multivariate Cox analysis. The concordance index of nomogram to predict overall survival was 0.788, based on RCAN1.4 level, tumor stage and lymph node metastasis status. In conclusion, our findings suggest that RCAN1.4 is a novel prognostic marker for gastric cancer, targeting RCAN1.4 may provide a promising therapeutic strategy in GC management.
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Affiliation(s)
- Qiang Zhao
- Department of Gastrointestinal Surgery, Heping Hospital, Changzhi Medical College, Changzhi, Shanxi, China
| | - Congxiu Miao
- Department of Science and Technology, Changzhi Medical College, Changzhi, Shanxi, China
| | - Qingpu Lu
- Department of Gastrointestinal Surgery, Heping Hospital, Changzhi Medical College, Changzhi, Shanxi, China
| | - Weipeng Wu
- Department of Gastrointestinal Surgery, Heping Hospital, Changzhi Medical College, Changzhi, Shanxi, China
| | - Yuan He
- Department of General Surgery, Heping Hospital, Changzhi Medical College, Changzhi, Shanxi, China
| | - Mengzhu Wang
- Shanghai Biotecan Medical Diagnostics Co., Ltd., Shanghai Zhangjiang Institute of Medical Innovation, Shanghai, China
| | - Huimin Liu
- Shanghai Biotecan Medical Diagnostics Co., Ltd., Shanghai Zhangjiang Institute of Medical Innovation, Shanghai, China
| | - Jiangman Zhao
- Shanghai Biotecan Medical Diagnostics Co., Ltd., Shanghai Zhangjiang Institute of Medical Innovation, Shanghai, China
| | - Changhong Lian
- Department of Gastrointestinal Surgery, Heping Hospital, Changzhi Medical College, Changzhi, Shanxi, China
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Shahi A, Kidane D. Aberrant DNA polymerase beta expression is associated with dysregulated tumor immune microenvironment and its prognostic value in gastric cancer. Clin Exp Med 2024; 24:239. [PMID: 39402431 PMCID: PMC11473650 DOI: 10.1007/s10238-024-01498-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND Gastric cancer is caused by different exogenous risk factors. Polymerase beta (POLB) is critical to repair oxidative and alkylating-induced DNA damage in genome maintenance. It is unknown whether overexpression of POLB genes in GC modulates tumor immunogenicity and plays a role in its prognostic value. METHODS RNA-Seq of GC data retrieved from TCGA and GEO database and patient survival were compared using Kaplan-Meier statistical test. The TIMER algorithm was used to calculate the abundance of tumor-infiltrating immune cells. Furthermore, ROC analysis was applied to evaluate the prognostic value of POLB overexpression. RESULTS Our data analysis of TCGA and GEO gastric cancer genomics datasets reveals that POLB overexpression is significantly associated with intestinal subtypes of stomach cancer. In addition, POLB overexpression is associated with low expression of innate immune signaling genes. In contrast, POLB-overexpressed tumor harbors high mutation frequency and MSI score. Furthermore, POLB-overexpressed tumor with high immune score exhibits a better prognosis. Interestingly, our ROC analysis results suggested that POLB overexpression has a potential for prognostic markers for stomach cancer. CONCLUSIONS Our analysis suggests that aberrant POLB overexpression in stomach cancer impacts the diverse aspects of tumor immune microenvironment. In addition, POLB might be a potential prognosis marker and/or an attractive target for immune-based therapy in GC. However, our observation still requires further experimental-based scientific validation studies.
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Affiliation(s)
- Aashirwad Shahi
- Department of Physiology & Biophysics, College of Medicine, Howard University, 520 W Street NW, Washington, DC, 20059, USA
| | - Dawit Kidane
- Department of Physiology & Biophysics, College of Medicine, Howard University, 520 W Street NW, Washington, DC, 20059, USA.
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Aslani A, Soheili A, Mousavi SE, Ebrahimi A, Antar RM, Yekta Z, Nejadghaderi SA. Incidence trends of gastric cancer in the United States over 2000-2020: A population-based analysis. PLoS One 2024; 19:e0310040. [PMID: 39321169 PMCID: PMC11423999 DOI: 10.1371/journal.pone.0310040] [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: 05/26/2024] [Accepted: 08/21/2024] [Indexed: 09/27/2024] Open
Abstract
BACKGROUND Gastric cancer ranks among the top cancers in terms of both occurrence and death rates in the United States (US). Our objective was to provide the incidence trends of gastric cancer in the US from 2000 to 2020 by age, sex, histology, and race/ethnicity, and to evaluate the effects of the COVID-19 pandemic. METHODS We obtained data from the Surveillance, Epidemiology, and End Results 22 program. The morphologies of gastric cancer were classified as adenocarcinoma, gastrointestinal stromal tumor, signet ring cell carcinoma, and carcinoid tumor. We used average annual percent change (AAPC) and compared pairs using parallelism and coincidence. The numbers were displayed as both counts and age-standardized incidence rates (ASIRs) per 100000 individuals, along with their corresponding 95% confidence intervals (CIs). RESULTS Over 2000-2019, most gastric cancers were among those aged ≥55 years (81.82%), men (60.37%), and Non-Hispanic Whites (62.60%). By histology, adenocarcinoma had the highest incident cases. During the COVID-19 pandemic, there was a remarkable decline in ASIRs of gastric cancer in both sexes and all races (AAPC: -8.92; 95% CI: -11.18 to -6.67). The overall incidence trends of gastric cancer were not parallel, nor identical. CONCLUSIONS The incidence of gastric cancer shows notable variations by age, race, and sex, with a rising trend across ethnicities. While the overall incidence has declined, a noteworthy increase has been observed among younger adults, particularly young Hispanic women; however, rates decreased significantly in 2020.
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Affiliation(s)
- Armin Aslani
- Social Determinants of Health Research Center, Department of Community Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirali Soheili
- Medical Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Ehsan Mousavi
- Social Determinants of Health Research Center, Department of Community Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Neurosciences Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Ebrahimi
- Medical Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ryan Michael Antar
- The George Washington University School of Medicine & Health Sciences, Washington, DC, United States of America
| | - Zahra Yekta
- Calaveras County Department of Health, Calaveras County, California, United States of America
| | - Seyed Aria Nejadghaderi
- HIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
- Systematic Review and Meta‑analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Yoon JH, Byun HJ, Kim SY, Jung DH, Lee SK. Exosomal LINC00853 promotes progression of gastric cancer via the MAP17/PDZK1/AKT signaling pathway. Noncoding RNA Res 2024; 9:876-886. [PMID: 38586313 PMCID: PMC10997811 DOI: 10.1016/j.ncrna.2024.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/26/2024] [Accepted: 03/26/2024] [Indexed: 04/09/2024] Open
Abstract
Although rare, there is ongoing research into biomarkers that predict the onset and recurrence of gastric cancer, particularly focusing on substances found in exosomes. Long non-coding RNAs (lncRNAs) have garnered attention for their potential in diagnosing gastric cancer. This study investigates the role of lncRNAs in gastric cancer, focusing on their presence in exosomes as potential biomarkers for the disease's onset and recurrence. We utilized the ArrayStar Human LncRNA array 2.0 to analyze lncRNA expression in tissues from early-stage gastric cancer patients. Our analysis highlighted LINC00853, which was significantly upregulated in cancer tissues and implicated in promoting epithelial-mesenchymal transition via the MAP17/PDZK1/AKT pathway. Functional studies on AGS and MKN74 gastric cancer cell lines demonstrated that LINC00853 facilitates cell proliferation, invasion, and migration. Additionally, RNA immunoprecipitation and electrophoretic mobility shift assays confirmed LINC00853 interaction with MAP17. Importantly, LINC00853 was also detected in exosomes from both patient samples and cell lines, and its downregulation led to decreased tumorigenicity in AGS cells. These findings suggest that both cellular and exosomal LINC00853 contribute to gastric cancer pathogenesis and may serve as valuable biomarkers for the disease.
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Affiliation(s)
| | | | - Seo Yeon Kim
- Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Da Hyun Jung
- Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Sang Kil Lee
- Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
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8
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Guan M, Wang Y. Common variants of vitamin D receptor gene polymorphisms and risk of gastric cancer: A meta-analysis. Medicine (Baltimore) 2024; 103:e39527. [PMID: 39213223 PMCID: PMC11365690 DOI: 10.1097/md.0000000000039527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 07/11/2024] [Accepted: 08/09/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND While earlier studies have suggested that variations in the vitamin D receptor (VDR) gene could influence the susceptibility to gastric cancer (GC), the results have shown inconsistency. This meta-analysis aimed to examine the association of 5 common polymorphisms in VDR, including Taq1 rs731236 (T > C), FokI rs2228570 (C > T), Cdx2 rs11568820 (G > A), BsmI rs1544410 (G > A), and ApaI rs7975232 (G > T) with the risk of GC. METHODS A comprehensive search was carried out in PubMed, Web of Science, and Scopus to identify relevant studies published until January 2024. Odds ratios (ORs) with 95% confidence intervals (CIs) were utilized to assess the magnitude of associations. RESULTS Nine studies, with 2837 participants (1215 GC cases and 1622 healthy controls), were eligible. The FokI rs2228570 polymorphism showed a significant correlation with heightened susceptibility to GC under the recessive model (OR = 1.52; 95% CI: 1.06-2.19) and homozygote comparison (TT vs CC; OR = 1.59; 95% CI: 1.09-2.31). Taq1 rs731236 was also linked to an elevated risk of GC under the same models (recessive OR = 1.65; 95% CI: 1.14-2.39; homozygote OR = 1.68; 95% CI: 1.11-2.54). In the sensitivity analysis, when studies not adhering to Hardy-Weinberg equilibrium were excluded, the relationship between FokI rs2228570 polymorphism and GC disappeared, while the association for Taq1 rs731236 remained consistent. No significant association was identified for BsmI rs1544410, ApaI rs7975232, and Cdx2 rs11568820. CONCLUSION This study revealed that FokI rs2228570 and Taq1 rs731236 polymorphisms of VDR might be linked to the odds of GC.
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Affiliation(s)
- Min Guan
- Department of Gastrointestinal Surgery, Shandong Provincial Third Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Yong Wang
- Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital Affiliated to Shandong University, Jinan, Shandong, China
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9
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Dai Y, Xu Y, Shen J, Hu C, Li X, Chen Y, Liu Y, Hu D. MiR-30a-5p isoform -1|1 promotes the progression of gastric cancer by inhibiting TMEM66 and reducing intratumoral cytotoxic T cells. Exp Cell Res 2024; 439:114099. [PMID: 38802035 DOI: 10.1016/j.yexcr.2024.114099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 05/19/2024] [Accepted: 05/22/2024] [Indexed: 05/29/2024]
Abstract
Gastric cancer is histologically classified into the intestinal subtype, which forms tubular structures, and the aggressive diffuse subtype, characterized by rapid invasion and poor prognosis. The variety and quantity of miRNA isoforms between different histological subtypes of gastric cancer were unknown. Through systematic filtering, we found that more diverse miR-30a-5p isoforms was present in the diffuse subtype of gastric cancer, and was associated with patients' worse survival independent of tumor stage based on the TCGA miRNA-seq data. Among all nine isoforms of miR-30a-5p, miR-30a-5p -1|1 was more abundant than the archetype of miR-30a-5p. Higher expression of miR-30a-5p -1|1 was observed in patients with advanced tumor stage and poor survival. Furthermore, miR-30a-5p -1|1 could promote the metastasis of gastric cancer cells both in vitro and in vivo by down-regulating TMEM66. In clinical samples, decreased expression of TMEM66 was characteristic of gastric cancer, and the low level of TMEM66 correlated with deceased CD8 positive cells in the tumor microenvironment probably due to decreased cytokines production. In conclusion, the variety of miR-30a-5p isoforms correlates with worse survival in gastric cancer patients. Moreover, miR-30a-5p -1|1 could promote gastric cancer metastasis by inhibiting TMEM66 and the infiltration of intratumoral CD8 positive cells.
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Affiliation(s)
- Yanmiao Dai
- Department of Gastroenterology, Traditional Chinese Medicine Hospital of Kunshan, Kunshan, China
| | - Yudong Xu
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jie Shen
- Department of Gastroenterology, Traditional Chinese Medicine Hospital of Kunshan, Kunshan, China
| | - Caihong Hu
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou, China
| | - Xiaoli Li
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou, China
| | - Yongyu Chen
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou, China
| | - Yao Liu
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou, China.
| | - Duanmin Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
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Wang Q, Shen K, Fei B, Wei M, Ge X, Xie Z. Development and validation of a nomogram to predict cancer-specific survival of elderly patients with unresected gastric cancer who received chemotherapy. Sci Rep 2024; 14:9008. [PMID: 38637579 PMCID: PMC11026516 DOI: 10.1038/s41598-024-59516-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 04/11/2024] [Indexed: 04/20/2024] Open
Abstract
This investigation aimed to explore the prognostic factors in elderly patients with unresected gastric cancer (GC) who have received chemotherapy and to develop a nomogram for predicting their cancer-specific survival (CSS). Elderly gastric cancer patients who have received chemotherapy but no surgery in the Surveillance, Epidemiology, and End Results Database between 2004 and 2015 were included in this study. Cox analyses were conducted to identify prognostic factors, leading to the formulation of a nomogram. The nomogram was validated using receiver operating characteristic (ROC) and calibration curves. The findings elucidated six prognostic factors encompassing grade, histology, M stage, radiotherapy, tumor size, and T stage, culminating in the development of a nomogram. The ROC curve indicated that the area under curve of the nomogram used to predict CSS for 3, 4, and 5 years in the training queue as 0.689, 0.708, and 0.731, and in the validation queue, as 0.666, 0.693, and 0.708. The calibration curve indicated a high degree of consistency between actual and predicted CSS for 3, 4, and 5 years. This nomogram created to predict the CSS of elderly patients with unresected GC who have received chemotherapy could significantly enhance treatment accuracy.
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Affiliation(s)
- Qi Wang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Kexin Shen
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Bingyuan Fei
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Mengqiang Wei
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xinbin Ge
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhongshi Xie
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
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11
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Larios-Serrato V, Valdez-Salazar HA, Ruiz-Tachiquín ME. The landscape of 8q24 cytoband in gastric cancer (Review). Oncol Lett 2024; 27:179. [PMID: 38464340 PMCID: PMC10921260 DOI: 10.3892/ol.2024.14311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 02/07/2024] [Indexed: 03/12/2024] Open
Abstract
Worldwide, gastric cancer (GC) is estimated to be the fifth most common type of cancer type in both sexes, ranking sixth for new cases, with >640,850 cases per year, and fourth in terms of mortality rate. Cancer presents numerical and structural alterations in chromosomes, often through gains and losses of regions. In GC, there are multiple genetic alterations, in which those located in cytoband 8q24 have been frequently described; essential genes are present in this cytoband, regulating the homeostasis of crucial biological processes, such as the MYC gene, which induces expression of selective genes to promote cell growth and proliferation. Conversely, DNA sequence variations can also occur when a single nucleotide in the genome sequence is altered, and this is termed a single nucleotide polymorphism (SNP). These alterations, which can serve as a biological marker, are present in at least 1% of the population and assist in identifying genes associated with GC. In the present review, 12 genes present in cytoband 8q24 related to GC (NSMCE2, PCAT1, CASC19, CASC8, CCAT2, PRNCR1, POU5F1B, PSCA, JRK, MYC, PVT1 and PTK2) are discussed. The PSCA gene was cited more frequently than others; it has four known SNPs associated with GC (rs2978980, rs2294008, rs2976392 and rs9297976). Thus, these SNPs should be further studied in different populations to determine their risk value in patients with GC.
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Affiliation(s)
- Violeta Larios-Serrato
- Genomics Biotechnology and Bioinformatics Laboratory, National School of Biological Sciences (ENCB), National Polytechnic Institute (IPN), Lázaro Cárdenas Professional Unit, Mexico City 11340, Mexico
| | - Hilda-Alicia Valdez-Salazar
- Medical Research Unit in Infectious and Parasitic Diseases (UIMEIP), Pediatrics Hospital ‘Dr. Silvestre Frenk Freund’, Mexico City 06720, Mexico
| | - Martha-Eugenia Ruiz-Tachiquín
- Medical Research Unit in Oncological Diseases (UIMEO), Oncology Hospital, Century XXI National Medical Center, Mexican Social Security Institute (IMSS), Mexico City 06720, Mexico
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12
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Wu ZH, Wang YX, Song JJ, Zhao LQ, Zhai YJ, Liu YF, Guo WJ. LncRNA SNHG26 promotes gastric cancer progression and metastasis by inducing c-Myc protein translation and an energy metabolism positive feedback loop. Cell Death Dis 2024; 15:236. [PMID: 38553452 PMCID: PMC10980773 DOI: 10.1038/s41419-024-06607-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 03/07/2024] [Accepted: 03/11/2024] [Indexed: 04/02/2024]
Abstract
Metastasis is a bottleneck in cancer treatment. Studies have shown the pivotal roles of long noncoding RNAs (lncRNAs) in regulating cancer metastasis; however, our understanding of lncRNAs in gastric cancer (GC) remains limited. RNA-seq was performed on metastasis-inclined GC tissues to uncover metastasis-associated lncRNAs, revealing upregulated small nucleolar RNA host gene 26 (SNHG26) expression, which predicted poor GC patient prognosis. Functional experiments revealed that SNHG26 promoted cellular epithelial-mesenchymal transition and proliferation in vitro and in vivo. Mechanistically, SNHG26 was found to interact with nucleolin (NCL), thereby modulating c-Myc expression by increasing its translation, and in turn promoting energy metabolism via hexokinase 2 (HK2), which facilitates GC malignancy. The increase in energy metabolism supplies sufficient energy to promote c-Myc translation and expression, forming a positive feedback loop. In addition, metabolic and translation inhibitors can block this loop, thus inhibiting cell proliferation and mobility, indicating potential therapeutic prospects in GC.
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Affiliation(s)
- Zhen-Hua Wu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yi-Xuan Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jun-Jiao Song
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai, 200032, China
| | - Li-Qin Zhao
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yu-Jia Zhai
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yan-Fang Liu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai, 200032, China
| | - Wei-Jian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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13
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Pyun H, Gunathilake M, Lee J, Choi IJ, Kim YI, Sung J, Kim J. Functional Annotation and Gene Set Analysis of Gastric Cancer Risk Loci in a Korean Population. Cancer Res Treat 2024; 56:191-198. [PMID: 37340842 PMCID: PMC10789951 DOI: 10.4143/crt.2022.958] [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: 08/13/2022] [Accepted: 06/17/2023] [Indexed: 06/22/2023] Open
Abstract
PURPOSE We aimed to identify the associated single nucleotide polymorphisms (SNPs) with gastric cancer (GC) risk by genome-wide association study (GWAS) and to explore the pathway enrichment of implicated genes and gene-sets with expression patterns. MATERIALS AND METHODS The study population was comprised of 1,253 GC cases and 4,827 controls from National Cancer Center and an urban community of the Korean Genome Epidemiology Study and their genotyping was performed. SNPs were annotated, and mapped to genes to prioritize by three mapping approaches by functional mapping and annotation (FUMA). The gene-based analysis and gene-set analysis were conducted with full GWAS summary data using MAGMA. Gene-set pathway enrichment test with those prioritized genes were performed. RESULTS In GWAS, rs2303771, a nonsynonymous variant of KLHDC4 gene was top SNP associated significantly with GC (odds ratio, 2.59; p=1.32×10-83). In post-GWAS, 71 genes were prioritized. In gene-based GWAS, seven genes were under significant p < 3.80×10-6 (0.05/13,114); DEFB108B had the lowest p=5.94×10-15, followed by FAM86C1 (p=1.74×10-14), PSCA (p=1.81×10-14), and KLHDC4 (p=5.00×10-10). In gene prioritizing, KLDHC4 was the only gene mapped with all three gene-mapping approaches. In pathway enrichment test with prioritized genes, FOLR2, PSCA, LY6K, LYPD2, and LY6E showed strong enrichment related to cellular component of membrane; a post-translation modification by synthesis of glycosylphosphatidylinositol (GPI)-anchored proteins pathway. CONCLUSION While 37 SNPs were significantly associated with the risk of GC, genes involved in signaling pathways related to purine metabolism and GPI-anchored protein in cell membrane are pinpointed to be playing important role in GC.
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Affiliation(s)
- Hyojin Pyun
- Division of Genome and Health Big Data, Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul,
Korea
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Goyang,
Korea
| | - Madhawa Gunathilake
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Goyang,
Korea
| | - Jeonghee Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Goyang,
Korea
| | - Il Ju Choi
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang,
Korea
| | - Young-Il Kim
- Center for Gastric Cancer, National Cancer Center Hospital, National Cancer Center, Goyang,
Korea
| | - Joohon Sung
- Division of Genome and Health Big Data, Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul,
Korea
- Institute of Health and Environment, Seoul National University, Seoul,
Korea
| | - Jeongseon Kim
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Goyang,
Korea
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14
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Zhang X, Zhang H, Wang Z, Ma X, Luo J, Zhu Y. PWSC: a novel clustering method based on polynomial weight-adjusted sparse clustering for sparse biomedical data and its application in cancer subtyping. BMC Bioinformatics 2023; 24:490. [PMID: 38129803 PMCID: PMC10740247 DOI: 10.1186/s12859-023-05595-4] [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: 06/07/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Clustering analysis is widely used to interpret biomedical data and uncover new knowledge and patterns. However, conventional clustering methods are not effective when dealing with sparse biomedical data. To overcome this limitation, we propose a hierarchical clustering method called polynomial weight-adjusted sparse clustering (PWSC). RESULTS The PWSC algorithm adjusts feature weights using a polynomial function, redefines the distances between samples, and performs hierarchical clustering analysis based on these adjusted distances. Additionally, we incorporate a consensus clustering approach to determine the optimal number of classifications. This consensus approach utilizes relative change in the cumulative distribution function to identify the best number of clusters, resulting in more stable clustering results. Leveraging the PWSC algorithm, we successfully classified a cohort of gastric cancer patients, enabling categorization of patients carrying different types of altered genes. Further evaluation using Entropy showed a significant improvement (p = 2.905e-05), while using the Calinski-Harabasz index demonstrates a remarkable 100% improvement in the quality of the best classification compared to conventional algorithms. Similarly, significantly increased entropy (p = 0.0336) and comparable CHI, were observed when classifying another colorectal cancer cohort with microbial abundance. The above attempts in cancer subtyping demonstrate that PWSC is highly applicable to different types of biomedical data. To facilitate its application, we have developed a user-friendly tool that implements the PWSC algorithm, which canbe accessed at http://pwsc.aiyimed.com/ . CONCLUSIONS PWSC addresses the limitations of conventional approaches when clustering sparse biomedical data. By adjusting feature weights and employing consensus clustering, we achieve improved clustering results compared to conventional methods. The PWSC algorithm provides a valuable tool for researchers in the field, enabling more accurate and stable clustering analysis. Its application can enhance our understanding of complex biological systems and contribute to advancements in various biomedical disciplines.
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Affiliation(s)
- Xiaomeng Zhang
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
| | - Hongtao Zhang
- School of Mathematics and Statistics, Wuhan University, Wuhan, 430070, Hubei Province, China
| | - Zhihao Wang
- School of Mathematics and Statistics, Wuhan University, Wuhan, 430070, Hubei Province, China
| | - Xiaofei Ma
- School of Mathematics and Statistics, Wuhan University, Wuhan, 430070, Hubei Province, China
| | - Jiancheng Luo
- School of Mathematics and Statistics, Wuhan University, Wuhan, 430070, Hubei Province, China.
| | - Yingying Zhu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
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15
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Fang KT, Hung H, Lau NYS, Chi JH, Wu DC, Cheng KH. Development of a Genetically Engineered Mouse Model Recapitulating LKB1 and PTEN Deficiency in Gastric Cancer Pathogenesis. Cancers (Basel) 2023; 15:5893. [PMID: 38136437 PMCID: PMC10741874 DOI: 10.3390/cancers15245893] [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: 11/27/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
The LKB1 and PTEN genes are critical in gastric cancer (G.C.) development. LKB1, a robust tumor suppressor gene, encodes a serine/threonine kinase that directly triggers the activation of AMPK-an integral cellular metabolic kinase. The role of the LKB1 pathway extends to maintaining the stability of epithelial junctions by regulating E-cadherin expression. Conversely, PTEN, a frequently mutated tumor suppressor gene in various human cancers, emerges as a pivotal negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. This study is set to leverage the H+/K+ ATPase Cre transgene strain to precisely target Cre recombinase expression at parietal cells within the stomach. This strategic maneuver seeks to selectively nullify the functions of both LKB1 and PTEN in a manner specific to the stomach, thereby instigating the development of G.C. in a fashion akin to human gastric adenocarcinoma. Moreover, this study endeavors to dissect the intricate ways in which these alterations contribute to the histopathologic advancement of gastric tumors, their potential for invasiveness and metastasis, their angiogenesis, and the evolving tumor stromal microenvironment. Our results show that conditional deletion of PTEN and LKB1 provides an ideal cancer microenvironment for G.C. tumorigenesis by promoting cancer cell proliferation, angiogenesis, and metastasis.
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Affiliation(s)
- Kuan-Te Fang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
| | - Hsin Hung
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
| | - Nga Yin Sadonna Lau
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Jou-Hsi Chi
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Kuang-Hung Cheng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; (K.-T.F.); (H.H.); (N.Y.S.L.); (J.-H.C.)
- Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan
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16
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Wang Z, Wang Q, Chen C, Zhao X, Wang H, Xu L, Fu Y, Huang G, Li M, Xu J, Zhang Q, Wang B, Xu G, Wang L, Zou X, Wang S. NNMT enriches for AQP5 + cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma. Gut 2023; 73:63-77. [PMID: 36977555 DOI: 10.1136/gutjnl-2022-328408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 03/15/2023] [Indexed: 03/30/2023]
Abstract
OBJECTIVE Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq). DESIGN scRNA-seq was conducted on 95 551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed. RESULTS Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+ stem cells during EGCA malignant progression. CONCLUSION Our study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.
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Affiliation(s)
- Zhangding Wang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
| | - Qiang Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People's Republic of China
| | - Chen Chen
- Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Xiaoya Zhao
- Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Honggang Wang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu Province, People's Republic of China
| | - Lei Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
| | - Yao Fu
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
| | - Guang Huang
- Center for Global Health, Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Mengmeng Li
- Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Jiawen Xu
- Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Qianyi Zhang
- Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Bo Wang
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
| | - Guifang Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
| | - Lei Wang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
| | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
- Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
| | - Shouyu Wang
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, People's Republic of China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China
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Orășeanu A, Brisc MC, Maghiar OA, Popa H, Brisc CM, Șolea SF, Maghiar TA, Brisc C. Landscape of Innovative Methods for Early Diagnosis of Gastric Cancer: A Systematic Review. Diagnostics (Basel) 2023; 13:3608. [PMID: 38132192 PMCID: PMC10742893 DOI: 10.3390/diagnostics13243608] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/28/2023] [Accepted: 12/01/2023] [Indexed: 12/23/2023] Open
Abstract
From a global perspective, gastric cancer (GC) persists as a significant healthcare issue. In the Western world, the majority of cases are discovered at late stages, when the treatment is generally unsuccessful. There are no organized screening programs outside of Asia (Japan and Republic of Korea). Traditional diagnosis techniques (such as upper endoscopy), conventional tumor markers (CEA, CA19-9, and CA72-4), radiographic imaging, and CT scanning all have drawbacks. The gold standard for the earliest detection of cancer and related premalignant lesions is still endoscopy with a proper biopsy follow-up. Since there are currently no clinically approved biomarkers for the early diagnosis of GC, the identification of non-invasive biomarkers is expected to help improve the prognosis and survival rate of these patients. The search for new screening biomarkers is currently underway. These include genetic biomarkers, such as circulating tumor cells, microRNAs, and exosomes, as well as metabolic biomarkers obtained from biofluids. Meanwhile, cutting-edge high-resolution endoscopic technologies are demonstrating promising outcomes in the visual diagnosis of mucosal lesions with the aid of linked color imaging and machine learning models. Following the PRISMA guidelines, this study examined the articles in databases such as PubMed, resulting in 167 included articles. This review discusses the currently available and emerging methods for diagnosing GC early on, as well as new developments in the endoscopic detection of early lesions of the stomach.
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Affiliation(s)
- Alexandra Orășeanu
- Clinic of Gastroenterology, Bihor Clinical County Emergency Hospital, 410169 Oradea, Romania; (A.O.); (S.F.Ș.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
| | | | - Octavian Adrian Maghiar
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
| | - Horia Popa
- Clinical Emergency Hospital “Prof. Dr. Agrippa Ionescu”, 011356 Bucharest, Romania;
| | - Ciprian Mihai Brisc
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
| | - Sabina Florina Șolea
- Clinic of Gastroenterology, Bihor Clinical County Emergency Hospital, 410169 Oradea, Romania; (A.O.); (S.F.Ș.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
| | - Teodor Andrei Maghiar
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
| | - Ciprian Brisc
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; (O.A.M.); (T.A.M.); (C.B.)
- Faculty of Medicine and Pharmacy, University of Oradea, 410068 Oradea, Romania;
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18
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Wang T, Wang C, Wang J, Wang B. An Intrabody against B-Cell Receptor-Associated Protein 31 (BAP31) Suppresses the Glycosylation of the Epithelial Cell-Adhesion Molecule (EpCAM) via Affecting the Formation of the Sec61-Translocon-Associated Protein (TRAP) Complex. Int J Mol Sci 2023; 24:14787. [PMID: 37834237 PMCID: PMC10572819 DOI: 10.3390/ijms241914787] [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: 07/31/2023] [Revised: 09/12/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
The epithelial cell-adhesion molecule (EpCAM) is hyperglycosylated in carcinoma tissue and the oncogenic function of EpCAM primarily depends on the degree of glycosylation. Inhibiting EpCAM glycosylation is expected to have an inhibitory effect on cancer. We analyzed the relationship of BAP31 with 84 kinds of tumor-associated antigens and found that BAP31 is positively correlated with the protein level of EpCAM. Triple mutations of EpCAM N76/111/198A, which are no longer modified by glycosylation, were constructed to determine whether BAP31 has an effect on the glycosylation of EpCAM. Plasmids containing different C-termini of BAP31 were constructed to identify the regions of BAP31 that affects EpCAM glycosylation. Antibodies against BAP31 (165-205) were screened from a human phage single-domain antibody library and the effect of the antibody (VH-F12) on EpCAM glycosylation and anticancer was investigated. BAP31 increases protein levels of EpCAM by promoting its glycosylation. The amino acid region from 165 to 205 in BAP31 plays an important role in regulating the glycosylation of EpCAM. The antibody VH-F12 significantly inhibited glycosylation of EpCAM which, subsequently, reduced the adhesion of gastric cancer cells, inducing cytotoxic autophagy, inhibiting the AKT-PI3K-mTOR signaling pathway, and, finally, resulting in proliferation inhibition both in vitro and in vivo. Finally, we clarified that BAP31 plays a key role in promoting N-glycosylation of EpCAM by affecting the Sec61 translocation channels. Altogether, these data implied that BAP31 regulates the N-glycosylation of EpCAM and may represent a potential therapeutic target for cancer therapy.
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Affiliation(s)
| | | | | | - Bing Wang
- College of Life Science and Health, Northeastern University, 195 Chuangxin Road, Hunnan District, Shenyang 110819, China; (T.W.); (C.W.); (J.W.)
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19
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Wang Y, Zhang C, Yu J, Zhang Q, Wang Y, Xia Y, Dong J. Circulating ghrelin levels in patients with gastric cancer: a systematic review and meta-analysis. Front Oncol 2023; 13:1255112. [PMID: 37790757 PMCID: PMC10542895 DOI: 10.3389/fonc.2023.1255112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 08/24/2023] [Indexed: 10/05/2023] Open
Abstract
Background Ghrelin plays a critical role in regulating energy metabolism and homeostasis. The association between circulating ghrelin levels and gastric cancer has not been systematically analyzed. Objective This work explored the association between circulating ghrelin levels and gastric cancer. Methods The literature search for relevant articles published until November 2022 was performed using PubMed, Cochrane Library, EMBASE, and Web of Science with the keywords "ghrelin" and "gastric cancer". Standardized mean differences (SMD) with 95% confidence intervals were used to measure the effectiveness. We assessed pooled data by use of a random-effects model. Results Of 5,302 identified studies, nine were included (N=3,196 participants). Circulating ghrelin levels were lower in gastric cancer patients (SMD=-0.255, 95%CI: -0.528 to 0.017, P < 0.00001), but with high heterogeneity (I2 = 88.8%). Conclusion The circulating ghrelin levels in patients with gastric cancer were lower than in controls. However, there was heterogeneity among results; therefore, studies with larger sample sizes are recommended.
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Affiliation(s)
- Yuxuan Wang
- Clinical Medicine Department, College of Basic Medicine, Qingdao University, Qingdao, China
| | - Caishun Zhang
- College of Nursing, Qingdao University, Qingdao, China
| | - Jiaqing Yu
- Clinical Medicine Department, College of Basic Medicine, Qingdao University, Qingdao, China
| | - Qing Zhang
- Special Medicine Department, College of Basic Medicine, Qingdao University, Qingdao, China
| | - Yukai Wang
- Clinical Medicine Department, College of Basic Medicine, Qingdao University, Qingdao, China
| | - Yunqiu Xia
- Laboratory of Human Body Function, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Jing Dong
- Special Medicine Department, College of Basic Medicine, Qingdao University, Qingdao, China
- Physiology Department, College of Basic Medicine, Qingdao University, Qingdao, China
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20
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Pachathundikandi SK, Tegtmeyer N, Backert S. Masking of typical TLR4 and TLR5 ligands modulates inflammation and resolution by Helicobacter pylori. Trends Microbiol 2023; 31:903-915. [PMID: 37012092 DOI: 10.1016/j.tim.2023.03.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/28/2023] [Accepted: 03/13/2023] [Indexed: 04/03/2023]
Abstract
Helicobacter pylori is a paradigm of chronic bacterial infection and is associated with peptic ulceration and malignancies. H. pylori uses specific masking mechanisms to avoid canonical ligands from activating Toll-like receptors (TLRs), such as lipopolysaccharide (LPS) modification and specific flagellin sequences that are not detected by TLR4 and TLR5, respectively. Thus, it was believed for a long time that H. pylori evades TLR recognition as a crucial strategy for immune escape and bacterial persistence. However, recent data indicate that multiple TLRs are activated by H. pylori and play a role in the pathology. Remarkably, H. pylori LPS, modified through changes in acylation and phosphorylation, is mainly sensed by other TLRs (TLR2 and TLR10) and induces both pro- and anti-inflammatory responses. In addition, two structural components of the cag pathogenicity island-encoded type IV secretion system (T4SS), CagL and CagY, were shown to contain TLR5-activating domains. These domains stimulate TLR5 and enhance immunity, while LPS-driven TLR10 signaling predominantly activates anti-inflammatory reactions. Here, we discuss the specific roles of these TLRs and masking mechanisms during infection. Masking of typical TLR ligands combined with evolutionary shifting to other TLRs is unique for H. pylori and has not yet been described for any other species in the bacterial kingdom. Finally, we highlight the unmasked T4SS-driven activation of TLR9 by H. pylori, which mainly triggers anti-inflammatory responses.
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Affiliation(s)
- Suneesh Kumar Pachathundikandi
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Dept. of Biology, Chair of Microbiology, Staudtstr. 5, 91058 Erlangen, Germany; Babasaheb Bhimrao Ambedkar University, Dept. of Environmental Microbiology, School of Earth and Environmental Sciences, Vidya Vihar, Raebareli Road, Lucknow 226025, India
| | - Nicole Tegtmeyer
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Dept. of Biology, Chair of Microbiology, Staudtstr. 5, 91058 Erlangen, Germany
| | - Steffen Backert
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Dept. of Biology, Chair of Microbiology, Staudtstr. 5, 91058 Erlangen, Germany.
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Jiang W, Meng K, Yang T. Long non-coding RNA PROX1-AS1 promotes the proliferation and migration in gastric cancer by epigenetically activating FGFR1. Panminerva Med 2023; 65:434-436. [PMID: 31355614 DOI: 10.23736/s0031-0808.19.03709-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Affiliation(s)
- Wei Jiang
- Department of General Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Kewei Meng
- Department of General Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Tao Yang
- Department of General Surgery, Tianjin First Central Hospital, Tianjin, China -
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22
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Sharafutdinov I, Tegtmeyer N, Linz B, Rohde M, Vieth M, Tay ACY, Lamichhane B, Tuan VP, Fauzia KA, Sticht H, Yamaoka Y, Marshall BJ, Backert S. A single-nucleotide polymorphism in Helicobacter pylori promotes gastric cancer development. Cell Host Microbe 2023; 31:1345-1358.e6. [PMID: 37490912 DOI: 10.1016/j.chom.2023.06.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 05/23/2023] [Accepted: 06/27/2023] [Indexed: 07/27/2023]
Abstract
Single-nucleotide polymorphisms (SNPs) in various human genes are key factors in carcinogenesis. However, whether SNPs in bacterial pathogens are similarly crucial in cancer development is unknown. Here, we analyzed 1,043 genomes of the stomach pathogen Helicobacter pylori and pinpointed a SNP in the serine protease HtrA (position serine/leucine 171) that significantly correlates with gastric cancer. Our functional studies reveal that the 171S-to-171L mutation triggers HtrA trimer formation and enhances proteolytic activity and cleavage of epithelial junction proteins occludin and tumor-suppressor E-cadherin. 171L-type HtrA, but not 171S-HtrA-possessing H. pylori, inflicts severe epithelial damage, enhances injection of oncoprotein CagA into epithelial cells, increases NF-κB-mediated inflammation and cell proliferation through nuclear accumulation of β-catenin, and promotes host DNA double-strand breaks, collectively triggering malignant changes. These findings highlight the 171S/L HtrA mutation as a unique bacterial cancer-associated SNP and as a potential biomarker for risk predictions in H. pylori infections.
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Affiliation(s)
- Irshad Sharafutdinov
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany
| | - Nicole Tegtmeyer
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany
| | - Bodo Linz
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany
| | - Manfred Rohde
- Central Facility for Microscopy, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
| | - Michael Vieth
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Klinikum Bayreuth, 95445 Bayreuth, Germany
| | - Alfred Chin-Yen Tay
- Helicobacter Research Laboratory, Marshall Centre for Infectious Diseases Research and Training, School of Pathology and Laboratory Medicine, University of Western Australia, 6009 Perth, Australia
| | - Binit Lamichhane
- Helicobacter Research Laboratory, Marshall Centre for Infectious Diseases Research and Training, School of Pathology and Laboratory Medicine, University of Western Australia, 6009 Perth, Australia
| | - Vo Phuoc Tuan
- Department of Endoscopy, Choray Hospital, Ho Chi Minh, Vietnam; Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Oita, Japan
| | - Kartika Afrida Fauzia
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Oita, Japan; Department of Public Health and Preventive Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Heinrich Sticht
- Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Oita, Japan; Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, USA
| | - Barry J Marshall
- Helicobacter Research Laboratory, Marshall Centre for Infectious Diseases Research and Training, School of Pathology and Laboratory Medicine, University of Western Australia, 6009 Perth, Australia; University of Western Australia, Marshall Centre, M504, Crawley, WA, Australia; Marshall Laboratory of Biomedical Engineering, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, China
| | - Steffen Backert
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany.
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23
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Saxena K, Deshwal A, Pudake RN, Jain U, Tripathi RM. Recent progress in biomarker-based diagnostics of Helicobacter pylori, gastric cancer-causing bacteria. Biomark Med 2023; 17:679-691. [PMID: 37934044 DOI: 10.2217/bmm-2023-0316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2023] Open
Abstract
The progression of any disease and its outcomes depend on the complicated interaction between pathogens, host and environmental factors. Thus, complete knowledge of bacterial toxins involved in pathogenesis is necessary to develop diagnostic methods and alternative therapies, including vaccines. This review summarizes recently employed biomarkers to diagnose the presence of Helicobacter pylori bacteria. The authors review distinct types of disease-associated biomarkers such as urease, DNA, miRNA, aptamers and bacteriophages that can be utilized as targets to detect Helicobacter pylori and, moreover, gastric cancer in its early stage. A detailed explanation is also given in the context of the recent utilization of these biomarkers in the development of a highly specific and sensitive biosensing platform.
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Affiliation(s)
- Kirti Saxena
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh (AUUP), Sector 125, Noida, 201313, India
| | - Akanksha Deshwal
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh (AUUP), Sector 125, Noida, 201313, India
| | - Ramesh Namdeo Pudake
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh (AUUP), Sector 125, Noida, 201313, India
| | - Utkarsh Jain
- School of Health Sciences & Technology (SoHST), University of Petroleum & Energy Studies (UPES), Bidholi, Dehradun, 248007, India
| | - Ravi Mani Tripathi
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh (AUUP), Sector 125, Noida, 201313, India
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24
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Vidal-Realpe A, Dueñas-Cuellar RA, Niño-Castaño VE, Mora-Obando DL, Arias-Agudelo JJ, Bolaños HJ. Clinical and pathologic characteristics of gastric adenocarcinoma associated with Epstein-Barr virus in a region with a high incidence of gastric cancer in Colombia. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2023; 88:256-266. [PMID: 35810098 DOI: 10.1016/j.rgmxen.2021.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 10/18/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND AIMS Epstein-Barr virus (EBV) infection is an etiologic factor in EBV-associated gastric carcinoma (EBVaGC). The aim of our study was to describe the clinical and histopathologic characteristics of EBV infection in intestinal-type gastric adenocarcinoma samples. MATERIAL AND METHODS Of 180 paraffin-embedded gastrectomy samples, 28 were studied. Chromogenic in situ hybridization was performed to detect EBV. Sociodemographic and histopathologic data were obtained from the patients' clinical histories. RESULTS A total of 21.4% of the samples were positive for EBV. The predominant morphologic characteristic was the lace pattern, with dense inflammatory infiltration. Fifty percent of the EBVaGC+ patients were men, and the median age of the positive patients was 59 years (range: 50-75); 77.2% of the EBVaGC- patients were men, and the median age of the negative patients was 66 years (range: 34-89). Helicobacter pylori infection was associated with 10.7% of the EBVaGC+ patients and 53.6% of the EBVaGC- patients. In the EBVaGC+ patients, the cardia was the most frequent tumor location (17.9%), 7.1% had histologic grades 2 and 3, and 17.9% presented with Borrmann classification type III. In the EBVaGC- patients, the cardia and fundus were the most frequent tumor locations (71.4%), 35.7% had histologic grade 2, and 39.3% and 21.4% presented with Borrmann classification type III and IV, respectively. CONCLUSIONS The present study describes the clinical and histopathologic characteristics associated with EBVaGC positivity. Those data may aid in the selection of cases that are candidates for analysis through molecular methods aimed at identifying EBV infection in intestinal-type gastric adenocarcinoma.
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Affiliation(s)
- A Vidal-Realpe
- Programa de Medicina, Grupo de Investigación en Inmunología y Enfermedades Infecciosas, Facultad de Ciencias de la Salud, Universidad del Cauca, Popayán, Cauca, Colombia
| | - R A Dueñas-Cuellar
- Departamento de Patología, Grupo de Investigación en Inmunología y Enfermedades Infecciosas, Facultad de Ciencias de la Salud, Universidad del Cauca, Popayán, Cauca, Colombia
| | - V E Niño-Castaño
- Departamento de Patología, Grupo de Investigación en Inmunología y Enfermedades Infecciosas, Facultad de Ciencias de la Salud, Universidad del Cauca, Popayán, Cauca, Colombia
| | - D L Mora-Obando
- Grupo de Investigación en Inmunología y Enfermedades Infecciosas, Facultad de Ciencias de la Salud, Universidad del Cauca, Popayán, Cauca, Colombia
| | - J J Arias-Agudelo
- Médico Especialista en Patología Anatómica y Clínica, Bogotá, Colombia
| | - H J Bolaños
- Departamento de Patología, Grupo de Investigación en Inmunología y Enfermedades Infecciosas, Facultad de Ciencias de la Salud, Universidad del Cauca, Popayán, Cauca, Colombia.
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25
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Lee S, Yang HK, Lee HJ, Park DJ, Kong SH, Park SK. Cross-phenotype association analysis of gastric cancer: in-silico functional annotation based on the disease-gene network. Gastric Cancer 2023; 26:517-527. [PMID: 36995485 DOI: 10.1007/s10120-023-01380-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 03/02/2023] [Indexed: 03/31/2023]
Abstract
BACKGROUND A gene or variant has pleiotropic effects, and genetic variant identification across multiple phenotypes can provide a comprehensive understanding of biological pathways shared among different diseases or phenotypes. Discovery of genetic loci associated with multiple diseases can simultaneously support general interventions. Several meta-analyses have shown genetic associations with gastric cancer (GC); however, no study has identified associations with other phenotypes using this approach. METHODS Here, we applied disease network analysis and gene-based analysis (GBA) to examine genetic variants linked to GC and simultaneously associated with other phenotypes. We conducted a single-nucleotide polymorphism (SNP) level meta-analysis and GBA through a systematic genome-wide association study (GWAS) linked to GC, to integrate published results for the SNP variants and group them into major GC-associated genes. We then performed disease network and expression quantitative trait loci (eQTL) analyses to evaluate cross-phenotype associations and expression levels of GC-related genes. RESULTS Seven genes (MTX1, GBAP1, MUC1, TRIM46, THBS3, PSCA, and ABO) were associated with GC as well as blood urea nitrogen (BUN), glomerular filtration rate (GFR), and uric acid (UA). In addition, 17 SNPs regulated the expression of genes located on 1q22, 24 SNPs regulated the expression of PSCA on 8q24.3, and rs7849820 regulated the expression of ABO on 9q34.2. Furthermore, rs1057941 and rs2294008 had the highest posterior causal probabilities of being a causal candidate SNP in 1q22, and 8q24.3, respectively. CONCLUSIONS These findings identified seven GC-associated genes exhibiting a cross-association with GFR, BUN, and UA.
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Affiliation(s)
- Sangjun Lee
- Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-Ro, Jongro-Gu, Seoul, 03080, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea
| | - Han-Kwang Yang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk-Joon Lee
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Do Joong Park
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Seong-Ho Kong
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sue K Park
- Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-Ro, Jongro-Gu, Seoul, 03080, Korea.
- Cancer Research Institute, Seoul National University, Seoul, Korea.
- Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, Korea.
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26
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Kijan C, Hugen S, Thomas RE, Oberbauer AM, Leegwater PAJ, Fieten H, German AJ, Mandigers PJJ. The Histopathological Characteristic of Gastric Carcinoma in the Belgian Tervueren and Groenendael Dog: A Comparison of Two Classification Methods. Animals (Basel) 2023; 13:ani13091532. [PMID: 37174569 PMCID: PMC10177043 DOI: 10.3390/ani13091532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/27/2023] [Accepted: 05/01/2023] [Indexed: 05/15/2023] Open
Abstract
Gastric carcinoma is generally considered to be a rare disease in dogs, carrying a grave prognosis. However, in the Tervueren and Groenendael varieties of the Belgian Shepherd dog breed, the disease is highly prevalent. While histopathology is the gold standard for diagnosing gastric carcinoma, there is no general consensus on the methods for histological classification in these cases. Biopsies of a group of 61 dogs with confirmed gastric carcinoma (45 Tervueren and 16 Groenendael) were examined and classified according to World Health Organization (WHO) and Laurén classifications. Kaplan-Meier curves were used to compare survival between the different subtypes and simple and multiple linear regression were used to analyse the association between age of onset and breed variant, sex, neuter status, location of the tumour, inflammation score, and Laurén and WHO classifications. Mean age at diagnosis was significantly different in Groenendael (10.1 ± 2.01) and Tervueren dogs (8.5 ± 1.90). The Laurén classification resulted in 29 (48%) diffuse- and 32 (52%) intestinal-type tumours. Applying the WHO classification resulted in 30 (49%) tubular carcinoma growth patterns and 31 (51%) others. Median survival time was significantly reduced for the diffuse type as compared to the intestinal type according to the Laurén classification, with the same median survival time results for tubular compared to non-tubular subtypes according to the WHO classification (median survival time of 61 vs. 182 days, respectively). Using the WHO and Lauren classification on tumour biopsies may help the practising clinician in the prognostication of gastric carcinoma in Tervueren and Groenendael dogs.
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Affiliation(s)
- Christina Kijan
- Expertise Centre Genetics, Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands
| | - Sanne Hugen
- Expertise Centre Genetics, Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands
| | - Rachel E Thomas
- Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands
| | - Anita M Oberbauer
- Department of Animal Science, University of California, Davis, CA 95616, USA
| | - Peter A J Leegwater
- Expertise Centre Genetics, Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands
| | - Hille Fieten
- Expertise Centre Genetics, Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands
| | - Alexander J German
- Institute of Life Course and Medical Sciences, University of Liverpool, Leahurst Campus, Wirral, Neston CH64 7TE, UK
| | - Paul J J Mandigers
- Expertise Centre Genetics, Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, The Netherlands
- IVC Evidensia Referral Hospital Arnhem, Meander 10, 6825 MB Arnhem, The Netherlands
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27
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Sun Y, Li Z, Tian Y, Gao C, Liang B, Cao S, Liu X, Liu X, Meng C, Xu J, Yang H, Zhou Y. Development and validation of nomograms for predicting overall survival and cancer-specific survival in elderly patients with locally advanced gastric cancer: a population-based study. BMC Gastroenterol 2023; 23:117. [PMID: 37041468 PMCID: PMC10091668 DOI: 10.1186/s12876-023-02749-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 03/28/2023] [Indexed: 04/13/2023] Open
Abstract
OBJECTIVE To evaluate the multiple factors influencing the survival of elderly patients with locally advanced gastric cancer (LAGC) and develop and validate the novel nomograms for predicting the survival. METHODS The clinical features of patients treated between 2000 and 2018 were collected and collated from the Surveillance, Epidemiology, and End Results (SEER) database and three medical centres in China, and the patients were randomly divided into a training cohort (3494), internal validation cohort (1497) and external validation cohort (841). Univariate and multivariate analyses of the prognostic values were performed to identify independent prognostic factors associated with overall survival (OS) and cancer-specific survival (CSS), and two nomogram models were developed. Harrell's concordance index (C-index) and calibration curves were employed to assess discrimination and calibration. Decision curve analysis (DCA) and receiver-operating characteristic (ROC) curves were utilized to investigate the clinical usefulness. RESULTS In the SEER database, the 5-year OS of the patients was 31.08%, while the 5-year CSS of the patients was 44.09%. Furthermore, in the external validation set, the 5-year OS of the patients was 49.58%, and the 5-year CSS of these patients was 53.51%. After statistical analysis, nine independent prognostic factors of OS and CSS were identified, including age, race, tumour size, differentiation, TNM stage, gastrectomy type, lymph node metastasis (LNM), lymph node ratio (LNR) and chemotherapy. The C-index (approximately 0.7) and calibration curve (close to the optimal calibration line) indicated satisfactory discrimination and calibration of the nomogram. DCA and ROC curves showed that the developed nomogram was superior to TNM stage. CONCLUSION The novel validated nomogram could accurately predict the prognosis of individual elderly patients with LAGC and guide the selection of clinical treatment measures.
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Affiliation(s)
- Yuqi Sun
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Zequn Li
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Yulong Tian
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Chao Gao
- Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Benjia Liang
- Shandong Provincial Hospital, Jinan, Shandong Province, China
| | - Shougen Cao
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Xiaodong Liu
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Xuechao Liu
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Cheng Meng
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Jianfei Xu
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Hao Yang
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Yanbing Zhou
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China.
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28
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Kesharwani A, Dighe OR, Lamture Y. Role of Helicobacter pylori in Gastric Carcinoma: A Review. Cureus 2023; 15:e37205. [PMID: 37159779 PMCID: PMC10163845 DOI: 10.7759/cureus.37205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 04/06/2023] [Indexed: 04/08/2023] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related deaths globally. Gastritis caused by Helicobacter pylori (H. pylori) is a potent cause of gastrointestinal malignancies. The majority of all humans on the planet have H. pylori invasion in their stomachs, yet only a few diseased people develop GC. The human gastrointestinal system contains a broad population of microorganisms in addition to H. pylori. H. pylori heterogeneity has been studied because not all H. pylori diseases result in cancer. Individuals in the adult age group account for the bulk of gastric carcinoma cases. H. pylori has various strains, which is beneficial for its survival in host cell epithelium for a longer duration of time. Along with H. pylori, oral microbes have a major role in the pathogenicity of gastric carcinoma. The complex ecology of oral microbiota helps to defend against infections, preserve homeostasis, and regulate the immune system. In contrast, oral microbiota is involved in various mechanisms like anti-apoptotic activity, suppression of the immune system of the host, and initiation of chronic inflammation. These oral microbes are also responsible for the development of mutations. Interactions between the host immune system and bacteria promote the progression of cancer. For this review, various research articles were studied, and information was collected using databases like PubMed and Google Scholar. This review emphasizes on the role of H. pylori in gastric carcinoma, its pathogenesis, the role of various virulence factors and risk factors related to it, the role of oral microbiota in gastric carcinoma pathogenesis, diagnostic modalities, treatment options, and preventive measures for gastric carcinoma.
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29
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Ge L, Zhao G, Lan C, Song H, Qi D, Huang P, Ke X, Cui H. MESP2 binds competitively to TCF4 to suppress gastric cancer progression by regulating the SKP2/p27 axis. Cell Death Discov 2023; 9:79. [PMID: 36854722 PMCID: PMC9975210 DOI: 10.1038/s41420-023-01367-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 03/02/2023] Open
Abstract
Gastric cancer (GC) is a major cause of human deaths worldwide, and is notorious for its high incidence and mortality rates. Mesoderm Posterior Basic Helix-loop-helix (bHLH) transcription factor 2 (MESP2) acts as a transcription factor with a conserved bHLH domain. However, whether MESP2 contributes to tumorigenesis and its potential molecular mechanisms, remain unexplored. Noticeably, MESP2 expression levels are decreased in GC tissues and cell lines compared to those in normal tissue. Further, in vitro and in vivo experiments have confirmed that MESP2 overexpression suppresses GC cell growth, migration, and invasion, whereas MESP2 knockdown results in the exact opposite. Here, we present the first report that MESP2 binds to transcription factor 7-like 2 (TCF7L2/TCF4) to inhibit the activation of the TCF4/beta-catenin transcriptional complex, decrease the occupancy of the complex on the S-phase kinase Associated Protein 2 (SKP2) promoter, and promote p27 accumulation. MESP2 knockdown facilitated tumorigenesis, which was partially suppressed by SKP2 knockdown. Taken together, we conclude that MESP2 binds competitively to TCF4 to suppress GC progression by regulating the SKP2/p27 axis, thus offering a potential therapeutic strategy for future treatment.
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Affiliation(s)
- Lingjun Ge
- grid.263906.80000 0001 0362 4044State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400716 China
| | - Gaichao Zhao
- grid.263906.80000 0001 0362 4044State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400716 China
| | - Chao Lan
- grid.263906.80000 0001 0362 4044State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400716 China
| | - Houji Song
- grid.263906.80000 0001 0362 4044Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716 China
| | - Dan Qi
- grid.263906.80000 0001 0362 4044Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716 China
| | - Pan Huang
- grid.263906.80000 0001 0362 4044State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400716 China
| | - Xiaoxue Ke
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400716, China. .,Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716, China.
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400716, China. .,Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716, China.
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30
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Wang XY, Wang LL, Xu L, Liang SZ, Yu MC, Zhang QY, Dong QJ. Evaluation of polygenic risk score for risk prediction of gastric cancer. World J Gastrointest Oncol 2023; 15:276-285. [PMID: 36908320 PMCID: PMC9994049 DOI: 10.4251/wjgo.v15.i2.276] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/11/2023] [Accepted: 02/02/2023] [Indexed: 02/14/2023] Open
Abstract
Genetic variations are associated with individual susceptibility to gastric cancer. Recently, polygenic risk score (PRS) models have been established based on genetic variants to predict the risk of gastric cancer. To assess the accuracy of current PRS models in the risk prediction, a systematic review was conducted. A total of eight eligible studies consisted of 544842 participants were included for evaluation of the performance of PRS models. The overall accuracy was moderate with Area under the curve values ranging from 0.5600 to 0.7823. Incorporation of epidemiological factors or Helicobacter pylori (H. pylori) status increased the accuracy for risk prediction, while selection of single nucleotide polymorphism (SNP) and number of SNPs appeared to have little impact on the model performance. To further improve the accuracy of PRS models for risk prediction of gastric cancer, we summarized the association between gastric cancer risk and H. pylori genomic variations, cancer associated bacteria members in the gastric microbiome, discussed the potentials for performance improvement of PRS models with these microbial factors. Future studies on comprehensive PRS models established with human SNPs, epidemiological factors and microbial factors are indicated.
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Affiliation(s)
- Xiao-Yu Wang
- Central Laboratories and Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Li-Li Wang
- Central Laboratories and Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Lin Xu
- Central Laboratories and Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Shu-Zhen Liang
- Central Laboratories and Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Meng-Chao Yu
- Central Laboratories and Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Qiu-Yue Zhang
- Department of Clinical Laboratory, the Eighth Medical Center of the General Hospital of the People’s Liberation Army, Beijing 100000, China
| | - Quan-Jiang Dong
- Central Laboratories and Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, Shandong Province, China
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Joo M, Kim D, Lee MW, Lee HJ, Kim JM. GDF15 Promotes Cell Growth, Migration, and Invasion in Gastric Cancer by Inducing STAT3 Activation. Int J Mol Sci 2023; 24:ijms24032925. [PMID: 36769245 PMCID: PMC9917887 DOI: 10.3390/ijms24032925] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/25/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer is still unclear. Immunohistochemical staining was performed to estimate the expression of GDF15 in 178 gastric cancer tissues. The biological role and action mechanism of GDF15 were investigated by examining the effect of GDF15 knockdown in AGS and SNU216 gastric cancer cells. Here, we report that the high expression of GDF15 was associated with invasion depth (p = 0.002), nodal involvement (p = 0.003), stage III/IV (p = 0.01), lymphatic invasion (p = 0.05), and tumor size (p = 0.049), which are related to poor survival in gastric cancer patients. GDF15 knockdown induced G0/G1 cell cycle arrest and remarkably inhibited cell proliferation and reduced cell motility, migration, and invasion compared to the control. GDF15 knockdown inhibited the epithelial-mesenchymal transition by regulating the STAT3 phosphorylation signaling pathways. Taken together, our results indicate that GDF15 expression is associated with aggressive gastric cancer by promoting STAT3 phosphorylation, suggesting that the GDF15-STAT3 signaling axis is a potential therapeutic target against gastric cancer progression.
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Affiliation(s)
- Mina Joo
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Donghyun Kim
- Department of Pathology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Myung-Won Lee
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Hyo Jin Lee
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Correspondence: (H.J.L.); (J.-M.K.); Tel.: +82-42-280-8369 (H.J.L.); +82-42-580-8237 (J.-M.K.)
| | - Jin-Man Kim
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Pathology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Correspondence: (H.J.L.); (J.-M.K.); Tel.: +82-42-280-8369 (H.J.L.); +82-42-580-8237 (J.-M.K.)
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Huang JM, Zhuang LP, Wang HG, Zhong LY, Xue SJ, Tian FX, Lin HY. Radiomics signature for prediction of long-term survival and recurrence patterns in patients with gastric cancer after radical gastrectomy: A multicenter study. Saudi J Gastroenterol 2023; 29:21-30. [PMID: 36588364 PMCID: PMC10117004 DOI: 10.4103/sjg.sjg_253_22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND This study aimed to develop and validate a radiomics score to predict the long-term survival and patterns of recurrence of gastric cancer (GC). METHODS A total of 513 patients who underwent radical gastrectomy for GC after curative resection between 2008 and 2016 at two institutions were analyzed. A radiomics score was generated using the least absolute shrinkage and selection operator Cox regression model on 327 patients and was validated in 186 patients. A nomogram consisting of the radiomics score and clinicopathological factors was created and compared with the tumor-lymph node-metastasis (TNM) staging system. Model performance was assessed using calibration, discrimination, and clinical usefulness. RESULTS The radiomics score was established based on five selected features. A higher score was significantly associated with poorer recurrence-free survival (RFS) and overall survival (OS) rates, both in the training and validation cohorts (P < 0.05). Multivariate analysis demonstrated that the radiomics score was an independent prognostic factor for both RFS and OS (P < 0.05). A nomogram incorporating the radiomics score had a significantly better prognostic value than the TNM system alone. Moreover, a high score was significantly associated with an increased risk of distant recurrence, a medium score was significantly associated with an increased risk of peritoneal recurrence, and a low score was significantly associated with an increased risk of locoregional recurrence, in the entire cohort (P < 0.05). CONCLUSIONS The newly proposed radiomics score may be a powerful predictor of long-term outcomes and recurrence patterns of GC. Further studies are warranted to confirm these findings.
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Affiliation(s)
- Jing-Min Huang
- The Graduate School of Qinghai University, Qinghai University; Department of General Surgery, Qinghai Provincial People's Hospital, Xining, China
| | - Lv-Ping Zhuang
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Hua-Gen Wang
- The Graduate School of Fujian Medical University, Fujian Medical University, Fuzhou, China
| | - Li-Ying Zhong
- Department of Clinical Medicine, Xiamen Medical College, Xiamen, China
| | - Sheng-Jin Xue
- Department of Stomatology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Fang-Xi Tian
- Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Hua-Yang Lin
- Department of Anesthesiology, The Third Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
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Kanda M, Terashima M, Kinoshita T, Yabusaki H, Tokunaga M, Kodera Y. A multi-institutional study to evaluate the feasibility of next-generation sequencing and genomic analysis using formalin-fixed, paraffin-embedded biopsies of gastric cancer. Gastric Cancer 2023; 26:108-115. [PMID: 36369312 DOI: 10.1007/s10120-022-01351-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/03/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND Formalin-fixed, paraffin-embedded (FFPE) samples acquired and preserved adequately are expected to faithfully maintain tumor characteristics. Endoscopic biopsy tissues represent an attractive resource for identifying predictive biomarkers to evaluate pretreatment responses of patients with advanced gastric cancer (GC). However, whether genomic profiles obtained through next-generation sequencing (NGS) using biopsy samples match well with those gained from surgical FFPE samples remains a concern. METHODS We collected 50 FFPE samples (26 biopsies and 24 surgical samples) from patients with GC who participated in phase III clinical trial JCOG1509. The quality and quantity of FFPE samples were determined for deep sequencing using NGS. We queried a 435-gene panel CANCERPLEX-JP to generate comprehensive genomic profiling data including the tumor mutation burden (TMB). RESULTS The median DNA yields and NGS success rates of biopsy samples compared with surgical samples were 879 ng and 80.8% vs 8523 ng and 100%, respectively. Epstein-Barr virus and microsatellite instability-high were detected in 9.5% of biopsy samples. Comparing the genomic profiles of 18 paired samples for which NGS data were available, we detected identical somatic mutations in paired biopsy and surgical samples (kappa coefficient, 0.8692). TMB positively correlated between paired biopsy and surgical samples (correlation coefficient, 0.6911). CONCLUSIONS NGS is applicable to the analysis of FFPE samples of GC acquired by the endoscopic biopsy, and the data were highly concordant with those obtained from surgical specimens of the same patients.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan.
| | | | - Takahiro Kinoshita
- Department of Gastric Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroshi Yabusaki
- Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Masanori Tokunaga
- Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
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Yamaoka Y, Saruuljavkhlan B, Alfaray RI, Linz B. Pathogenomics of Helicobacter pylori. Curr Top Microbiol Immunol 2023; 444:117-155. [PMID: 38231217 DOI: 10.1007/978-3-031-47331-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
The human stomach bacterium Helicobacter pylori, the causative agent of gastritis, ulcers and adenocarcinoma, possesses very high genetic diversity. H. pylori has been associated with anatomically modern humans since their origins over 100,000 years ago and has co-evolved with its human host ever since. Predominantly intrafamilial and local transmission, along with genetic isolation, genetic drift, and selection have facilitated the development of distinct bacterial populations that are characteristic for large geographical areas. H. pylori utilizes a large arsenal of virulence and colonization factors to mediate the interaction with its host. Those include various adhesins, the vacuolating cytotoxin VacA, urease, serine protease HtrA, the cytotoxin-associated genes pathogenicity island (cagPAI)-encoded type-IV secretion system and its effector protein CagA, all of which contribute to disease development. While many pathogenicity-related factors are present in all strains, some belong to the auxiliary genome and are associated with specific phylogeographic populations. H. pylori is naturally competent for DNA uptake and recombination, and its genome evolution is driven by extraordinarily high recombination and mutation rates that are by far exceeding those in other bacteria. Comparative genome analyses revealed that adaptation of H. pylori to individual hosts is associated with strong selection for particular protein variants that facilitate immune evasion, especially in surface-exposed and in secreted virulence factors. Recent studies identified single-nucleotide polymorphisms (SNPs) in H. pylori that are associated with the development of severe gastric disease, including gastric cancer. Here, we review the current knowledge about the pathogenomics of H. pylori.
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Affiliation(s)
- Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu Oita, 879-5593, Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Batsaikhan Saruuljavkhlan
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu Oita, 879-5593, Japan
| | - Ricky Indra Alfaray
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu Oita, 879-5593, Japan
- Helicobacter pylori and Microbiota Study Group, Universitas Airlangga, Surabaya, 60286, East Java, Indonesia
| | - Bodo Linz
- Division of Microbiology, Department Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
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Backert S, Linz B, Tegtmeyer N. Helicobacter pylori-Induced Host Cell DNA Damage and Genetics of Gastric Cancer Development. Curr Top Microbiol Immunol 2023; 444:185-206. [PMID: 38231219 DOI: 10.1007/978-3-031-47331-9_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Gastric cancer is a very serious and deadly disease worldwide with about one million new cases every year. Most gastric cancer subtypes are associated with genetic and epigenetic aberrations caused by chromosome instability, microsatellite instability or Epstein-Barr virus infection. Another risk factor is an infection with Helicobacter pylori, which also triggers severe alterations in the host genome. This pathogen expresses an extraordinary repertoire of virulence determinants that take over control of important host cell signaling functions. In fact, H. pylori is a paradigm of persistent infection, chronic inflammation and cellular destruction. In particular, H. pylori profoundly induces chromosomal DNA damage by introducing double-strand breaks (DSBs) followed by genomic instability. DSBs appear in response to oxidative stress and pro-inflammatory transcription during the S-phase of the epithelial cell cycle, which mainly depends on the presence of the bacterial cag pathogenicity island (cagPAI)-encoded type IV secretion system (T4SS). This scenario is closely connected with the T4SS-mediated injection of ADP-glycero-β-D-manno-heptose (ADP-heptose) and oncoprotein CagA. While ADP-heptose links transcription factor NF-κB-induced innate immune signaling with RNA-loop-mediated DNA replication stress and introduction of DSBs, intracellular CagA targets the tumor suppressor BRCA1. The latter scenario promotes BRCAness, a disease characterized by the deficiency of effective DSB repair. In addition, genetic studies of patients demonstrated the presence of gastric cancer-associated single nucleotide polymorphisms (SNPs) in immune-regulatory and other genes as well as specific pathogenic germline variants in several crucial genes involved in homologous recombination and DNA repair, all of which are connected to H. pylori infection. Here we review the molecular mechanisms leading to chromosomal DNA damage and specific genetic aberrations in the presence or absence of H. pylori infection, and discuss their importance in gastric carcinogenesis.
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Affiliation(s)
- Steffen Backert
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
| | - Bodo Linz
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany
| | - Nicole Tegtmeyer
- Division of Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
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Naumann M, Ferino L, Sharafutdinov I, Backert S. Gastric Epithelial Barrier Disruption, Inflammation and Oncogenic Signal Transduction by Helicobacter pylori. Curr Top Microbiol Immunol 2023; 444:207-238. [PMID: 38231220 DOI: 10.1007/978-3-031-47331-9_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Helicobacter pylori exemplifies one of the most favourable bacterial pathogens worldwide. The bacterium colonizes the gastric mucosa in about half of the human population and constitutes a major risk factor for triggering gastric diseases such as stomach cancer. H. pylori infection represents a prime example of chronic inflammation and cancer-inducing bacterial pathogens. The microbe utilizes a remarkable set of virulence factors and strategies to control cellular checkpoints of inflammation and oncogenic signal transduction. This chapter emphasizes on the pathogenicity determinants of H. pylori such as the cytotoxin-associated genes pathogenicity island (cagPAI)-encoded type-IV secretion system (T4SS), effector protein CagA, lipopolysaccharide (LPS) metabolite ADP-glycero-β-D-manno-heptose (ADP-heptose), cytotoxin VacA, serine protease HtrA, and urease, and how they manipulate various key host cell signaling networks in the gastric epithelium. In particular, we highlight the H. pylori-induced disruption of cell-to-cell junctions, pro-inflammatory activities, as well as proliferative, pro-apoptotic and anti-apoptotic responses. Here we review these hijacked signal transduction events and their impact on gastric disease development.
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Affiliation(s)
- Michael Naumann
- Institute of Experimental Internal Medicine, Medical Faculty, Otto Von Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany.
| | - Lorena Ferino
- Institute of Experimental Internal Medicine, Medical Faculty, Otto Von Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany
| | - Irshad Sharafutdinov
- Dept. Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany
| | - Steffen Backert
- Dept. Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, 91058, Erlangen, Germany.
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Huang G, Cai G, Hu D, Li J, Xu Q, Chen Z, Xu B. Low SP1 SUMOylation-dependent SNHG17 upregulation promotes drug resistance of gastric cancer through impairing hsa-miR-23b-3p-induced Notch2 inhibition. Cell Oncol (Dordr) 2022; 45:1329-1346. [PMID: 36214997 DOI: 10.1007/s13402-022-00722-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Specificity protein 1 (SP1), a transcription factor mediated by SUMOylation modifiers, is upregulated in gastric cancer (GC) and shares negative correlation with patient prognosis. Here, we paid main attention to the role of SP1 SUMOylation in the drug resistance of GC cells and the possible long non-coding RNA (lncRNA) SNHG17/microRNA-23b-3p (miR-23b-3p)/Notch2 network engaged in this process. METHODS Tumor tissues and non-tumor tissues were isolated from GC patients who received treatment with capecitabine and cisplatin (DDP). Co-immunoprecipitation was utilized to detect the SUMOylation level of SP1. Using gain- and loss-of-function approaches, we assessed the impacts of SNHG17/miR-23b-3p/Notch2 on sensitivity of DDP-resistant GC cells in vitro and in vivo. A series of assays such as luciferase activity detection and RNA pull-down were conducted for mechanistic exploration. RESULTS SP1 expression was increased due to low SP1 SUMOylation level in the recurrent GC tissues. This increase led to upregulated SNHG17 expression and SP1 binding sites existed in the SNHG17 promoter. In addition, SNHG17 could bind to miR-23b-3p while miR-23b-3p targeted Notch2. Loss of SNHG17 reduced the resistance of DDP-resistant GC cells to DDP, which was achieved through miR-23b-3p-dependent Notch2 inhibition. Finally, SP1 silencing attenuated the resistance of GC to DDP in mice. CONCLUSION Low SP1 SUMOylation induces SNHG17 upregulation and blocks miR-23b-3p-induced Notch2 inhibition, contributing to the resistance of GC to DDP. This study may aid in the development of therapeutic targets overcoming the chemoresistance of GC.
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Affiliation(s)
- Guoyu Huang
- Department of AnoRectal Surgery, Hainan General Hospital, Hainan, 570105, Haikou, People's Republic of China
| | - Guohao Cai
- Department of AnoRectal Surgery, Hainan General Hospital, Hainan, 570105, Haikou, People's Republic of China
| | - Dongwei Hu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, 325000, Wenzhou, People's Republic of China
| | - Jinjie Li
- Department of Hepato-pancreato-biliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Shangcai Village, South Baixiang Street, Ouhai District, Zhejiang, 325000, Wenzhou, People's Republic of China
| | - Qigang Xu
- Department of Hepato-pancreato-biliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Shangcai Village, South Baixiang Street, Ouhai District, Zhejiang, 325000, Wenzhou, People's Republic of China
| | - Zongjing Chen
- Department of Hepato-pancreato-biliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Shangcai Village, South Baixiang Street, Ouhai District, Zhejiang, 325000, Wenzhou, People's Republic of China
| | - Bo Xu
- Department of Hepato-pancreato-biliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Shangcai Village, South Baixiang Street, Ouhai District, Zhejiang, 325000, Wenzhou, People's Republic of China.
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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Sukri A, Hanafiah A, Kosai NR. The Roles of Immune Cells in Gastric Cancer: Anti-Cancer or Pro-Cancer? Cancers (Basel) 2022; 14:cancers14163922. [PMID: 36010915 PMCID: PMC9406374 DOI: 10.3390/cancers14163922] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Gastric cancer is still one of the leading causes of death caused by cancer in developing countries. The emerging role of immunotherapy in cancer treatment has led to more research to elucidate the roles of essential immune cells in gastric cancer prognosis. We reviewed the roles of immune cells including T cells, B cells, dendritic cells, macrophages and natural killer cells in gastric cancer. Although the studies conducted on the roles of immune cells in gastric cancer pathogenesis produced conflicting results, understanding the roles of immune cells in gastric cancer will help us to harness them for application in immunotherapy for better prognosis and management of gastric cancer patients. Abstract Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world’s leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late stage of cancer progression. Thus, the prognosis of gastric cancer is poor, and the current treatment for improving patients’ outcomes involves the application of surgery and chemotherapy. Immunotherapy is one of the most recent therapies for gastric cancer, whereby the immune system of the host is programmed to combat cancer cells, and the therapy differs based upon the patient’s immune system. However, an understanding of the role of immune cells, namely the cell-mediated immune response and the humoral immune response, is pertinent for applications of immunotherapy. The roles of immune cells in the prognosis of gastric cancer have yielded conflicting results. This review discusses the roles of immune cells in gastric cancer pathogenesis, specifically, T cells, B cells, macrophages, natural killer cells, and dendritic cells, as well as the evidence presented thus far. Understanding how cancer cells interact with immune cells is of paramount importance in designing treatment options for gastric cancer immunotherapy.
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Affiliation(s)
- Asif Sukri
- Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Bandar Puncak Alam, Shah Alam 43200, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
- Correspondence:
| | - Nik Ritza Kosai
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
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MicroRNA-574-3p Regulates HIF-α Isoforms Promoting Gastric Cancer Epithelial-Mesenchymal Transition via Targeting CUL2. Dig Dis Sci 2022; 67:3714-3724. [PMID: 34655362 DOI: 10.1007/s10620-021-07263-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 09/21/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. MicroRNAs (miRNAs) have been widely validated as potential biomarkers for cancer treatment and diagnosis. AIMS This paper intends to study the effect and specific mechanism of miR-574-3p/CUL2 axis in GC. METHODS The miR-574-3p expression in GC tissues and cell lines was analyzed by reverse transcription polymerase chain reaction (RT-PCR). GC cell (N87) proliferation, migration and invasion were determined by the Brdu assay and Transwell assay, respectively. The tumor xenotransplantation model was established in vivo to test the effect of miR-574-3p or Cullin 2 (CUL2) on tumor growth. The relationship between miR-574-3p and CUL2 was predicated by bioinformatic analysis and verified by dual-luciferase reporter assay and RIP experiment. The expression of CUL2, hypoxia-induced transcription factor-1α (HIF-1α) as well as E-cadherin, Snail and Vimentin was monitored by western blot and immunohistochemistry. RESULTS miR-574-3p was overexpressed in GC tissues and cells. Forced upregulation of miR-574-3p enhanced proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of GC cells (N87), while downregulation of miR-574-3p resulted in reverse effects. Additionally, miR-574-3p promoted N87 cells growth and EMT in vivo. CUL2 was negatively regulated by miR-574-3p in N87 cells, and upregulation of CUL2 repressed the malignant behaviors of N87 cells. Moreover, CUL2 directly interacted with HIF-1α and suppressed HIF-1α expression both in vitro and in vivo. CONCLUSIONS miR-574-3p targeted CUL2 to upregulate HIF-1α, thus facilitating the progression of GC.
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Yu S, Meng H, Shi S, Cao S, Bian T, Zhao H. miR-548d-3p inhibits the invasion and migration of gastric cancer cells by targeting GKN1. J Clin Lab Anal 2022; 36:e24520. [PMID: 35666636 PMCID: PMC9279950 DOI: 10.1002/jcla.24520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 04/07/2022] [Accepted: 05/03/2022] [Indexed: 12/15/2022] Open
Abstract
Background The aim of this study was to explore the function and mechanism of GKN1 in gastric cancer (GC) progression. Methods Firstly, we used GEO2R to perform differential gene analysis on GSE26942 and GSE79973 and constructed the protein–protein interaction network of differential genes by STRING. Next, the cytoHubba, Mcode plugins, and GEPIA were used to obtain our follow‐up research object GKN1. Then, the function of GKN1 in GC was verified by scratch and transwell assay in GC cells. We further analyzed the genes related to GKN1 through LinkedOmics, and exported top 100 genes positively or negatively correlated with GKN1. Meanwhile, Metascape was performed on these genes. Finally, we analyzed the miRNAs that bind to GKN1 through the miRDB and verified the correlation between miR‐548d‐3p and GKN1 using dual‐fluorescence and quantitative PCR experiments. Results Bioinformatics analysis showed that there were 52 differential genes on GSE26942 and GSE79973. In addition, the results of functional assays indicated that overexpressed GKN1 can inhibit GC cell migration and invasion, while GKN1 knockdown demonstrated the opposite effect. Additionally, Metascape analysis results showed that the 3′‐UTR region of mRNA is rich in AU sequences, based on which we infer that mRNA may be regulated by miRNA. Dual‐fluorescence and quantitative PCR assays clarified that miR‐548d‐3p may be one of the target miRNAs of GKN1, which was up‐regulated in GC tissues. Conclusions In summary, we clarified that miR‐548d‐3p regulates GKN1 to participate in GC cell migration and invasion, and provides a possible target for the prognostic diagnosis and treatment of GC.
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Affiliation(s)
- Senlong Yu
- Department of Gastrointestinal Surgery, Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, China
| | - Hongjie Meng
- Department of Gastrointestinal Surgery, Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, China
| | - Shengguang Shi
- Department of Gastrointestinal Surgery, Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, China
| | - Shenghui Cao
- Department of General Surgery, Zhuji Chinese Traditional Medicine Hospital, Zhuji, China
| | - Tianhua Bian
- Department of General Surgery, Zhuji Chinese Traditional Medicine Hospital, Zhuji, China
| | - Haifeng Zhao
- Department of General Surgery, Zhuji Chinese Traditional Medicine Hospital, Zhuji, China
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Ghojazadeh M, Somi MH, Naseri A, Salehi-Pourmehr H, Hassannezhad S, Hajikamanaj Olia A, Kafshdouz L, Nikniaz Z. Systematic Review and Meta-analysis of TP53, HER2/ERBB2, KRAS, APC, and PIK3CA Genes Expression Pattern in Gastric Cancer. Middle East J Dig Dis 2022; 14:335-345. [PMID: 36619267 PMCID: PMC9489438 DOI: 10.34172/mejdd.2022.292] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 05/19/2022] [Indexed: 11/06/2022] Open
Abstract
Background: With a global prevalence of about 10%, gastric cancer is among the most prevalent cancers. Currently, there has been an ongoing trend toward investigating genetic disruptions in different cancers because they can be used as a target-specific therapy. We aimed to systemically review some gene expression patterns in gastric cancer. Methods: The current systematic review was designed and executed in 2020. Scopus, PubMed, Cochrane Library, Google Scholar, web of knowledge, and Science Direct were searched for relevant studies. A manual search of articles (hand searching), reference exploring, checking for grey literature, and seeking expert opinion were also done. Results: In this review, 65 studies were included, and the expression pattern of HER2/ ERBB2, ER1/Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, FGFR2 and MET was investigated. TP53, APC, KRAS, and PIK3CA mutation cumulative frequency were 24.8 (I2=95.05, Q value=525.53, df=26, P<0.001), 7.2 (I2=89.79, Q value=48.99, df=5, P<0.001), 7.8 (I2=93.60, Q value=140.71, df=9, P=0.001) and 8.6 (I2=80.78, Q value=525.53, df=9, P<0.001) percent, respectively. Overexpression was investigated for HER1/ Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, CCND1, FGFR2, MET and MYC. The frequency of TP53 and HER2/ERBB2 were 43.1 (I2=84.06, Q value=58.09, df=9, P<0.001) and 20.8 (I2=93.61, Q value=234.89, df=15, P<0.001) percent, respectively. Conclusion: More research is encouraged to investigate the genes for which we could not perform a meta-analysis.
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Affiliation(s)
- Morteza Ghojazadeh
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirreza Naseri
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hanieh Salehi-Pourmehr
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Hassannezhad
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arash Hajikamanaj Olia
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Kafshdouz
- Genetic Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeinab Nikniaz
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran,Corresponding Author: Zeinab Nikniaz, PhD Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Tel:+98 4133367473 Fax:+984133367473
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Neuper T, Frauenlob T, Posselt G, Horejs-Hoeck J. Beyond the gastric epithelium - the paradox of Helicobacter pylori-induced immune responses. Curr Opin Immunol 2022; 76:102208. [PMID: 35569416 DOI: 10.1016/j.coi.2022.102208] [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: 01/26/2022] [Revised: 04/08/2022] [Accepted: 04/14/2022] [Indexed: 11/03/2022]
Abstract
Chronic infections are typically characterized by an ineffective immune response to the inducing pathogen. While failing to clear the infectious microbe, the provoked inflammatory processes may cause severe tissue damage culminating in functional impairment of the affected organ. The human pathogen Helicobacter pylori is a uniquely successful Gram-negative microorganism inhabiting the gastric mucosa in approximately 50% of the world's population. This bacterial species has evolved spectacular means of evading immune surveillance and influencing host immunity, leading to a fragile equilibrium between proinflammatory and anti-inflammatory signals, the breakdown of which can have serious consequences for the host, including gastric ulceration and cancer. This review highlights novel insights into this delicate interaction between host and pathogen from an immunological perspective.
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Affiliation(s)
- Theresa Neuper
- Department of Biosciences and Medical Biology, University of Salzburg, Austria
| | - Tobias Frauenlob
- Department of Biosciences and Medical Biology, University of Salzburg, Austria; Cancer Cluster Salzburg (CCS), Austria
| | - Gernot Posselt
- Department of Biosciences and Medical Biology, University of Salzburg, Austria
| | - Jutta Horejs-Hoeck
- Department of Biosciences and Medical Biology, University of Salzburg, Austria; Cancer Cluster Salzburg (CCS), Austria.
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Yin X, Lin H, Lin L, Miao L, He J, Zhuo Z. LncRNAs and CircRNAs in cancer. MedComm (Beijing) 2022; 3:e141. [PMID: 35592755 PMCID: PMC9099016 DOI: 10.1002/mco2.141] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Xin Yin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
- College of Pharmacy Jinan University Guangzhou Guangdong China
| | - Huiran Lin
- Faculty of Medicine Macau University of Science and Technology Macau China
| | - Lei Lin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
| | - Zhenjian Zhuo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
- Laboratory Animal Center, School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Shenzhen China
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Larios-Serrato V, Martínez-Ezquerro JD, Valdez-Salazar HA, Torres J, Camorlinga-Ponce M, Piña-Sánchez P, Ruiz-Tachiquín ME. Copy number alterations and epithelial‑mesenchymal transition genes in diffuse and intestinal gastric cancers in Mexican patients. Mol Med Rep 2022; 25:191. [PMID: 35362543 PMCID: PMC8985205 DOI: 10.3892/mmr.2022.12707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 02/28/2022] [Indexed: 01/06/2023] Open
Abstract
Gastric cancer (GC) is a common malignancy with the highest mortality rate among diseases of the digestive system, worldwide. The present study of GC alterations is crucial to the understanding of tumor biology and the establishment of important aspects of cancer prognosis and treatment response. In the present study, DNA from Mexican patients with diffuse GC (DGC), intestinal GC (IGC) or non‑atrophic gastritis (NAG; control) was purified and whole‑genome analysis was performed with high‑density arrays. Shared and unique copy number alterations (CNA) were identified between the different tissues involving key genes and signaling pathways associated with cancer. This led to the molecular distinction and identification of the most relevant molecular functions to be identified. A more detailed bioinformatics analysis of epithelial‑mesenchymal transition (EMT) genes revealed that the altered network associated with chromosomal alterations included 11 genes that were shared between DGC, IGC and NAG, as well as 19 DGC‑ and 7 IGC‑exclusive genes. Furthermore, the main molecular functions included adhesion, angiogenesis, migration, metastasis, morphogenesis, proliferation and survival. The present study provided the first whole‑genome high‑density array analysis in Mexican patients with GC and revealed shared and exclusive CNA‑associated genes in DGC and IGC. In addition, a bioinformatics‑predicted network was generated, focusing on CNA‑altered genes associated with EMT and the hallmarks of cancer, as well as precancerous alterations that may lead to GC. Molecular signatures of diffuse and intestinal GC, predicted bioinformatically, involve common and distinct CNA‑EMT genes related to the hallmarks of cancer that are potential candidates for screening biomarkers of GC, including early stages.
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Affiliation(s)
- Violeta Larios-Serrato
- Laboratory of Biotechnology and Genomic Bioinformatics, National School of Biological Sciences (ENCB), National Polytechnic Institute (IPN), Lázaro Cárdenas Professional Unit, Mexico City 11340, Mexico
| | - José-Darío Martínez-Ezquerro
- Epidemiological and Health Services Research Unit, Aging Area (UIESSAE), XXI Century National Medical Center, Mexican Social Security Institute (IMSS), Mexico City 06720, Mexico
| | - Hilda-Alicia Valdez-Salazar
- Infectious and Parasitic Diseases Medical Research Unit (UIMEIP), High Specialty Medical Unit (UMAE)‑Pediatrics Hospital 'Dr. Silvestre Frenk Freund', XXI Century National Medical Center, IMSS, Mexico City 06720, Mexico
| | - Javier Torres
- Infectious and Parasitic Diseases Medical Research Unit (UIMEIP), High Specialty Medical Unit (UMAE)‑Pediatrics Hospital 'Dr. Silvestre Frenk Freund', XXI Century National Medical Center, IMSS, Mexico City 06720, Mexico
| | - Margarita Camorlinga-Ponce
- Infectious and Parasitic Diseases Medical Research Unit (UIMEIP), High Specialty Medical Unit (UMAE)‑Pediatrics Hospital 'Dr. Silvestre Frenk Freund', XXI Century National Medical Center, IMSS, Mexico City 06720, Mexico
| | - Patricia Piña-Sánchez
- Oncological Diseases Medical Research Unit (UIMEO), UMAE‑Oncology Hospital, XXI Century National Medical Center, Mexican Social Security Institute (IMSS), Mexico City 06720, Mexico
| | - Martha-Eugenia Ruiz-Tachiquín
- Oncological Diseases Medical Research Unit (UIMEO), UMAE‑Oncology Hospital, XXI Century National Medical Center, Mexican Social Security Institute (IMSS), Mexico City 06720, Mexico
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Lin JX, Lin JP, Weng Y, Lv CB, Chen JH, Zhan CY, Li P, Xie JW, Wang JB, Lu J, Chen QY, Cao LL, Lin M, Zhou WX, Zhang XJ, Zheng CH, Cai LS, Ma YB, Huang CM. Radiographical Evaluation of Tumor Immunosuppressive Microenvironment and Treatment Outcomes in Gastric Cancer: A Retrospective, Multicohort Study. Ann Surg Oncol 2022; 29:5022-5033. [PMID: 35532827 DOI: 10.1245/s10434-022-11499-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/05/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND The tumor immunosuppressive microenvironment can influence treatment response and outcomes. A previously validated immunosuppression scoring system (ISS) assesses multiple immune checkpoints in gastric cancer (GC) using tissue-based assays. We aimed to develop a radiological signature for non-invasive assessment of ISS and treatment outcomes. METHODS A total of 642 patients with resectable GC from three centers were divided into four cohorts. Radiomic features were extracted from portal venous-phase CT images of GC. A radiomic signature for predicting ISS (RISS) was constructed using the least absolute shrinkage and selection operator (LASSO) regression method. Moreover, we investigated the value of the RISS in predicting survival and chemotherapy response. RESULTS The RISS, which consisted of 10 selected features, showed good discrimination of immunosuppressive status in three independent cohorts (area under the curve = 0.840, 0.809, and 0.843, respectively). Multivariate analysis revealed that the RISS was an independent prognostic factor for both disease-free survival (DFS) and overall survival (OS) in all cohorts (all p < 0.05). Further analysis revealed that stage II and III GC patients with low RISS exhibited a favorable response to adjuvant chemotherapy (OS: hazard ratio [HR] 0.407, 95% confidence interval [CI] 0.284-0.584); DFS: HR 0.395, 95% CI 0.275-0.568). Furthermore, the RISS could predict prognosis and select stage II and III GC patients who could benefit from adjuvant chemotherapy independent of microsatellite instability status and Epstein-Barr virus status. CONCLUSION The new, non-invasive radiomic signature could effectively predict the immunosuppressive status and prognosis of GC. Moreover, the RISS could help identify stage II and III GC patients most likely to benefit from adjuvant chemotherapy and avoid overtreatment.
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Affiliation(s)
- Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jun-Peng Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Yong Weng
- Department of Gastrointestinal Surgery, Affiliated Hospital of Qinghai University, Xining, Qinghai Province, China
| | - Chen-Bin Lv
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, China
| | - Jian-Hua Chen
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Chuan-Yin Zhan
- Department of Radiology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Wen-Xing Zhou
- Department of Gastrointestinal Surgery, Affiliated Hospital of Qinghai University, Xining, Qinghai Province, China
| | - Xiao-Jing Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Qinghai University, Xining, Qinghai Province, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China.,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Li-Sheng Cai
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, China
| | - Yu-Bin Ma
- Department of Gastrointestinal Surgery, Affiliated Hospital of Qinghai University, Xining, Qinghai Province, China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou,, Fujian Province, China. .,Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China. .,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China.
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Varkalaite G, Vaitkeviciute E, Inciuraite R, Salteniene V, Juzenas S, Petkevicius V, Gudaityte R, Mickevicius A, Link A, Kupcinskas L, Leja M, Kupcinskas J, Skieceviciene J. Atrophic gastritis and gastric cancer tissue miRNome analysis reveals hsa-miR-129-1 and hsa-miR-196a as potential early diagnostic biomarkers. World J Gastroenterol 2022; 28:653-664. [PMID: 35317427 PMCID: PMC8900545 DOI: 10.3748/wjg.v28.i6.653] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/19/2021] [Accepted: 01/20/2022] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most frequently diagnosed tumor globally. In most cases, GC develops in a stepwise manner from chronic gastritis or atrophic gastritis (AG) to cancer. One of the major issues in clinical settings of GC is diagnosis at advanced disease stages resulting in poor prognosis. MicroRNAs (miRNAs) are small noncoding molecules that play an essential role in a variety of fundamental biological processes. However, clinical potential of miRNA profiling in the gastric cancerogenesis, especially in premalignant GC cases, remains unclear.
AIM To evaluate the AG and GC tissue miRNomes and identify specific miRNAs’ potential for clinical applications (e.g., non-invasive diagnostics).
METHODS Study included a total of 125 subjects: Controls (CON), AG, and GC patients. All study subjects were recruited at the Departments of Surgery or Gastroenterology, Hospital of Lithuanian University of Health Sciences and divided into the profiling (n = 60) and validation (n = 65) cohorts. Total RNA isolated from tissue samples was used for preparation of small RNA sequencing libraries and profiled using next-generation sequencing (NGS). Based on NGS data, deregulated miRNAs hsa-miR-129-1-3p and hsa-miR-196a-5p were analyzed in plasma samples of independent cohort consisting of CON, AG, and GC patients. Expression level of hsa-miR-129-1-3p and hsa-miR-196a-5p was determined using the quantitative real-time polymerase chain reaction and 2-ΔΔCt method.
RESULTS Results of tissue analysis revealed 20 differentially expressed miRNAs in AG group compared to CON group, 129 deregulated miRNAs in GC compared to CON, and 99 altered miRNAs comparing GC and AG groups. Only 2 miRNAs (hsa-miR-129-1-3p and hsa-miR-196a-5p) were identified to be step-wise deregulated in healthy-premalignant-malignant sequence. Area under the curve (AUC)-receiver operating characteristic analysis revealed that expression level of hsa-miR-196a-5p is significant for discrimination of CON vs AG, CON vs GC and AG vs GC and resulted in AUCs: 88.0%, 93.1% and 66.3%, respectively. Compar-ing results in tissue and plasma samples, hsa-miR-129-1-3p was significantly down-regulated in GC compared to AG (P = 0.0021 and P = 0.024, tissue and plasma, respectively). Moreover, analysis revealed that hsa-miR-215-3p/5p and hsa-miR-934 were significantly deregulated in GC based on Helicobacter pylori (H. pylori) infection status [log2 fold change (FC) = -4.52, P-adjusted = 0.02; log2FC = -4.00, P-adjusted = 0.02; log2FC = 6.09, P-adjusted = 0.02, respectively].
CONCLUSION Comprehensive miRNome study provides evidence for gradual deregulation of hsa-miR-196a-5p and hsa-miR-129-1-3p in gastric carcinogenesis and found hsa-miR-215-3p/5p and hsa-miR-934 to be significantly deregulated in H. pylori carrying GC patients.
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Affiliation(s)
- Greta Varkalaite
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Evelina Vaitkeviciute
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Ruta Inciuraite
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Violeta Salteniene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Simonas Juzenas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Vytenis Petkevicius
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Rita Gudaityte
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Antanas Mickevicius
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg 39120, Germany
| | - Limas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Marcis Leja
- Institute of Clinical and Preventive Medicine & Faculty of Medicine, University of Latvia, Riga 1586, Latvia
| | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
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Circ_0003159 upregulates LIFR expression through competitively binding to miR-221-3p/miR-222-3p to block gastric cancer development. J Mol Histol 2022; 53:173-186. [PMID: 35034206 DOI: 10.1007/s10735-021-10044-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 11/21/2021] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) remains a major cause of cancer-related deaths. Increasing studies suggest that cancer development is accompanied by the deregulation of circular RNAs. We investigated the function of circ_0003159 in GC. The expression levels of circ_0003159, miR-221-3p/miR-222-3p and leukemia inhibitory factor receptor (LIFR) mRNA were measured by real-time quantitative polymerase chain reaction. Cell colony formation ability was assessed by colony formation assay, and cell viability was assessed by cell counting kit-8 assay. Cell apoptosis was assessed by flow cytometry assay and caspase3 activity. Cell migration and invasion were assessed by transwell assay. Glycolysis energy metabolism was assessed by 5'-triphosphate production, glucose uptake and lactate production. The protein levels of related marker proteins and LIFR were detected by western blot. The relationship between circ_0003159 and miR-221-3p/miR-222-3p, or LIFR and miR-221-3p/miR-222-3p was obtained from bioinformatics tools and verified by dual-luciferase reporter assay. A cancer tumorogenicity xenograft experiment in nude mice was conducted to determine the role of circ_0003159 in tumor growth by AGS cells. Our results showed that circ_0003159 expression was decreased in GC tissues and cells. Circ_0003159 overexpression sequestered GC cell viability, migration, invasion and glycolysis and induced cell apoptosis. MiR-221-3p and miR-222-3p were targets of circ_0003159, and the inhibition of miR-221-3p and miR-222-3p also blocked GC cell viability, migration, invasion and glycolysis and promoted cell apoptosis. LIFR was a common target of miR-221-3p and miR-222-3p. Interestingly, LIFR knockdown reversed the effects of circ_0003159 overexpression on GC cell behaviors. Circ_0003159 increased the expression level of LIFR by targeting miR-221-3p and miR-222-3p. The tumorigenicity assay showed that circ_0003159 overexpression inhibited tumor growth in vivo. In conclusion, circ_0003159 inhibited GC development in vitro and in vivo by enriching the level of LIFR via direct binding to miR-221-3p/miR-222-3p.
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Abstract
Gastric cancer (GC) is a major health concern in many countries. GC is a heterogeneous disease stratified by histopathological differences. However, these variations are not used to determine GC management. Next-generation sequencing (NGS) technologies have become widely used, and cancer genomic analysis has recently revealed the relationships between various malignant tumors and genomic information. In 2014, studies using whole-exome sequencing (WES) and whole-genome sequencing (WGS) for GC revealed the entire structure of GC genomics. Genomics with NGS has been used to identify new therapeutic targets for GC. Moreover, personalized medicine to provide specific therapy for targets based on multiplex gene panel testing of tumor tissues has become of clinical use. Recently, immune checkpoint inhibitors (ICIs) have been used for GC treatment; however, their response rates are limited. To predict the anti-tumor effects of ICIs for GC and to select patients suitable for ICI treatment, genomics also provides informative data not only of tumors but also of tumor microenvironments, such as tumor-infiltrating lymphocytes. In therapeutic strategies for unresectable or recurrent malignant tumors, the target is not only the primary lesion but also metastatic lesions, and metastatic lesions are often resistant to chemotherapy. Unlike colorectal carcinoma, there is a heterogeneous status of genetic variants between the primary and metastatic lesions in GC. Liquid biopsy analysis is also helpful for predicting the genomic status of both primary and metastatic lesions. Genomics has become an indispensable tool for GC treatment and is expected to be further developed in the future.
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Affiliation(s)
- Takumi Onoyama
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
| | - Shumpei Ishikawa
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Hajime Isomoto
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Tottori University Faculty of Medicine, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan
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Landeros N, Corvalan AH, Musleh M, Quiñones LA, Varela NM, Gonzalez-Hormazabal P. Novel Risk Associations between microRNA Polymorphisms and Gastric Cancer in a Chilean Population. Int J Mol Sci 2021; 23:ijms23010467. [PMID: 35008894 PMCID: PMC8745138 DOI: 10.3390/ijms23010467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 11/16/2022] Open
Abstract
Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis.
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Affiliation(s)
- Natalia Landeros
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile; (N.L.); (A.H.C.)
- Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile
| | - Alejandro H. Corvalan
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile; (N.L.); (A.H.C.)
- Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile
| | - Maher Musleh
- Department of Surgery, University of Chile Clinical Hospital, Santiago 8380456, Chile;
| | - Luis A. Quiñones
- Department of Basic-Clinical Oncology, School of Medicine, University of Chile, Santiago 8380453, Chile; (L.A.Q.); (N.M.V.)
- Latin American Network for the Implementation and Validation of Pharmacogenomic Clinical Guidelines (RELIVAF-CYTED), 28015 Madrid, Spain
| | - Nelson M. Varela
- Department of Basic-Clinical Oncology, School of Medicine, University of Chile, Santiago 8380453, Chile; (L.A.Q.); (N.M.V.)
- Latin American Network for the Implementation and Validation of Pharmacogenomic Clinical Guidelines (RELIVAF-CYTED), 28015 Madrid, Spain
| | - Patricio Gonzalez-Hormazabal
- Human Genetics Program, Institute of Biomedical Sciences (ICBM), School of Medicine, Universidad de Chile, Santiago 8380453, Chile
- Correspondence:
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