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Xi X, Liu L, Tuano N, Tailhades J, Mouradov D, Steen J, Sieber O, Cryle M, Nguyen-Dumont T, Segelov E, Rosenbluh J. SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss. Proc Natl Acad Sci U S A 2025; 122:e2409677122. [PMID: 40208946 PMCID: PMC12012561 DOI: 10.1073/pnas.2409677122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 02/27/2025] [Indexed: 04/12/2025] Open
Abstract
Loss of the tumor suppressor gene (TSG) Adenomatous Polyposis Coli (APC) is a hallmark event in colorectal cancers. Since it is not possible to directly target a TSG, no treatment options are available for these patients. Here, we identify SRP19 and the protein secretion machinery as a unique vulnerability in cancers with heterozygous APC loss. SRP19 is located 15 kb from APC and is almost always codeleted in these tumors. Heterozygous APC/SRP19 loss leads to lower levels of SRP19 mRNA and protein. Consequently, cells with APC/SRP19 loss are vulnerable to partial suppression of SRP19. Moreover, we show that SRP19 is rate limiting for the formation of the Signal Recognition Particle, a complex that mediates ER-protein translocation, and thus, heterozygous SRP19 loss leads to less protein secretion and higher levels of ER-stress. As a result, low-dose arsenic trioxide induces ER-stress and inhibits proliferation in cultured cell lines and animal models. Our work identifies a strategy to treat cancers with APC deletion and provides a framework for identifying and translating vulnerabilities associated with loss of a TSG.
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Affiliation(s)
- Xinqi Xi
- Department of Biochemistry and Molecular Biology and Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia
| | - Ling Liu
- Department of Biochemistry and Molecular Biology and Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia
| | - Natasha Tuano
- Murdoch Children Research Institute, Parkville, VIC3052, Australia
| | - Julien Tailhades
- Department of Biochemistry and Molecular Biology and Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia
| | - Dmitri Mouradov
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC3052, Australia
| | - Jason Steen
- Clinical Genomics, School of Translational Medicine, Monash University, Melbourne, VIC3168, Australia
| | - Oliver Sieber
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC3052, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC3052, Australia
- Department of Surgery, The University of Melbourne, Parkville, VIC3050, Australia
| | - Max Cryle
- Department of Biochemistry and Molecular Biology and Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia
| | - Tu Nguyen-Dumont
- Clinical Genomics, School of Translational Medicine, Monash University, Melbourne, VIC3168, Australia
- Department of Clinical Pathology, University of Melbourne, Parkville, VIC3010, Australia
| | - Eva Segelov
- Department of Clinical Research, Faculty of Medicine, University of Bern, Inselspital, Bern3000, Switzerland
- Department of Radiation Oncology, Bern University Hospital, Inselspital, Bern3000, Switzerland
| | - Joseph Rosenbluh
- Department of Biochemistry and Molecular Biology and Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia
- Functional Genomics Platform, Monash University, Melbourne, VIC3800, Australia
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Kemp LJS, Monster JL, Wood CS, Moers M, Vliem MJ, Khalil AA, Jamieson NB, Brosens LAA, Kodach LL, van Dieren JM, Bisseling TM, van der Post RS, Gloerich M. Tumour-intrinsic alterations and stromal matrix remodelling promote Wnt-niche independence during diffuse-type gastric cancer progression. Gut 2025:gutjnl-2024-334589. [PMID: 40169243 DOI: 10.1136/gutjnl-2024-334589] [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: 12/13/2024] [Accepted: 03/05/2025] [Indexed: 04/03/2025]
Abstract
BACKGROUND Development of diffuse-type gastric cancer (DGC) starts with intramucosal lesions that are primarily composed of differentiated, non-proliferative signet ring cells (SRCs). These indolent lesions can advance into highly proliferative and metastatic tumours, which requires suppression of DGC cell differentiation. OBJECTIVE Our goal was to identify molecular changes contributing to the progression of indolent to aggressive DGC lesions. DESIGN We conducted spatial transcriptomic analysis of patient tumours at different stages of hereditary DGC, comparing transcriptional differences in tumour cell populations and tumour-associated cells. We performed functional analysis of identified changes in a human gastric (CDH1 KO) organoid model recapitulating DGC initiation. RESULTS Our analysis reveals that distinct DGC cell populations exhibit varying levels of Wnt-signalling activity, and high levels of Wnt signalling prevent differentiation into SRCs. We identify multiple adaptations during DGC progression that converge on Wnt signalling, allowing tumour cells to remain in an undifferentiated state as they disseminate away from the gastric stem cell niche. First, DGC cells establish a cell-autonomous source for Wnt-pathway activation through upregulated expression of Wnt-ligands and 'secreted frizzled-related protein 2' (SFRP2) that potentiates ligand-induced Wnt signalling. Second, early tumour development is marked by extracellular matrix remodelling, including increased deposition of collagen I whose interactions with DGC cells suppress their differentiation in the absence of exogenous Wnt ligands. CONCLUSIONS Our findings demonstrate that tumour cell-derived ligand expression and extracellular matrix remodelling sustain Wnt signalling during DGC progression. These complementary mechanisms promote niche independence enabling expansion of undifferentiated DGC cells needed for the development of advanced tumours.
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Affiliation(s)
- Lars J S Kemp
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
- Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Jooske L Monster
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Colin S Wood
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Martijn Moers
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Marjolein J Vliem
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Antoine A Khalil
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | | | - Lodewijk A A Brosens
- Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Liudmila L Kodach
- Deparment of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Jolanda M van Dieren
- Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Tanya M Bisseling
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, Netherlands
| | | | - Martijn Gloerich
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
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Liu J, Zhang X, Ren Q, Song C, Yu J, Cai Y, Chen D. Negative response to immunotherapy in dMMR or MSI-H gastric cancer with APC and PTEN mutations: a case report. Front Oncol 2024; 14:1484802. [PMID: 39669365 PMCID: PMC11634749 DOI: 10.3389/fonc.2024.1484802] [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: 08/22/2024] [Accepted: 11/11/2024] [Indexed: 12/14/2024] Open
Abstract
Background Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) represents a distinct molecular phenotype observed in malignant tumors. These tumors typically exhibit high levels of programmed cell death 1 ligand 1 (PD-L1) expression and high tumor mutational burden (TMB), resulting in an enhanced response to immune checkpoint inhibitors (ICI) therapy. The emergence of ICI has transformed the therapeutic strategy of gastric cancer (GC). Immune checkpoint blockade significantly improves the survival of gastric cancer patients, especially those with MSI-H or dMMR. However, it's worth noting that not all patients with MSI-H respond favorably to this treatment. It has been reported that factors such as tumor heterogeneity, alterations in the tumor microenvironment, and aberrant activation of tumor-related signaling pathways have been linked with resistance to ICI therapy. Case presentation Here, we describe a case of dMMR and MSI-H GC with adenomatous polyposis coli (APC) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) mutations that failed to respond to anti-PD-1 combined with anti-HER2 (human epidermal growth factor receptor-2) therapy and chemotherapy. We attempted to elucidate the underlying causes and mechanisms behind this lack of response, and to provide new insights into treatment options for these patients. Conclusions Mutations of key genes within tumor-related signaling pathways and the infiltration of CD8+T cells in the tumor microenvironment may influence the efficacy of immunotherapy for MSI-H solid tumors.
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Affiliation(s)
- Jiang Liu
- *Correspondence: Jiang Liu, ; Dadong Chen,
| | | | | | | | | | | | - Dadong Chen
- Department of Oncology, The Affiliated Xinghua People’s Hospital, Medical School of Yangzhou University, Xinghua, Jiangsu, China
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Tsai CC, Wang CY, Chang HH, Chang PTS, Chang CH, Chu TY, Hsu PC, Kuo CY. Diagnostics and Therapy for Malignant Tumors. Biomedicines 2024; 12:2659. [PMID: 39767566 PMCID: PMC11726849 DOI: 10.3390/biomedicines12122659] [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: 10/31/2024] [Revised: 11/20/2024] [Accepted: 11/20/2024] [Indexed: 01/03/2025] Open
Abstract
Malignant tumors remain one of the most significant global health challenges and contribute to high mortality rates across various cancer types. The complex nature of these tumors requires multifaceted diagnostic and therapeutic approaches. This review explores current advancements in diagnostic methods, including molecular imaging, biomarkers, and liquid biopsies. It also delves into the evolution of therapeutic strategies, including surgery, chemotherapy, radiation therapy, and novel targeted therapies such as immunotherapy and gene therapy. Although significant progress has been made in the understanding of cancer biology, the future of oncology lies in the integration of precision medicine, improved diagnostic tools, and personalized therapeutic approaches that address tumor heterogeneity. This review aims to provide a comprehensive overview of the current state of cancer diagnostics and treatments while highlighting emerging trends and challenges that lie ahead.
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Affiliation(s)
- Chung-Che Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-C.T.); (C.-H.C.); (T.Y.C.)
| | - Chun-Yu Wang
- Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan;
| | - Hsu-Hung Chang
- Division of Nephrology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei City 221, Taiwan;
| | | | - Chuan-Hsin Chang
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-C.T.); (C.-H.C.); (T.Y.C.)
| | - Tin Yi Chu
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-C.T.); (C.-H.C.); (T.Y.C.)
| | - Po-Chih Hsu
- Department of Dentistry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan;
- Institute of Oral Medicine and Materials, College of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan; (C.-C.T.); (C.-H.C.); (T.Y.C.)
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Ooki A, Osumi H, Yoshino K, Yamaguchi K. Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair. Gastric Cancer 2024; 27:907-931. [PMID: 38922524 PMCID: PMC11335850 DOI: 10.1007/s10120-024-01523-4] [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: 04/17/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024]
Abstract
Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Koichiro Yoshino
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
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Kim B, Kim Y, Cho JY, Lee KA. Identification of Potential Genomic Alterations Using Pan-Cancer Cell-Free DNA Next-Generation Sequencing in Patients With Gastric Cancer. Ann Lab Med 2024; 44:164-173. [PMID: 37903652 PMCID: PMC10628753 DOI: 10.3343/alm.2023.0187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/27/2023] [Accepted: 09/12/2023] [Indexed: 11/01/2023] Open
Abstract
Background Molecular cancer profiling may lead to appropriate trials for molecularly targeted therapies. Cell-free DNA (cfDNA) is a promising diagnostic and/or prognostic biomarker in gastric cancer (GC). We characterized somatic genomic alterations in cfDNA of patients with GC. Methods Medical records and cfDNA data of 81 patients diagnosed as having GC were reviewed. Forty-nine and 32 patients were tested using the Oncomine Pan-Cancer Cell-Free Assay on the Ion Torrent platform and AlphaLiquid 100 kit on the Illumina platform, respectively. Results Tier I or II alterations were detected in 64.2% (52/81) of patients. Biomarkers for potential targeted therapy were detected in 55.6% of patients (45/81), and clinical trials are underway. ERBB2 amplification is actionable and was detected in 4.9% of patients (4/81). Among biomarkers showing potential for possible targeted therapy, TP53 mutation (38.3%, 35 variants in 31 patients, 31/81) and FGFR2 amplification (6.2%, 5/81) were detected the most. Conclusions Next-generation sequencing of cfDNA is a promising technique for the molecular profiling of GC. Evidence suggests that cfDNA analysis can provide accurate and reliable information on somatic genomic alterations in patients with GC, potentially replacing tissue biopsy as a diagnostic and prognostic tool. Through cfDNA analysis for molecular profiling, it may be possible to translate the molecular classification into therapeutic targets and predictive biomarkers, leading to personalized treatment options for patients with GC in the future.
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Affiliation(s)
- Boyeon Kim
- Division of Biotechnology, Invites BioCore Co. Ltd., Yongin, Korea
- Genome Service Development, Invites Genomics Co. Ltd., Jeju, Korea
| | - Yoonjung Kim
- Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Yong Cho
- Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung-A Lee
- Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Hossain MU, Ahammad I, Moniruzzaman M, Akter Lubna M, Bhattacharjee A, Mahmud Chowdhury Z, Ahmed I, Hosen MB, Biswas S, Chandra Das K, Keya CA, Salimullah M. Investigation of pathogenic germline variants in gastric cancer and development of "GasCanBase" database. Cancer Rep (Hoboken) 2023; 6:e1906. [PMID: 37867380 PMCID: PMC10728505 DOI: 10.1002/cnr2.1906] [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: 04/29/2023] [Revised: 08/29/2023] [Accepted: 09/14/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Gastric cancer, which is also known as stomach cancer, can be influenced by both germline and somatic mutations. Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in germline have long been reported to play a pivotal role in cancer progression. AIM The aim of this study is to examine the nsSNP in GC-associated genes. The study also aims to develop a database with extensive information regarding the nsSNPs in the GC-associated genes and their impacts. METHODS AND RESULTS A total of 34,588 nsSNPs from 1,493,460 SNPs of the 40 genes were extracted from the available SNP database. Drug binding and energy minimization were examined by molecular docking and YASARA. To validate the existence of the germline CDH1 gene mutation (rs34466743) in the isolated blood DNA of gastric cancer (GC) patients, polymerase chain reaction (PCR) and DNA sequencing were performed. According to the results of the gene network analysis, 17 genes may interact with other types of cancer. A total of 11,363 nsSNPs were detected within the 40 GC genes. Among these, 474 nsSNPs were predicted to be damaging and 40 to be the most damaging. The SNPs in domain regions were thought to be strong candidates that alter protein functions. Our findings proposed that most of the selected nsSNPs were within the domains or motif regions. Free Energy Deviation calculation of protein structure pointed toward noteworthy changes in the structure of each protein that can demolish its natural function. Subsequently, drug binding confirmed the structural variation and the ineffectiveness of the drug against the mutant model in individuals with these germline variants. Furthermore, in vitro analysis of the rs34466743 germline variant from the CDH1 gene confirmed the strength and robustness of the pipeline that could expand the somatic alteration for causing cancer. In addition, a comprehensive gastric cancer polymorphism database named "GasCanBase" was developed to make data available to researchers. CONCLUSION The findings of this study and the "GasCanBase" database may greatly contribute to our understanding of molecular epidemiology and the development of precise therapeutics for gastric cancer. GasCanBase is available at: https://www.gascanbase.com/.
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Affiliation(s)
| | - Ishtiaque Ahammad
- Bioinformatics DivisionNational Institute of BiotechnologyDhakaBangladesh
| | - Md. Moniruzzaman
- Molecular Biotechnology DivisionNational Institute of BiotechnologyDhakaBangladesh
| | | | | | | | - Istiak Ahmed
- Department of PharmacyNoakhali Science and Technology UniversityNoakhaliBangladesh
| | - Md. Billal Hosen
- Department of PharmacyNoakhali Science and Technology UniversityNoakhaliBangladesh
| | - Shourov Biswas
- Department of Clinical OncologyBangabandhu Sheikh Mujib Medical UniversityDhakaBangladesh
| | - Keshob Chandra Das
- Molecular Biotechnology DivisionNational Institute of BiotechnologyDhakaBangladesh
| | - Chaman Ara Keya
- Department of Biochemistry and MicrobiologyNorth South UniversityDhakaBangladesh
| | - Md. Salimullah
- Molecular Biotechnology DivisionNational Institute of BiotechnologyDhakaBangladesh
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Lee R, Li J, Li J, Wu CJ, Jiang S, Hsu WH, Chakravarti D, Chen P, LaBella KA, Li J, Spring DJ, Zhao D, Wang YA, DePinho RA. Synthetic Essentiality of Tryptophan 2,3-Dioxygenase 2 in APC-Mutated Colorectal Cancer. Cancer Discov 2022; 12:1702-1717. [PMID: 35537038 PMCID: PMC9262860 DOI: 10.1158/2159-8290.cd-21-0680] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 02/18/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022]
Abstract
Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/β-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit macrophages into the tumor microenvironment. Therapeutically, APC-deficient colorectal cancer models were susceptible to TDO2 depletion or pharmacologic inhibition, which impaired cancer cell proliferation and enhanced antitumor immune profiles. Thus, APC deficiency activates a TCF4-TDO2-AhR-CXCL5 circuit that affects multiple cancer hallmarks via autonomous and nonautonomous mechanisms and illuminates a genotype-specific vulnerability in colorectal cancer. SIGNIFICANCE This study identifies critical effectors in the maintenance of APC-deficient colorectal cancer and demonstrates the relationship between APC/WNT pathway and kynurenine pathway signaling. It further determines the tumor-associated macrophage biology in APC-deficient colorectal cancer, informing genotype-specific therapeutic targets and the use of TDO2 inhibitors. This article is highlighted in the In This Issue feature, p. 1599.
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Affiliation(s)
- Rumi Lee
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jiexi Li
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jun Li
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Chang-Jiun Wu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shan Jiang
- Department of The Translational Research to AdvanCe Therapeutics and Innovation in ONcology (TRACTION), The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wen-Hao Hsu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Deepavali Chakravarti
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Peiwen Chen
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Kyle A. LaBella
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jing Li
- Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Denise J. Spring
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Di Zhao
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Y. Alan Wang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ronald A. DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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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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11
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Zhang W, Cui N, Ye J, Yang B, Sun Y, Kuang H. Curcumin's prevention of inflammation-driven early gastric cancer and its molecular mechanism. CHINESE HERBAL MEDICINES 2022; 14:244-253. [PMID: 36117672 PMCID: PMC9476644 DOI: 10.1016/j.chmed.2021.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 10/29/2021] [Accepted: 11/27/2021] [Indexed: 02/07/2023] Open
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12
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A tumour-resident Lgr5 + stem-cell-like pool drives the establishment and progression of advanced gastric cancers. Nat Cell Biol 2021; 23:1299-1313. [PMID: 34857912 DOI: 10.1038/s41556-021-00793-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 10/12/2021] [Indexed: 12/31/2022]
Abstract
Gastric cancer is among the most prevalent and deadliest of cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a Claudin18-IRES-CreERT2 allele to selectively drive conditional dysregulation of the Wnt, Receptor Tyrosine Kinase and Trp53 pathways within the gastric epithelium. This resulted in highly reproducible metastatic, chromosomal-instable-type gastric cancer. In parallel, we developed orthotopic cancer organoid transplantation models to evaluate tumour-resident Lgr5+ populations as functional cancer stem cells via in vivo ablation. We show that Cldn18 tumours accurately recapitulate advanced human gastric cancer in terms of disease morphology, aberrant gene expression, molecular markers and sites of distant metastases. Importantly, we establish that tumour-resident Lgr5+ stem-like cells are critical to the initiation and maintenance of tumour burden and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically relevant mechanistic insights into cancer progression and as preclinical models for evaluating therapeutic targets.
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13
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Sharma A, Mir R, Galande S. Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer. Front Genet 2021; 12:681053. [PMID: 34552611 PMCID: PMC8450413 DOI: 10.3389/fgene.2021.681053] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Studies over the past four decades have elucidated the role of Wnt/β-catenin mediated regulation in cell proliferation, differentiation and migration. These processes are fundamental to embryonic development, regeneration potential of tissues, as well as cancer initiation and progression. In this review, we focus on the epigenetic players which influence the Wnt/β-catenin pathway via modulation of its components and coordinated regulation of the Wnt target genes. The role played by crosstalk with other signaling pathways mediating tumorigenesis is also elaborated. The Hippo/YAP pathway is particularly emphasized due to its extensive crosstalk via the Wnt destruction complex. Further, we highlight the recent advances in developing potential therapeutic interventions targeting the epigenetic machinery based on the characterization of these regulatory networks for effective treatment of various cancers and also for regenerative therapies.
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Affiliation(s)
- Ankita Sharma
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune, India
| | - Rafeeq Mir
- Centre for Interdisciplinary Research and Innovations, University of Kashmir, Srinagar, India
| | - Sanjeev Galande
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune, India.,Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, India
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14
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Chen H, Guan Q, Guo H, Miao L, Zhuo Z. The Genetic Changes of Hepatoblastoma. Front Oncol 2021; 11:690641. [PMID: 34367972 PMCID: PMC8335155 DOI: 10.3389/fonc.2021.690641] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 07/05/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatoblastoma is the most common malignant liver cancer in childhood. The etiology of hepatoblastoma remains obscure. Hepatoblastoma is closely related to genetic syndromes, hinting that hepatoblastoma is a genetic predisposition disease. However, no precise exposures or genetic events are reported to hepatoblastoma occurrence. During the past decade, significant advances have been made in the understanding of etiology leading to hepatoblastoma, and several important genetic events that appear to be important for the development and progression of this tumor have been identified. Advances in our understanding of the genetic changes that underlie hepatoblastoma may translate into better patient outcomes. Single nucleotide polymorphisms (SNPs) have been generally applied in the research of etiology's exploration, disease treatment, and prognosis assessment. Here, we reviewed and discussed the molecular epidemiology, especially SNPs progresses in hepatoblastoma, to provide references for future studies and promote the study of hepatoblastoma's etiology.
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Affiliation(s)
- Huitong Chen
- 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, China
| | - Qian Guan
- 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, China
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Huiqin Guo
- 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, China
- School of Medicine, South China University of Technology, Guangzhou, 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, 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, China
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15
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Wang J, Shao X, Liu Y, Shi R, Yang B, Xiao J, Liu Y, Qu X, Li Z. Mutations of key driver genes in gastric cancer metastasis risk: a systematic review and meta-analysis. Expert Rev Mol Diagn 2021; 21:963-972. [PMID: 34196586 DOI: 10.1080/14737159.2021.1946394] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Objective: Associations between gene mutations and metastasis in gastric cancer (GC) remain contradictory, resulting in the inaccurate estimation of the magnitude of the risk associated with specific genotypes.Methods: In this study, we first screened out four key driver genes (TP53, PIK3CA, APC and ARID1A) by jointly analyzing the mutation levels and searching the literature for genes associated with GC metastasis. We then performed a meta-analysis to demonstrate the relationship between these key driver gene mutations and GC metastasis, including lymphatic and distance metastasis.Results: We found out four key driver genes (TP53, PIK3CA, APC and ARID1A), associated with risk of GC metastasis. The results showed that TP53 (OR 1.39, 95% CI 1.12-1.72) and APC mutations (OR 0.58, 95% CI 0.38-0.89) were associated with lymph node metastasis and distant metastasis in GC. And TP53 mutations (OR 1.65, 95% CI 1.25-2.18) were significantly related to GC metastasis in the Asian population. APC mutations (OR 0.54, 95% CI 0.29-1.00) were also related to GC metastasis in the European and American populations. There was no significant association with GC metastasis in PIK3CA or ARID1A mutations.Expert opinion:Mutations of TP53 and APC play important roles in lymph node metastasis and distant metastasis of GC and may be potential important biomarkers of progression and therapeutic targets. These observations should be further prospectively verified.
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Affiliation(s)
- Jin Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Xinye Shao
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Yang Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Ruichuan Shi
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Bowen Yang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Jiawen Xiao
- Department of Medical Oncology, Shenyang Fifth People Hospital, Shenyang, China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Zhi Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
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16
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Noe O, Filipiak L, Royfman R, Campbell A, Lin L, Hamouda D, Stanbery L, Nemunaitis J. Adenomatous polyposis coli in cancer and therapeutic implications. Oncol Rev 2021; 15:534. [PMID: 34267890 PMCID: PMC8256374 DOI: 10.4081/oncol.2021.534] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
Inactivating mutations of the adenomatous polyposis coli (APC) gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests APCmutations are also found in gastric, breast and other cancers. The APC gene, located on chromosome 5q, is responsible for negatively regulating the b-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3b, and CK1. In the event of an APC mutation, b-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to APC mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with APC mutations.
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Affiliation(s)
- Olivia Noe
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Louis Filipiak
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Rachel Royfman
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Austin Campbell
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Leslie Lin
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Danae Hamouda
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
| | - Laura Stanbery
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH
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17
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Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Pirsalehi A, Safaroghli-Azar A, Zali MR, Bashash D. The PI3K/Akt/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur J Pharmacol 2021; 898:173983. [PMID: 33647255 DOI: 10.1016/j.ejphar.2021.173983] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/13/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022]
Abstract
Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy.
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Affiliation(s)
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Pirsalehi
- Department of Internal Medicine, School of Medicine, Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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18
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Machlowska J, Kapusta P, Baj J, Morsink FHM, Wołkow P, Maciejewski R, Offerhaus GJA, Sitarz R. High-Throughput Sequencing of Gastric Cancer Patients: Unravelling Genetic Predispositions Towards an Early-Onset Subtype. Cancers (Basel) 2020; 12:1981. [PMID: 32708070 PMCID: PMC7409326 DOI: 10.3390/cancers12071981] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/15/2020] [Accepted: 07/17/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cancer is the fourth most common cause of cancer-related death. Currently, it is broadly accepted that the molecular complexity and heterogeneity of gastric cancer, both inter- and intra-tumor, display important barriers for finding specific biomarkers for the early detection and diagnosis of this malignancy. Early-onset gastric cancer is not as prevalent as conventional gastric carcinoma, but it is a preferable model for studying the genetic background, as young patients are less exposed to environmental factors, which influence cancer development. AIM The main objective of this study was to reveal age-dependent genotypic characteristics of gastric cancer subtypes, as well as conduct mutation profiling for the most frequent alterations in gastric cancer development, using targeted next-generation sequencing technology. PATIENTS AND METHODS The study group included 53 patients, consisting of 18 patients with conventional gastric cancer and 35 with an early-onset subtype. The DNA of all index cases was used for next-generation sequencing, employing a panel of 94 genes and 284 single nucleotide polymorphisms (SNPs) (TruSight Cancer Panel, Illumina), which is characteristic for common and rare types of cancer. RESULTS From among the 53 samples processed for sequencing, we were able to identify seven candidate genes (STK11, RET, FANCM, SLX4, WRN, MEN1, and KIT) and nine variants among them: one splice_acceptor, four synonymous, and four missense variants. These were selected for the age-dependent differentiation of gastric cancer subtypes. We found four variants with C-Score ≥ 10, as 10% of the most deleterious substitutions: rs1800862 (RET), rs10138997 (FANCM), rs2230009 (WRN), and rs2959656 (MEN1). We identified 36 different variants, among 24 different genes, which were the most frequent genetic alterations among study subjects. We found 16 different variants among the genes that were present in 100% of the total cohort: SDHB (rs2746462), ALK (rs1670283), XPC (rs2958057), RECQL4 (rs4925828; rs11342077, rs398010167; rs2721190), DDB2 (rs326212), MEN1 (rs540012), AIP (rs4930199), ATM (rs659243), HNF1A (rs1169305), BRCA2 (rs206075; rs169547), ERCC5 (rs9514066; rs9514067), and FANCI (rs7183618). CONCLUSIONS The technology of next-generation sequencing is a useful tool for studying the development and progression of gastric carcinoma in a high-throughput way. Our study revealed that early-onset gastric cancer has a different mutation frequency profile in certain genes compared to conventional subtype.
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Affiliation(s)
- Julita Machlowska
- Center for Medical Genomics-OMICs high-throughput technologies (OMICRON) project, Jagiellonian University Medical College, 31-034 Kraków, Poland; (J.M.); (P.K.); (P.W.)
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
| | - Przemysław Kapusta
- Center for Medical Genomics-OMICs high-throughput technologies (OMICRON) project, Jagiellonian University Medical College, 31-034 Kraków, Poland; (J.M.); (P.K.); (P.W.)
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
| | - Folkert H. M. Morsink
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (F.H.M.M.); (G.J.A.O.)
| | - Paweł Wołkow
- Center for Medical Genomics-OMICs high-throughput technologies (OMICRON) project, Jagiellonian University Medical College, 31-034 Kraków, Poland; (J.M.); (P.K.); (P.W.)
| | - Ryszard Maciejewski
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
| | - G. Johan A. Offerhaus
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (F.H.M.M.); (G.J.A.O.)
| | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (J.B.); (R.M.)
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (F.H.M.M.); (G.J.A.O.)
- Department of Surgery, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-090 Lublin, Poland
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19
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Shen T, Chen Z, Qiao J, Sun X, Xiao Q. Neutralizing monoclonal antibody against Dickkopf2 impairs lung cancer progression via activating NK cells. Cell Death Discov 2019; 5:123. [PMID: 31372243 PMCID: PMC6668384 DOI: 10.1038/s41420-019-0204-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 07/03/2019] [Accepted: 07/12/2019] [Indexed: 12/14/2022] Open
Abstract
Adenomatous polyposis coli (APC) and KRAS proto-oncogene (KRAS) mutations frequently co-occur in non-small cell lung cancer. Inactivating APC mutations in colorectal carcinoma has been well characterized, leading to the approaches targeting on dysregulated APC pathway. However, it remains undetermined whether such approaches are also applicable to non-small cell lung cancer patients harboring similar mutations of APC. Dickkopf-related protein 2 (DKK2) is a Wnt antagonist. Our previous study has proved that anti-DKK2 antibody 5F8 suppressed the growth of colorectal carcinoma with APC mutations, illustrating a new target agent of APC-mutated tumors. This study aimed to investigate the potential of applying anti-DKK2 antibody to non-small cell lung cancer with APC mutations. We found significant upregulation of Dkk2 expression in APC-mutated lung cancers. Administration of DKK2 antibody inhibited cancer growth via modulating tumor immune microenvironment in lung cancer mouse models. Our study provided strong evidence supporting APC mutations-directed applications of anti-DKK2 targeted therapy in a wide range of cancer types, including lung cancer.
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Affiliation(s)
- Tianli Shen
- Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi China
- Department of Pharmacology, School of Medicine, Yale University, 10 Amistad St, New Haven, CT USA
| | - Zhengxi Chen
- Department of Pharmacology, School of Medicine, Yale University, 10 Amistad St, New Haven, CT USA
- Department of Orthodontics, Shanghai Ninth People׳s Hospital, School of Stomatology, Shanghai key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Ju Qiao
- Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA USA
| | - Xuejun Sun
- Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi China
| | - Qian Xiao
- Department of Pharmacology, School of Medicine, Yale University, 10 Amistad St, New Haven, CT USA
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20
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Fattahi S, Golpour M, Amjadi-Moheb F, Sharifi-Pasandi M, Khodadadi P, Pilehchian-Langroudi M, Ashrafi GH, Akhavan-Niaki H. DNA methyltransferases and gastric cancer: insight into targeted therapy. Epigenomics 2018; 10:1477-1497. [PMID: 30325215 DOI: 10.2217/epi-2018-0096] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer is a major health problem worldwide occupying most frequent causes of cancer-related mortality. In addition to genetic modifications, epigenetic alterations catalyzed by DNA methyltransferases (DNMTs) are a well-characterized epigenetic hallmark in gastric cancer. The reversible nature of epigenetic alterations and central role of DNA methylation in diverse biological processes provides an opportunity for using DNMT inhibitors to enhance the efficacy of chemotherapeutics. In this review, we discussed key factors or mechanisms such as SNPs, infections and genetic modifications that trigger DNMTs level modification in gastric cancer, and their potential roles in cancer progression. Finally, we focused on how inhibitors of the DNMTs can most effectively be used for the treatment of gastric cancer with multidrug resistance.
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Affiliation(s)
- Sadegh Fattahi
- Cellular & Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, 4717647745, Babol, Iran.,North Research Center, Pasteur Institute, Amol, 4615885399, Iran
| | - Monireh Golpour
- Molecular & Cell Biology Research Center, Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Science, Sari, 4817844718, Iran
| | - Fatemeh Amjadi-Moheb
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, 4717647745, Babol, Iran
| | - Marzieh Sharifi-Pasandi
- Molecular & Cell Biology Research Center, Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Science, Sari, 4817844718, Iran
| | - Parastesh Khodadadi
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, 4717647745, Babol, Iran
| | | | - Gholam Hossein Ashrafi
- School of Life Science, Pharmacy & Chemistry, SEC Faculty, Cancer Theme, Kingston University London, Kingston upon Thames, London KT1 2EE, UK
| | - Haleh Akhavan-Niaki
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, 4717647745, Babol, Iran
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21
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Youssef O, Sarhadi V, Ehsan H, Böhling T, Carpelan-Holmström M, Koskensalo S, Puolakkainen P, Kokkola A, Knuutila S. Gene mutations in stool from gastric and colorectal neoplasia patients by next-generation sequencing. World J Gastroenterol 2017; 23:8291-8299. [PMID: 29307989 PMCID: PMC5743500 DOI: 10.3748/wjg.v23.i47.8291] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 11/01/2017] [Accepted: 11/14/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To study cancer hotspot mutations by next-generation sequencing (NGS) in stool DNA from patients with different gastrointestinal tract (GIT) neoplasms.
METHODS Stool samples were collected from 87 Finnish patients diagnosed with various gastric and colorectal neoplasms, including benign tumors, and from 14 healthy controls. DNA was isolated from stools by using the PSP® Spin Stool DNA Plus Kit. For each sample, 20 ng of DNA was used to construct sequencing libraries using the Ion AmpliSeq Cancer Hotspot Panel v2 or Ion AmpliSeq Colon and Lung Cancer panel v2. Sequencing was performed on Ion PGM. Torrent Suite Software v.5.2.2 was used for variant calling and data analysis.
RESULTS NGS was successful in assaying 72 GIT samples and 13 healthy controls, with success rates of the assay being 78% for stomach neoplasia and 87% for colorectal tumors. In stool specimens from patients with gastric neoplasia, five hotspot mutations were found in APC, CDKN2A and EGFR genes, in addition to seven novel mutations. From colorectal patients, 20 mutations were detected in AKT1, APC, ERBB2, FBXW7, KIT, KRAS, NRAS, SMARCB1, SMO, STK11 and TP53. Healthy controls did not exhibit any hotspot mutations, except for two novel ones. APC and TP53 were the most frequently mutated genes in colorectal neoplasms, with five mutations, followed by KRAS with two mutations. APC was the most commonly mutated gene in stools of patients with premalignant/benign GIT lesions.
CONCLUSION Our results show that in addition to colorectal neoplasms, mutations can also be assayed from stool specimens of patients with gastric neoplasms.
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Affiliation(s)
- Omar Youssef
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
| | - Virinder Sarhadi
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
| | - Homa Ehsan
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
| | - Tom Böhling
- Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki 00014, Finland
| | | | - Selja Koskensalo
- The HUCH Gastrointestinal Clinic, University Central Hospital of Helsinki, Helsinki 00290, Finland
| | - Pauli Puolakkainen
- The HUCH Gastrointestinal Clinic, University Central Hospital of Helsinki, Helsinki 00290, Finland
| | - Arto Kokkola
- The HUCH Gastrointestinal Clinic, University Central Hospital of Helsinki, Helsinki 00290, Finland
| | - Sakari Knuutila
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
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22
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Sakitani K, Hayakawa Y, Deng H, Ariyama H, Kinoshita H, Konishi M, Ono S, Suzuki N, Ihara S, Niu Z, Kim W, Tanaka T, Liu H, Chen X, Tailor Y, Fox JG, Konieczny SF, Onodera H, Sepulveda AR, Asfaha S, Hirata Y, Worthley DL, Koike K, Wang TC. CXCR4-expressing Mist1+ progenitors in the gastric antrum contribute to gastric cancer development. Oncotarget 2017; 8:111012-111025. [PMID: 29340033 PMCID: PMC5762301 DOI: 10.18632/oncotarget.22451] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 10/30/2017] [Indexed: 12/11/2022] Open
Abstract
Mist1 was recently shown to identify a discrete population of stem cells within the isthmus of the oxyntic gland within the gastric corpus. Chief cells at the base of the gastric corpus also express Mist1. The relevance of Mist1 expression as a marker of specific cell populations within the antral glands of the distal stomach, however, is unknown. Using Mist1-CreERT mice, we revealed that Mist1+ antral cells, distinct from the Mist1+ population in the corpus, comprise long-lived progenitors that reside within the antral isthmus above Lgr5+ or CCK2R+ cells. Mist1+ antral progenitors can serve as an origin of antral tumors induced by loss of Apc or MNU treatment. Mist1+ antral progenitors, as well as other antral stem/progenitor population, express Cxcr4, and are located in close proximity to Cxcl12 (the Cxcr4 ligand)-expressing endothelium. During antral carcinogenesis, there is an expansion of Cxcr4+ epithelial cells as well as the Cxcl12+ perivascular niche. Deletion of Cxcl12 in endothelial cells or pharmacological blockade of Cxcr4 inhibits antral tumor growth. Cxcl12/Cxcr4 signaling may be a potential therapeutic target.
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Affiliation(s)
- Kosuke Sakitani
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.,Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Yoku Hayakawa
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.,Graduate School of Medicine, The University of Tokyo, Department of Gastroenterology, Tokyo, Japan
| | - Huan Deng
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.,Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hiroshi Ariyama
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
| | - Hiroto Kinoshita
- Graduate School of Medicine, The University of Tokyo, Department of Gastroenterology, Tokyo, Japan
| | - Mitsuru Konishi
- Graduate School of Medicine, The University of Tokyo, Department of Gastroenterology, Tokyo, Japan
| | - Satoshi Ono
- Graduate School of Medicine, The University of Tokyo, Department of Gastroenterology, Tokyo, Japan
| | - Nobumi Suzuki
- Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Sozaburo Ihara
- Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Zhengchuan Niu
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Woosook Kim
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
| | - Takayuki Tanaka
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
| | - Haibo Liu
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
| | - Xiaowei Chen
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
| | - Yagnesh Tailor
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
| | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Boston, MA, USA
| | - Stephen F Konieczny
- Department of Biological Sciences, The Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA
| | - Hiroshi Onodera
- Department of Electrical and Electronic Engineering, The University of Tokyo, Tokyo, Japan
| | - Antonia R Sepulveda
- Division of Clinical Pathology and Cell Biology, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Samuel Asfaha
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
| | - Yoshihiro Hirata
- Graduate School of Medicine, The University of Tokyo, Department of Gastroenterology, Tokyo, Japan
| | - Daniel L Worthley
- Cancer theme, SAHMRI and Department of Medicine, University of Adelaide, SA, Australia
| | - Kazuhiko Koike
- Graduate School of Medicine, The University of Tokyo, Department of Gastroenterology, Tokyo, Japan
| | - Timothy C Wang
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
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A novel pathogenic splice acceptor site germline mutation in intron 14 of the APC gene in a Chinese family with familial adenomatous polyposis. Oncotarget 2017; 8:21327-21335. [PMID: 28423518 PMCID: PMC5400587 DOI: 10.18632/oncotarget.15570] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 01/27/2017] [Indexed: 11/25/2022] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant precancerous condition, clinically characterized by the presence of multiple colorectal adenomas or polyps. Patients with FAP has a high risk of developing colorectal cancer (CRC) from these colorectal adenomatous polyps by the mean age of diagnosis at 40 years. Germline mutations of the APC gene cause familial adenomatous polyposis (FAP). Colectomy has recommended for the FAP patients with significant polyposis. Here, we present a clinical molecular study of a four generation Chinese family with FAP. Clinical diagnosis of FAP has been done according to the phenotype, family history and medical records. Patient's blood samples were collected and genomic DNA was extracted. In order to identify the pathogenic mutation underlying the disease phenotype targeted next-generation sequencing and confirmatory sanger sequencing has undertaken. Targeted next generation sequencing identified a novel heterozygous splice-acceptor site mutation [c.1744-1G>A] in intron 14 of APC gene, which is co-segregated with the FAP phenotypes in the proband and amongst all the affected family members. This mutation is not present in unaffected family members and in normal healthy controls of same ethnic origin. According to the LOVD database for Chinese colorectal cancer patients, in Chinese population, 60% of the previously reported APC gene mutations causes FAP, are missense mutations. This novel splice-acceptor site mutation causing FAP in this Chinese family expands the germline mutation spectrum of the APC gene in the Chinese population.
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24
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Abstract
Background Germline mutations in the coding sequence of the tumour suppressor APC gene give rise to familial adenomatous polyposis (which leads to colorectal cancer) and are associated with many other oncopathologies. The loss of APC function because of deletion of putative promoter 1A or 1B also results in the development of colorectal cancer. Since the regions of promoters 1A and 1B contain many single nucleotide polymorphisms (SNPs), the aim of this study was to perform functional analysis of some of these SNPs by means of an electrophoretic mobility shift assay (EMSA) and a luciferase reporter assay. Results First, it was shown that both putative promoters of APC (1A and 1B) drive transcription in an in vitro reporter experiment. From eleven randomly selected SNPs of promoter 1A and four SNPs of promoter 1B, nine and two respectively showed differential patterns of binding of nuclear proteins to oligonucleotide probes corresponding to alternative alleles. The luciferase reporter assay showed that among the six SNPs tested, the rs75612255 C allele and rs113017087 C allele in promoter 1A as well as the rs138386816 T allele and rs115658307 T allele in promoter 1B significantly increased luciferase activity in the human erythromyeloblastoid leukaemia cell line K562. In human colorectal cancer HCT-116 cells, none of the substitutions under study had any effect, with the exception of minor allele G of rs79896135 in promoter 1B. This allele significantly decreased the luciferase reporter’s activity Conclusion Our results indicate that many SNPs in APC promoters 1A and 1B are functionally relevant and that allele G of rs79896135 may be associated with the predisposition to colorectal cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12863-016-0460-8) contains supplementary material, which is available to authorized users.
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25
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Clinicopathologic features of gastric cancer with synchronous and metachronous colorectal cancer in Korea: are microsatellite instability and p53 overexpression useful markers for predicting colorectal cancer in gastric cancer patients? Gastric Cancer 2016; 19:798-807. [PMID: 26445944 DOI: 10.1007/s10120-015-0552-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 09/22/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND A large-scale study was performed to identify the risk factors for developing synchronous and metachronous colorectal cancer (CRC) in gastric cancer (GC) patients, including microsatellite instability (MSI) and p53 overexpression. METHODS A total of 1041 GC patients who underwent endoscopic resection or surgery and underwent colonoscopy simultaneously or during surveillance for GC were consecutively enrolled. Clinicopathologic characteristics, MSI, and p53 overexpression were compared between the GC patients with and those without synchronous and metachronous CRC. RESULTS Of the 1041 patients, CRCs were detected in 67 (6.4 %) patients with GC. Forty-six (4.4 %) had synchronous CRC and 21 (2.0 %) had metachronous CRC. Univariate analysis indicated that age ≥63 years (P < 0.001), male sex (P = 0.005), and p53 overexpression (P = 0.040) were significantly associated with a higher incidence of CRC. However, body mass index, smoking, tumor location, tumor multiplicity, tumor histology, TNM stage, and MSI were not significantly associated with the incidence of CRC. Age ≥63 years (OR: 5.881; 95 % CI: 3.083-11.221; P < 0.001) and male sex (OR: 2.933; 95 % CI: 1.307-6.584; P = 0.009) were risk factors for CRC in GC patients according to multivariate analysis. CONCLUSIONS GC patients who are male and/or ≥63 years old are recommended to receive colonoscopy to detect CRC. MSI and p53 overexpression were not useful molecular markers for predicting CRC in GC.
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26
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Jin EH, Lee SI, Kim J, Seo EY, Lee SY, Hur GM, Shin S, Hong JH. Association between Promoter Polymorphisms of TFF1, TFF2, and TFF3 and the Risk of Gastric and Diffuse Gastric Cancers in a Korean Population. J Korean Med Sci 2015; 30:1035-41. [PMID: 26240479 PMCID: PMC4520932 DOI: 10.3346/jkms.2015.30.8.1035] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 04/17/2015] [Indexed: 01/26/2023] Open
Abstract
Gastric cancer is one of the most common cancers in the world. The aims of this study were to evaluate the association between polymorphisms in TFF gene family, TFF1, TFF2, and TFF3 and the risk of gastric cancer (GC) and GC subgroups in a Korean population via a case-control study. The eight polymorphisms in TFF gene family were identified by sequencing and genotyped with 377 GC patients and 396 controls by using TaqMan genotyping assay. The rs184432 TT genotype of TFF1 was significantly associated with a reduced risk of GC (odds ratio, [OR) = 0.45; 95% confidence interval, [CI] = 0.25-0.82; P = 0.009), more protective against diffuse-type GC (OR = 0.20; 95% CI = 0.05-0.89; P = 0.035) than GC (OR = 0.34; 95% CI = 0.14-0.82; P = 0.017) in subjects aged < 60 yr, and correlated with lymph node metastasis negative GC and diffuse-type GC (OR = 0.44; 95% CI = 0.23-0.86; P = 0.016 and OR = 0.20; 95% CI = 0.05-0.87; P = 0.031, respectively). In addition, a decreased risk of lymph node metastasis negative GC and diffuse-type GC was observed for rs225359 TT genotype of TFF1 (OR = 0.46, 95% CI = 0.24-0.88; P = 0.020 and OR = 0.21, 95% CI = 0.05-0.88; P = 0.033, respectively). These findings suggest that the rs184432 and rs225359 polymorphisms in TFF1 have protective effects for GC and contribute to the development of GC in Korean individuals.
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Affiliation(s)
- Eun-Heui Jin
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Korea
| | - Sang-Il Lee
- Department of Surgery, Chungnam National University Hospital, Daejeon, Korea
| | - JaeWoo Kim
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Korea
| | - Eun Young Seo
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea
| | - Su Yel Lee
- National Biobank of Korea, Chungnam National University Hospital, Daejeon, Korea
| | - Gang Min Hur
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Sanghee Shin
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Jang Hee Hong
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Korea
- Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Korea
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27
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The association between DNA copy number aberrations at chromosome 5q22 and gastric cancer. PLoS One 2014; 9:e106624. [PMID: 25210923 PMCID: PMC4161348 DOI: 10.1371/journal.pone.0106624] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 07/30/2014] [Indexed: 01/04/2023] Open
Abstract
Background Gastric cancer is common cancer. Discovering novel genetic biomarkers might help to identify high-risk individuals. Copy number variation (CNV) has recently been shown to influence risk for several cancers. The aim of the present study was sought to test the association between copy number at a variant region and GC. Methods A total of 110 gastric cancer patients and 325 healthy volunteers were enrolled in this study. We searched for a CNV and found a CNV (Variation 7468) containing part of the APC gene, the SRP19 gene and the REEP5 gene. We chose four probes targeting at APC-intron8, APC-exon9, SRP19 and REEP5 to interrogate this CNV. Specific Taqman probes labeled by different reporter fluorophores were used in a real-time PCR platform to obtain copy number. Both the original non-integer data and transformed integer data on copy number were used for analyses. Results Gastric caner patients had a lower non-integer copy number than controls for the APC-exon9 probe (Adjusted p = 0.026) and SRP19 probe (Adjusted p = 0.002). The analysis of integer copy number yielded a similar pattern although less significant (Adjusted p = 0.07 for APC-exon9 probe and Adjusted p = 0.02 for SRP19 probe). Conclusions Losses of a CNV at 5q22, especially in the DNA region surrounding APC-exon 9, may be associated with a higher risk of gastric cancer.
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28
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Bottarelli L, Azzoni C, Pizzi S, D'Adda T, Silini EM, Bordi C, Rindi G. Adenomatous polyposis coli gene involvement in ileal enterochromaffin cell neuroendocrine neoplasms. Hum Pathol 2013; 44:2736-42. [PMID: 24139208 DOI: 10.1016/j.humpath.2013.06.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 06/11/2013] [Accepted: 06/17/2013] [Indexed: 02/09/2023]
Abstract
The adenomatous polyposis coli gene is a key tumor suppressor gene. Alterations in this gene have been found in most sporadic colon cancers; associated with familial adenomatous polyposis; and found in neoplasms of other organs, such as the liver, stomach, lung, breast, and cerebellar medulloblastoma. In the heterogeneous group of neuroendocrine neoplasms of the gastrointestinal tract, the involvement of adenomatous polyposis coli is debated, and only occasional reports found adenomatous polyposis coli alterations in foregut and midgut neuroendocrine neoplasms, with adenomatous polyposis coli mutations only in the latter. To elucidate the penetrance of adenomatous polyposis coli alterations in ileal neuroendocrine neoplasms, we performed DNA fragment analysis (loss of heterozygosity for 5q22-23 and 5q23) and sequencing on the mutation cluster region of the adenomatous polyposis coli gene on 30 ileal enterochromaffin cell neuroendocrine neoplasms. Adenomatous polyposis coli gene mutations were detected in 23% of cases (7/30); in particular, 57% were missense and 14%, nonsense/frameshift, all novel and different from those reported in colorectal or other cancers. Loss of heterozygosity analysis demonstrated a deletion frequency of 15% (4/27). No association was found with features of tumor progression. Our observations support the involvement of somatic adenomatous polyposis coli alterations in tumorigenesis of ileal enterochromaffin cell neuroendocrine neoplasms; the mechanisms of adenomatous polyposis coli gene inactivation appear to be different from those reported in other tumor types.
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Affiliation(s)
- Lorena Bottarelli
- Centre for Molecular and Translational Oncology (COMT), Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathological Anatomy University and University Hospital of Parma, 43126 Parma, Italy
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29
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Ayed-Guerfali DB, Hassairi B, Khabir A, Sellami-Boudawara T, Gargouri A, Mokdad-Gargouri R. Expression of APC, β-catenin and E-cadherin in Tunisian patients with gastric adenocarcinoma: clinical significance. Tumour Biol 2013; 35:1775-83. [PMID: 24197976 DOI: 10.1007/s13277-013-1236-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 09/18/2013] [Indexed: 12/13/2022] Open
Abstract
Aberrant activation of the Wnt signalling pathway is a key feature of many cancers. β-Catenin, adenomatous polyposis coli (APC) and E-cadherin are major players in this pathway. The aim of this study is to examine the expression of β-catenin, APC and E-cadherin in tumour tissues of 80 Tunisian patients with gastric carcinoma and to determine the methylation status of the APC promoter in tumour tissues. Associations between protein expression and clinico-pathological parameters, including prognosis, were performed. Positive expression of β-catenin, APC and E-cadherin was observed in 77.5, 68.7 and 60% of cases, respectively. Tumours lacking membranous expression of β-catenin had greater extent of lymph node metastasis, poor differentiation and advanced T-stage. The expression of E-cadherin correlated with poor differentiation (P = 0.05) and β-catenin expression (P = 0.004). With regards to prognosis, the overall survival time was significantly prolonged for patients showing normal β-catenin expression (exclusively or predominantly membranous staining) alone or combined with positive APC expression (P log rank = 0.008 and 0.003, respectively). The methylated pattern of APC promoter 1A was detected in 43.8% of cases and correlated with T-stage (P = 0.046) and distant metastasis (P = 0.037). No correlation was found between the methylated profile of APC promoter 1A and the expression of APC protein in tumour tissues. Our findings suggest that deregulation of the Wnt pathway via abnormal expression of β-catenin and E-cadherin occurred frequently in gastric carcinoma and correlated with worse clinical behaviour.
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Affiliation(s)
- Dorra Ben Ayed-Guerfali
- Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour Street Km 6, BP 1177, 3038, Sfax, Tunisia
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Hidaka Y, Mitomi H, Saito T, Takahashi M, Lee SY, Matsumoto K, Yao T, Watanabe S. Alteration in the Wnt/β-catenin signaling pathway in gastric neoplasias of fundic gland (chief cell predominant) type. Hum Pathol 2013; 44:2438-48. [PMID: 24011952 DOI: 10.1016/j.humpath.2013.06.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 06/04/2013] [Accepted: 06/12/2013] [Indexed: 12/13/2022]
Abstract
Gastric neoplasia of chief cell-predominant type (GN-CCP) has been reported as a new, rare variant of gastric tumor. GN-CCPs were defined as tumors consisting of irregular anastomosing glands of columnar cells mimicking chief cells of fundic gland with nuclear atypia and prolapse-type submucosal involvement. We comparatively evaluated clinicopathologic features between 31 GN-CCPs and 130 cases of conventional gastric adenocarcinoma invading into submucosa (CGA-SM) in addition to nuclear β-catenin immunolabeling and direct sequencing of members of the Wnt/β-catenin pathway, CTNNB1, APC, and AXIN, in a subset of these tumors. GN-CCP presented as small protruded lesions located in the upper third of the stomach, with minimal involvement into the submucosa and rare lymphovascular invasion. None of the lesions have demonstrated a recurrence of disease or metastasis on follow-up. Nuclear β-catenin immunolabeling was higher in GN-CCP (labeling index [LI]: median, 19.3%; high expresser [LI >30%], 7/27 cases [26%]) than CGA-SM (median LI, 14.7%; high expresser, 1/19 cases [6%]). Missense mutation of APC was observed in 1 GN-CCP but not CGA-SM. Missense or nonsense mutations of CTNNB1 and AXIN1 were higher in GN-CCPs (14.8%, both) than CGA-SMs (5.3%, both). Missense mutations of AXIN2 were higher in GN-CCPs (25.9%) than in CGA-SMs (10.5%). Overall, 14 (51.9%) of 27 GN-CCPs and 5 (26.3%) of 19 CGA-SM cases harbored at least 1 of these gene mutations. In conclusion, GN-CCPs as a unique variant of nonaggressive tumor are characterized by nuclear β-catenin accumulation and mutation of CTNNB1 or AXIN gene, suggesting activation of the Wnt/β-catenin pathway.
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Affiliation(s)
- Yasuhiro Hidaka
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Human Pathology, Juntendo University School of Medicine, 1-1-19 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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HDAC up-regulation in early colon field carcinogenesis is involved in cell tumorigenicity through regulation of chromatin structure. PLoS One 2013; 8:e64600. [PMID: 23724067 PMCID: PMC3665824 DOI: 10.1371/journal.pone.0064600] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 04/03/2013] [Indexed: 01/02/2023] Open
Abstract
Normal cell function is dependent on the proper maintenance of chromatin structure. Regulation of chromatin structure is controlled by histone modifications that directly influence chromatin architecture and genome function. Specifically, the histone deacetylase (HDAC) family of proteins modulate chromatin compaction and are commonly dysregulated in many tumors, including colorectal cancer (CRC). However, the role of HDAC proteins in early colorectal carcinogenesis has not been previously reported. We found HDAC1, HDAC2, HDAC3, HDAC5, and HDAC7 all to be up-regulated in the field of human CRC. Furthermore, we observed that HDAC2 up-regulation is one of the earliest events in CRC carcinogenesis and observed this in human field carcinogenesis, the azoxymethane-treated rat model, and in more aggressive colon cancer cell lines. The universality of HDAC2 up-regulation suggests that HDAC2 up-regulation is a novel and important early event in CRC, which may serve as a biomarker. HDAC inhibitors (HDACIs) interfere with tumorigenic HDAC activity; however, the precise mechanisms involved in this process remain to be elucidated. We confirmed that HDAC inhibition by valproic acid (VPA) targeted the more aggressive cell line. Using nuclease digestion assays and transmission electron microscopy imaging, we observed that VPA treatment induced greater changes in chromatin structure in the more aggressive cell line. Furthermore, we used the novel imaging technique partial wave spectroscopy (PWS) to quantify nanoscale alterations in chromatin. We noted that the PWS results are consistent with the biological assays, indicating a greater effect of VPA treatment in the more aggressive cell type. Together, these results demonstrate the importance of HDAC activity in early carcinogenic events and the unique role of higher-order chromatin structure in determining cell tumorigenicity.
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Mirza S, Sharma G, Parshad R, Gupta SD, Pandya P, Ralhan R. Expression of DNA methyltransferases in breast cancer patients and to analyze the effect of natural compounds on DNA methyltransferases and associated proteins. J Breast Cancer 2013; 16:23-31. [PMID: 23593078 PMCID: PMC3625766 DOI: 10.4048/jbc.2013.16.1.23] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 02/27/2013] [Indexed: 02/08/2023] Open
Abstract
Purpose The DNA methylation mediated by specific DNA methyltransferases (DNMTs), results in the epigenetic silencing of multiple genes which are implicated in human breast cancer. We hypothesized that the natural compounds modulate the expression of DNMTs and their associated proteins in the breast cancer cell lines and affect the methylation mediated gene silencing. Methods The DNMTs transcript expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) in the tumors and the adjacent normal breast tissues of the patients with invasive ductal breast carcinoma. We tested the hypothesis that the natural compounds, viz., epigallocatechin gallate (EGCG), genistein, withaferin A, curcumin, resveratrol, and guggulsterone, have demethylation potential. To investigate this hypothesis, we analyzed the DNMTs expression at the transcript levels, followed by the analysis of DNMT1 and its associated proteins (HDAC1, MeCP2, and MBD2). Results The increased DNMTs transcripts expression, viz., DNMT1, DNMT3a, and DNMT3b, in the breast cancer tissues suggest involvement of the DNMTs in the breast carcinogenesis. Quantitative RT-PCR analysis revealed that the treatment with natural compounds, viz., EGCG, genistein, withaferin A, curcumin, resveratrol, and guggulsterone, resulted in a significant decrease in the transcript levels of all the DNMTs investigated. Importantly, these natural compounds decreased the protein levels of DNMT1, HDAC1, and MeCP2. Conclusion Our results demonstrate that the natural compounds, EGCG, genistein, withaferin A, curcumin, resveratrol, and guggulsterone, have the potential to reverse the epigenetic changes. Moreover, their lack of toxicity makes these natural compounds promising candidates for the chemoprevention of the breast cancer. In-depth future mechanistic studies aimed to elucidate how these compounds affect the gene transcription are warranted.
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Affiliation(s)
- Sameer Mirza
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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Fang Z, Xiong Y, Li J, Liu L, Zhang W, Zhang C, Wan J. APC gene deletions in gastric adenocarcinomas in a Chinese population: a correlation with tumour progression. Clin Transl Oncol 2012; 14:60-5. [PMID: 22262720 DOI: 10.1007/s12094-012-0762-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
INTRODUCTION The adenomatous polyposis coli (APC) gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It has been shown to be involved in genetic instability and to be down-regulated in several human carcinomas. The chromosome locus of APC, 5q21-22, is frequently deleted in gastric cancers (GCs). The functional impact of such regions needs to be extensively investigated in large amount of clinical samples. PATIENTS AND MATERIALS Case-matched tissues of GC and adjacent normal epithelium (n = 141) were included in this study. Quantitative PCR was carried out to examine the copy number as well as mRNA expression of APC gene in gastric malignancies. RESULTS Our results showed that copy number deletions of APC were present in a relatively high percentage (25.9%, 34 out of 131) of gastric cancer samples. There was a correlation between APC deletion and tumor progression (p < 0.01) as well as gene expression (p < 0.05) in collected GC samples. On the other hand, mRNA levels of APC were also impaired in GC samples with unaltered copy numbers. CONCLUSION Sporadic GCs exhibit different mechanisms of APC regulation.
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Affiliation(s)
- Zhengyu Fang
- Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Guangdong Province, Shenzhen, People's Republic of China
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Zhang X, Zhang R, Jiang Y, Sun P, Tang G, Wang X, Lv H, Li X. The expanded human disease network combining protein-protein interaction information. Eur J Hum Genet 2011; 19:783-8. [PMID: 21386875 DOI: 10.1038/ejhg.2011.30] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The human disease network (HDN) has become a powerful tool for revealing disease-disease associations. Some studies have shown that genes that share similar or same disease phenotypes tend to encode proteins that interact with each other. Therefore, protein-protein interactions (PPIs) may help us to further understand the relationships between diseases with overlapping clinical phenotypes. In this study, we constructed the expanded HDN (eHDN) by combining disease gene information with PPI information, and analyzed its topological features and functional properties. We found that the network is hierarchical and, most diseases are connected to only a few diseases, whereas a small part of diseases are linked to many different diseases. Diseases in a specific disease class tend to cluster together, and genes associated with the same disease are functionally related. Comparing the eHDN with the original HDN (oHDN, constructed using disease gene information) revealed high consistency over all topological and functional properties. This, to some extent, indicates that our eHDN is reliable. In the eHDN, we found some new associations among diseases resulting from the shared genes interacting with disease genes. The new eHDN will provide a valuable reference for clinicians and medical researchers.
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Affiliation(s)
- Xuehong Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
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Zammarchi F, Morelli M, Menicagli M, Di Cristofano C, Zavaglia K, Paolucci A, Campani D, Aretini P, Boggi U, Mosca F, Cavazzana A, Cartegni L, Bevilacqua G, Mazzanti CM. KLF4 is a novel candidate tumor suppressor gene in pancreatic ductal carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 178:361-72. [PMID: 21224073 DOI: 10.1016/j.ajpath.2010.11.021] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 08/12/2010] [Accepted: 09/21/2010] [Indexed: 01/28/2023]
Abstract
Ductal pancreatic carcinoma (DPC) is a deadly disease with an incidence of 9 cases in 100,000 people per year and a mortality rate close to 100%. Allelic losses in the long arm of chromosome 9 are commonly encountered in many human malignancies but no data are yet available about DPC. We screened 40 laser-microdissected DPC samples and 6 pre-invasive lesions for 9 microsatellite mapping markers of region 9q21.3 through 9q34.2. A small overlapping region of deletion, spanning 8 million base pairs, was identified between D9S127 and D9S105. Two genes, RSG3 and KLF4, mapped to 9q31.1 through 9q32, were further investigated. A highly significant association was found between KLF4 gene expression levels and genomic status. Similarly, absence of immunohistochemical expression of KLF4 protein was found in 86.8% cases of DPC (33/38). Overexpression of KLF4 in a human pancreatic carcinoma cell line induced a significant decrease in the proliferation associated with up-regulation of p21 and the down-regulation of cyclin D1. In conclusion, we identified a novel oncosuppressor region located at the 9q 31.1-3 locus that is lost in DPC at high frequency. Loss of KLF4 expression is closely related to the genomic loss, and its restoration inhibits cancer cell proliferation, suggesting a key suppressor role in pancreatic tumorigenesis.
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Affiliation(s)
- Francesca Zammarchi
- Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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Chung WC, Jung SH, Lee KM, Paik CN, Kwak JW, Jung JH, Yoo JY, Lee MK, Chung IS. Genetic instability in gastric epithelial neoplasias categorized by the revised vienna classification. Gut Liver 2010; 4:179-85. [PMID: 20559519 DOI: 10.5009/gnl.2010.4.2.179] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2009] [Accepted: 07/27/2009] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND/AIMS The aim of this study was to determine the structural chromosomal aberrations, such as loss of heterozygosity (LOH) and microsatellite instability (MSI), at multiple tumor suppressor gene loci in gastric epithelial neoplasia categorized by the revised Vienna classification. METHODS All tissue samples were excised by endoscopic mucosal resection. Sixty category 3 (low-grade adenoma) tissue samples and 51 category 4 samples (high-grade adenoma and intramucosal carcinoma with adenoma) were examined at the 7 sets of microsatellite loci linked to the tumor suppressor gene locus. RESULTS For category 3 and 4 tissue samples, there were no differences in the frequencies of LOH-positive chromosomes or the extent of chromosomal loss. The Helicobacter-pylori (H. pylori)-positive rate was significantly higher in MSI-positive category 4 samples than in category 3 samples (p=0.04). The frequency of MSI positivity was significantly higher in category 4 samples than in category 3 samples (p=0.003). CONCLUSIONS H. pylori infection is associated with genetic instability of the premalignant lesion. MSI occurs in the early stages of gastric carcinogenesis and its occurrence increases during malignant transformation. Detection of MSI in premalignant gastric lesions may be a surveillant of risk of malignant transformation.
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Affiliation(s)
- Woo Chul Chung
- Department of Internal Medicine, St. Vincent Hospital, The Catholic University of Korea, College of Medicine, Suwon, Korea
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Morán A, Ortega P, de Juan C, Fernández-Marcelo T, Frías C, Sánchez-Pernaute A, Torres AJ, Díaz-Rubio E, Iniesta P, Benito M. Differential colorectal carcinogenesis: Molecular basis and clinical relevance. World J Gastrointest Oncol 2010; 2:151-8. [PMID: 21160823 PMCID: PMC2999176 DOI: 10.4251/wjgo.v2.i3.151] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2009] [Revised: 08/24/2009] [Accepted: 08/31/2009] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CCR) is one of the most frequent cancers in developed countries. It poses a major public health problem and there is renewed interest in understanding the basic principles of the molecular biology of colorectal cancer. It has been established that sporadic CCRs can arise from at least two different carcinogenic pathways. The traditional pathway, also called the suppressor or chromosomal instability pathway, follows the Fearon and Vogelstein model and shows mutation in classical oncogenes and tumour suppressor genes, such as K-ras, adenomatous polyposis coli, deleted in colorectal cancer, or p53. Alterations in the Wnt pathway are also very common in this type of tumour. The second main colorectal carcinogenesis pathway is the mutator pathway. This pathway is present in nearly 15% of all cases of sporadic colorectal cancer. It is characterized by the presence of mutations in the microsatellite sequences caused by a defect in the DNA mismatch repair genes, mostly in hMLH1 or hMSH2. These two pathways have clear molecular differences, which will be reviewed in this article, but they also present distinct histopathological features. More strikingly, their clinical behaviours are completely different, having the “mutator” tumours a better outcome than the “suppressor” tumours.
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Affiliation(s)
- Alberto Morán
- Alberto Morán, Paloma Ortega, Carmen de Juan, Tamara Fernández-Marcelo, Cristina Frías, Pilar Iniesta, Manuel Benito, the second Department of Biochemistry and Molecular Biology, School of Pharmacy, Complutense University, 28040-Madrid, Spain
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Abstract
BACKGROUND AND AIM In patients with gastric adenocarcinoma (GA), the most common double primary cancer is colorectal cancer. The aim of the present study was to evaluate the necessity of preoperative colonoscopy in patients with GA who have no symptoms of colorectal disease or any past/family history of colorectal cancer. MATERIALS Colonoscopy was carried out in 205 patients before gastric surgery for treatment of GA. The prevalence of colorectal neoplasms (CRN, adenoma and adenocarcinoma) was evaluated according to age, sex, body mass index (BMI) and stage, location and differentiation of GA. RESULTS The median age and BMI were 59 years (range 32-81) and 22.9 (range 17.0-42.3), respectively. There were 135 male patients (65.9%). Synchronous adenoma and adenocarcinoma were detected in 68 (33.2%) and four (2.0%) patients, respectively. Univariate analysis showed that patients 50 years and older, male or with multiple GA had a significantly higher incidence of CRN (P = 0.005, 0.019, and 0.023, respectively). All of the GA patients with synchronous colorectal adenocarcinoma were older than 50 years. The stage, location and differentiation of GA and BMI did not show a significant difference in the incidence of CRN. Multivariate analysis showed that age (50 years and older) was the only risk factor of CRN in GA patients (odds ratio 2.470; 95% confidence interval 1.058-5.767). CONCLUSION Preoperative colonoscopy for screening of CRN should be considered in GA patients > or = 50 years because of a relatively high prevalence of CRN and the possibility of synchronous CRC.
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Affiliation(s)
- Hyung Ook Kim
- Departments of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Kamalidehghan B, Houshmand M, Ismail P, Panahi MSS, Akbari MHH. Delta mtDNA4977 is more common in non-tumoral cells from gastric cancer sample. Arch Med Res 2006; 37:730-5. [PMID: 16824932 DOI: 10.1016/j.arcmed.2006.02.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2005] [Accepted: 02/03/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to determine the frequency of delta mtDNA4977 in tumoral cells as compared with adjacent normal cells in gastric cancer. METHODS In order to investigate whether a high incidence of mutation exists in mitochondrial DNA of gastric cancer tissues, we screened one of common region of the mitochondrial genome by PCR amplification and Southern blot followed by DNA sequence analysis. DNA isolated from these cells was used to amplify hypervariable regions ATPase8/6, COXIII, ND3, ND4 and ND5 of delta mtDNA4977. RESULTS In 107 cancer patients, delta mtDNA4977 was detected in 6 cases (5.60%) of the tumoral tissues and 18 cases (16.82%) of the non-tumoral tissues that were adjacent to the tumors. Levels of delta mtDNA4977 deletions were found to be more in non-tumoral tissues than in adjacent tumoral tissues. There was no correlation of patients with certain clinical parameters like age, sex, tumor location and tumor size; however, there was an obvious relationship with intestinal-type of gastric cancer. CONCLUSIONS Unknown genetic aspects, ambiguous environmental factors and reactive oxygen species (ROS) can cause the delta mtDNA4977 mutation rate to be increased in gastric cancer. The results suggest that percentage level of delta mtDNA4977 is less common and intolerable in tumoral tissue, probably because of high metabolism and ROS generation. We supposed that the cells initially had delta mtDNA4977 transform to tumoral cells and the existed deletion conferred metabolic disadvantage; thus, cells containing such a mtDNA deletion would be overgrown by other cancer cells without this mtDNA deletion. As a result, the presence of delta mtDNA4977 will be low in tumoral cells.
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Affiliation(s)
- Behnam Kamalidehghan
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
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Kamalidehghan B, Houshmand M, Panahi MSS, Abbaszadegan MR, Ismail P, Shiroudi MB. Tumoral Cell mtDNA ∼8.9 kb Deletion Is More Common than Other Deletions in Gastric Cancer. Arch Med Res 2006; 37:848-53. [PMID: 16971224 DOI: 10.1016/j.arcmed.2006.03.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2005] [Accepted: 03/03/2006] [Indexed: 12/19/2022]
Abstract
BACKGROUND The aim of the study was to clarify the role of deletion of mitochondrial DNA (mtDNA) in gastric carcinogenesis and to determine prevalence of mitochondrial deletions in different regions of tumoral tissue in comparison with adjacent non-tumoral tissue in gastric cancer. METHODS In order to investigate whether a high incidence of mutations exists in mtDNA of gastric cancer tissues, we screened five regions of the mitochondrial genome by PCR amplification, Southern blot and DNA sequence analysis. RESULTS Of 71 cancer patients, the approximately 8.9 kb deletion was detected among different deletions in 9 cases (12.67%) of the tumoral tissues and 1 case (1.40%) in non-tumoral tissues that were adjacent to the tumors. Level of the 8.9 kb deletion has been found to be more than other deletions in tumoral tissues. CONCLUSIONS The approximately 8.9 kb deletion has an obvious correlation with age and histological type. These data suggest that the approximately 8.9 kb deletion in mtDNA may play an important role in gastric carcinogenesis.
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Affiliation(s)
- Behnam Kamalidehghan
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
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Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, Wu TT, Huang S, Xie K. Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression. Cancer Res 2005; 65:2746-54. [PMID: 15805274 DOI: 10.1158/0008-5472.can-04-3619] [Citation(s) in RCA: 236] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Krüppel-like factor 4 (KLF4) is highly expressed in epithelial tissues such as the gut and skin. However, the role of KLF4 in human gastric cancer development and progression is unknown. Here we show that KLF4 protein expression was decreased or lost in primary tumors and, in particular, lymph node metastases when compared with that in normal gastric mucosa. Moreover, loss of KLF4 expression in the primary tumors was significantly associated with poor survival, and also an independent prognostic marker in a multivariate analysis. Consistently, most human gastric cancer cell lines exhibited loss of or a substantial decrease in KLF4 expression at both RNA and protein levels. Enforced restoration of KLF4 expression resulted in marked cell growth inhibition in vitro and significantly attenuated tumor growth and total abrogation of metastasis in an orthotopic animal model of gastric cancer. Mechanism studies indicated that promoter hypermethylation and hemizygous deletion contributed to the down-regulation of KLF4 expression and the induction of apoptosis contributed to the antitumor activity of KLF4. Collectively, our data provide first clinical and casual evidence and potential mechanism that the alteration of KLF4 expression plays a critical role in gastric cancer development and progression.
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Affiliation(s)
- Daoyan Wei
- Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
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Doucas H, Garcea G, Neal CP, Manson MM, Berry DP. Changes in the Wnt signalling pathway in gastrointestinal cancers and their prognostic significance. Eur J Cancer 2005; 41:365-79. [PMID: 15691635 DOI: 10.1016/j.ejca.2004.11.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2004] [Revised: 10/08/2004] [Accepted: 11/12/2004] [Indexed: 12/24/2022]
Abstract
Many steps in the Wnt signalling pathway may be altered during the process of carcinogenesis. This Review focuses on the changes observed in gastrointestinal cancers. A literature search was undertaken and the currently available data summarised. Understanding the alterations to this signalling pathway may help to reveal future targets for therapeutic agents. In addition, since in some tumours, levels of components of the Wnt pathway have been found to correlate with clinical stage, their potential use as prognostic indicators is highlighted.
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Affiliation(s)
- H Doucas
- Department of Cancer Biomarkers and Prevention Group, Biocentre, Leicester LE1 7RH, UK.
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Ramburan A, Oladiran F, Smith C, Hadley GP, Govender D. Microsatellite analysis of the adenomatous polyposis coli (APC) gene and immunoexpression of beta catenin in nephroblastoma: a study including 83 cases treated with preoperative chemotherapy. J Clin Pathol 2005; 58:44-50. [PMID: 15623481 PMCID: PMC1770552 DOI: 10.1136/jcp.2004.019752] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
AIMS To determine whether microsatellite mutations of the adenomatous polyposis coli (APC) gene have pathological or prognostic significance in nephroblastomas and to correlate APC alterations with beta catenin immunoexpression. METHODS One hundred nephroblastomas were analysed, 83 of which received preoperative chemotherapy. Normal and tumour DNA was isolated using standard proteinase K digestion and phenol/chloroform extraction from paraffin wax embedded tissue. Polymerase chain reaction using four APC microsatellite markers-D5S210, D5S299, D5S82, and D5S346-was performed and the products analysed. Immunohistochemistry was performed using the LSAB kit with diaminobenzidine as chromogen. Results were correlated with clinicopathological data using the chi(2) test. RESULTS Allelic imbalance/loss of heterozygosity was more frequent than microsatellite instability, with 30% of cases showing allelic imbalance/ loss of heterozygosity and 16% showing microsatellite instability. Although there was a significant correlation between the results for individual markers and the clinicopathological data, the overall results do not support a prognostic role for APC in nephroblastoma. Expression of beta catenin was seen in 93% of cases. Staining was predominantly membranous, with epithelium, blastema, and stroma being immunoreactive. Cytoplasmic redistribution was seen in 58% of cases, but no nuclear staining was detected. No significant associations between beta catenin expression and the clinicopathological parameters were found. Kaplan-Meier survival plots showed that patients with loss of membranous staining and pronounced cytoplasmic staining (score, 3) had a significantly shorter survival (p = 0.04; median survival, 5.87 months). CONCLUSION Microsatellite analysis of APC and immunoexpression of beta catenin did not provide significant pathological or prognostic information in this cohort of nephroblastomas.
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Affiliation(s)
- A Ramburan
- Molecular Biology Research Facility, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Congella, 7925 Durban, South Africa
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Wang JY, Hsieh JS, Chen CC, Tzou WS, Cheng TL, Chen FM, Huang TJ, Huang YS, Huang SY, Yang T, Lin SR. Alterations of APC, c-met, and p53 genes in tumor tissue and serum of patients with gastric cancers. J Surg Res 2004; 120:242-8. [PMID: 15234219 DOI: 10.1016/j.jss.2003.12.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2003] [Indexed: 12/31/2022]
Abstract
BACKGROUND Gastric cancer is one of the most significant causes of cancer-related death worldwide. A genetic model consisting of sequential accumulations of alterations in specific genes for gastric cancer has been proposed. MATERIALS AND METHODS The significance of adenomatous polyposis coli (APC) and p53 gene mutations in cancer tissues and their paired serum of 34 gastric cancer patients was investigated using polymerase chain reaction single-strand conformation polymorphism analysis (PCR-SSCP), followed by direct sequencing. c-met mRNA expression was evaluated by reverse-transcription PCR (RT-PCR). Additionally, analyses were carried out to detect the serum carcinoembryonic antigen (CEA) levels, and their correlation to these three molecular markers. Finally, serum molecular markers and their correlation to the presence of postoperative recurrence/metastasis were analyzed. RESULTS Of all, 32.4% of patients presented mutations in APC and p53, respectively, and 58.8% presented the overexpression in c-met, overall, at least one of these genetic alterations in 79.4% of tumor tissues. Comparison of three molecular markers showed that the individual detection rate in the serum of patients with tumors harboring the same abnormalities was 18.2, 70.0, and 36.4% for APC, c-met, and p53 genes, respectively. In general, 59.3% of serum from cancerous tissues with gene alterations was demonstrated as positive, whereas all healthy volunteers' sera remained negative. Regarding gene alterations in tumor tissues, c-met overexpression was significantly related to the tumor size (P = 0.017), depth of tumor invasion (P = 0.007), lymph-node metastasis (P < 0.001), and TNM stage (P = 0.001). In the serum, c-met overexpression was closely associated with lymph-node metastasis (P = 0.008) and TNM stage (P = 0.016). The overall positive tumor gene detection rate in the serum was prominently correlated to the serum CEA levels (P = 0.038). In addition, a significantly higher postoperative metastasis/recurrence rate in patients harboring gene mutations with serum molecular markers than those without serum molecular markers was also demonstrated (P = 0.014). CONCLUSIONS Our findings suggest that serum molecular markers can be detected in a substantial proportion of gastric cancer patients, and these may offer an auxiliary approach in the noninvasive detection and prognosis of gastric cancer.
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Affiliation(s)
- Jaw-Yuan Wang
- Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan
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Liu P, Zhang XY, Shao Y, Zhao ZQ. Microsatellite instability in dysplasia mucosa and gastric cancer. Shijie Huaren Xiaohua Zazhi 2004; 12:512-515. [DOI: 10.11569/wcjd.v12.i3.512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Gastric mucosa dysplasia has been regarded as a precancerous lesion of the stomach. Abnormal gene alterations in the mucosa dysplasia of the stomach, which may lead to cell transformation, are probably of great importance in the development of gastric cancer (GC). Microsatellite instability (MSI) is a good marker of genome instability. Investigation of MSI in the cancer and precancerous lesion of the stomach will help us to search into the carcinogenesis of stomach and the potential role of MSI in the development of gastric cancer.
METHODS: Silver staining single strand conformation polymorphis-polymerease chain reaction (PCR-SSCP) was used to screen MSI markers at 5 loci in formalin-fixed,paraffin-embeded tissues of GC (n = 30), dysplasia (n = 30) and corresponding normal gastric tissues.
RESULTS: The abnormal shifting of the single-strand DNA was identified in 7 (23.3%) out of GC, in 9 (30%) out of dysplasia samples respectively. Three (10%) tumors and two (6.7%) dysplasia displayed a high-level of MSI (two or more loci altered). Low-level MSI (one loci altered) was detected in 13.3% of the tumors and in 23.3% dysplasia samples. GC with MSI was associated with distal location of the tumors (P = 0.044). No association was detected between MSI and the grade of dysplasia.
CONCLUSION: The accumulation of MSI in the dysplasia of gastric mucosa may be an early molecular event in the development of gastric cancer. It contributes probably to the multistep gastric carcinogenesis.
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Hu ZL, Wen JF, Liu Y, Wang KS, Zhen H, Fu CY. Effects of TGIF antisense oligonucleotide on proliferation and apoptosis of gastric carcinoma cells. Shijie Huaren Xiaohua Zazhi 2004; 12:530-532. [DOI: 10.11569/wcjd.v12.i3.530] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: TG interacting factor(TGIF) can inhibit both TGF-β and retinoid signaling pathways, moreover, the activation of MAPK pathway can lengthen its half life. However, its role in carcinogenesis is still unclear. Thus we attempt to investigate the effect of TGIF antisense oligodeoxynucleo-tide(ASDON) on proliferation and apoptosis of gastric carcinoma cells.
METHODS: After gastric carcinoma cells, SGC-7901, were transfected with TGIF ASDON, we analyzed the transfect efficiency by RT-PCR, its proliferation by MTT method, cell cycle and apoptosis rate via flow cytometer.
RESULTS: After transfection with TGIF ASDON, the proliferation of SGC-7901 cells was partially inhibited, and its inhibitory rate was increased to 20.4% at 72 h, whereas it had no effect on cell cycle and apoptosis of SGC-7901 cells. Followed by the treatment of TGF-β1, the growth rate of cells transfected with TGIF ASDON was distinctly reduced by 30%, and the content of G1 phase cells increased more obviously compared with the cells transfected with mutated oligonucleotides or untransfected cells.
CONCLUSION: TGIF can resist the negative regulation of TGF-β1 over proliferation and cell cycle. Most of tumor cells and interstitial cells can secrete TGF-β1, and tumor cells may resist the TGF-β1 mediated growth inhibition via TGIF, leading to the progression and even metastasis of tumor.
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Li XH, Zhang WD, Wang BT, Xiao B, Zhang ZS. Gene expression profiling in intestinal-type gastric carcinoma by cDNA microarray. Shijie Huaren Xiaohua Zazhi 2004; 12:16-19. [DOI: 10.11569/wcjd.v12.i1.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify a set of genes involved in the development of intestinal-type gastric carcinoma.
METHODS: Pure mRNAs from 6 cases of intestinal-type gastric carcinoma and corresponding noncancerous mucosae were reversely transcribed into cDNAs labeled with Cy5 and Cy3 dyes for probes, then mixed and hybridized with the cDNA microarray consisting of 4 096 genes, and the fluorescent signals were scanned.
RESULTS: Among total genes, 333 were up-regulated and 333 down-regulated in intestinal-type gastric cancer tissues. Within altered expression of those genes, cell-cycle regulators and growth factors were up-regulated, and the promoter genes of apoptosis were down-regulated; Oncogenes and cell-adhesion molecules were more up-regulated; The cancer progression genes were up-regulated, while the anti-cancer progression genes were down-regulated.
CONCLUSION: The quick and high-throughout method of gene expression profile by cDNA array provides us with an overview of gene changes that may involved in intestinal-type gastric cancer development, and will open up new possibilities to identify novel molecular targets for diagnosis and therapy. Several genes are altered in intestinal-type gastric cancer, which need to be further investigated.
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Lu C, Xu HM, Ren Q, Ao Y, Wang ZN, Ao X, Jiang L, Luo Y, Zhang X. Somatic mutation analysis of p53 and ST7 tumor suppressor genes in gastric carcinoma by DHPLC. World J Gastroenterol 2003; 9:2662-5. [PMID: 14669308 PMCID: PMC4612027 DOI: 10.3748/wjg.v9.i12.2662] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To verify the effectiveness of denaturing high-performance liquid chromatography (DHPLC) in detecting somatic mutation of p53 gene in gastric carcinoma tissues. The superiority of this method has been proved in the detection of germline mutations, but it was not very affirmative with respect to somatic mutations in tumor specimens. ST7 gene, a candidate tumor suppressor gene identified recently at human chromosome 7q31.1, was also detected because LOH at this site has also been widely reported in stomach cancer.
METHODS: DNA was extracted from 39 cases of surgical gastric carcinoma specimen and their correspondent normal mucosa. Seven fragments spanning the 11 exons were used to detect the mutation of p53 gene and the four exons reported to have mutations in ST7 gene were amplified by PCR and directly analyzed by DHPLC without mixing with wild-type allele.
RESULTS: In the analysis of p53 gene mutation, 9 aberrant DHPLC chromatographies were found in tumor tissues, while their normal-adjacent counterparts running in parallel showed a normal shape. Subsequent sequencing revealed nine sequence variations, 1 polymorphism and 8 mutations including 3 mutations not reported before. The mutation rate of p53 gene (21%) was consistent with that previously reported. Furthermore, no additional aberrant chromatography was found when wild-type DNA was added into the DNA of other 30 tumor samples that showed normal shapes previously. The positivity of p53 mutations was significantly higher in intestinal-type carcinomas (40%) than that in diffuse-type (8.33%) carcinomas of the stomach. No mutation of ST7 gene was found.
CONCLUSION: DHPLC is a very convenient method for the detection of somatic mutations in gastric carcinoma. The amount of wild type alleles supplied by the non-tumorous cells in gastric tumor specimens is enough to form heteroduplex with mutant alleles for DHPLC detection. ST7 gene may not be the target gene of inactivation at 7q31 site in gastric carcinoma.
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Affiliation(s)
- Chong Lu
- Laboratory of Medical Genomics, Oncology Department, the First Affiliated Clinical College, China Medical University, Shenyang, 110001, Liaoning Province, China
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Lin WL, Li DG, Chen Q, Lu HM, Ma XM, Sun PL. Clinical efficacy and mechanism of oxaliplatin in treating human gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2003; 11:1535-1539. [DOI: 10.11569/wcjd.v11.i10.1535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the therapeutic effect of oxaliplatin on human gastric carcinoma and to explore the mechanisms.
METHODS 22 cases of stage IV gastric carcinoma patients received 4-6 (mean 4.6) cycles of first line combined chemotherapy with oxaliplatin (oxaliplatin 85 mg/m2, ivgtt, 1 h, d 1; leukovorin 200 mg/m2, iv, gtt, 1 h, d 1-5; 5-FU 300 mg/m2, iv, d 1-2; 5-FU, continuously iv, gtt, 48 h; 1 cycle/2w). Response rate, progression-free survival (PFS), total survival time, toxic side effects were evaluated. The inhibitory effect of oxaliplatin on human gastric cell line SGC-7901 was calculated by MTT and IC50 was measured. Flow cytometry and TUNEL were applied to evaluate the apoptosis of cell line induced by the drug. The expression of caspase-3 mRNA was detected by RT-PCR.
RESULTS Total response (complete and partial) occurred in 9 (40.9%) patients. Mean PFS was 4.2 months and mean total survival time was 7.2 months. Cumulative neurotoxicity (all grade I-II), vomiting and diarrhea, myelosuppression appeared in 93.5%, 20%, 32.9% of the patients, respectively. Apoptosis index was elevated after incubating with 1 mmol/L oxaliplatin for 30 min, but without statistic significance (P>0.05), but was much higher both by flowcytometry and TUNEL with statistical significance (P<0.05) after incubating with 1 mmol/L oxaliplatin for 2 days. Caspase-3 mRNA expression was elevated in oxaliplatin treated cells and correlated with apoptosis induced by the drug.
CONCLUSION Oxaliplatin is effective and well-tolerated on human advanced gastric carcinoma. Oxaliplatin could significantly inhibit the growth of human gastric cell line SGC-7901, inducing caspase-3 mRNA expression and cell apoptosis.
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Affiliation(s)
| | - Ding-Guo Li
- Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
| | - Qiang Chen
- Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
| | - Han-Min Lu
- Xinhua Hospital, Shanghai Second Medical University, Shanghai 200092, China
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