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Raza Y, Mubarak M, Memon MY, Alsulaimi MS. Update on molecular pathogenesis of Helicobacter pylori-induced gastric cancer. World J Gastrointest Pathophysiol 2025; 16:107052. [DOI: 10.4291/wjgp.v16.i2.107052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/09/2025] [Accepted: 04/21/2025] [Indexed: 06/19/2025] Open
Abstract
Helicobacter pylori (H. pylori) infection is one of the most prevalent bacterial infections affecting mankind. About half of the world’s population is infected with it. It causes several upper gastrointestinal diseases, including gastric cancer (GC). It has been identified as a major risk factor for GC. GC is one of the most common cancers affecting humans and the third leading cause of cancer-related deaths worldwide. H. pylori infection causes an inflammatory response that progresses through a series of intermediary stages of precancerous lesions (gastritis, atrophy, intestinal metaplasia, and dysplasia) to the final development of GC. Among infected individuals, approximately 10% develop severe gastric lesions such as peptic ulcer disease, 1%-3% progress to GC, and 0.1% develop mucosa-associated lymphoid tissue followed by the development of lymphoma. The bacterium has many virulence factors, including cytotoxin-associated gene A, vacuolating cytotoxin A, and the different outer membrane proteins that cause cancer by different mechanisms. These virulence factors activate cell signaling pathways such as PI3-kinase/Akt, JAK/STAT, Ras, Raf, and ERK signaling that control cell proliferation. Uncontrolled proliferation can lead to cancer. In addition, the repair of DNA damage may also be impaired by H. pylori infection. Reduced DNA repair in combination with increased DNA damage can result in carcinogenic mutations. The accurate identification of pathogenetic pathways is imperative for the development of targeted diagnostic markers and personalized treatments. This scoping review aims to update the readers on the role of H. pylori in the development of GC. It will focus on the molecular mechanisms underpinning gastric carcinogenesis in H. pylori infection. It will highlight the interaction between bacterial virulence factors and host cellular pathways, providing insights into potential therapeutic targets and preventive strategies.
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Affiliation(s)
- Yasir Raza
- Department of Microbiology, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Muhammad Yousuf Memon
- Department of Gastroenterology, King Saud Hospital, Unaizah, Unaizah 56437, Al Qassim, Saudi Arabia
| | - Mohammed Saud Alsulaimi
- Department of Gastroenterology, King Saud Hospital, Unaizah, Unaizah 56437, Al Qassim, Saudi Arabia
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Nakayama I. Therapeutic strategy for scirrhous type gastric cancer. Jpn J Clin Oncol 2025:hyaf081. [PMID: 40403741 DOI: 10.1093/jjco/hyaf081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Accepted: 05/09/2025] [Indexed: 05/24/2025] Open
Abstract
Scirrhous-type gastric cancer (SGC) is a rare but well-recognized subset of resectable gastric cancer (GC), accounting for ⁓10% of cases. Despite its long history of clinical recognition dating back to the pre-1900s, SGC remains one of the most challenging GC subtypes to treat. Traditionally, SGC has been clinically defined as Borrmann type 4 GC, with histological classifications such as signet ring cell carcinoma or diffuse-type histology serving as alternative diagnostic criteria. Therapeutic advancements for SGC have largely focused on locally advanced or oligometastatic disease, yet no SGC-specific treatment has been established. The phase III JCOG0501 trial failed to demonstrate a survival benefit of neoadjuvant S-1 plus cisplatin for Borrmann type 4 and large type 3 GC. Recent developments in biomarker-driven therapies may redefine SGC by molecular subtypes, with CLDN18.2-targeted therapy emerging as a potential option for some SGC cases. However, as the landscape of medical oncology evolves, SGC may not remain a distinct therapeutic entity. The focus should shift toward understanding the intrinsic biology of SGC. Treatment development for SGC is expected to continue advancing, becoming increasingly stratified based on molecular abnormalities while maintaining a commitment to addressing unmet needs, such as early-onset GC and GC with symptomatic peritoneal dissemination.
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Affiliation(s)
- Izuma Nakayama
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwanoha 6-5-1, Kashiwa, 277-8577, Japan
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Tsai MM, Lin HC, Yu MC, Lin WJ, Chu MY, Tsai CC, Cheng CY. Anticancer Effects of Helminthostachys zeylanica Ethyl acetate Extracts on Human Gastric Cancer Cells through Downregulation of the TNF-α-activated COX-2-cPLA2-PGE 2 Pathway. J Cancer 2021; 12:7052-7068. [PMID: 34729107 PMCID: PMC8558661 DOI: 10.7150/jca.64638] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/24/2021] [Indexed: 12/13/2022] Open
Abstract
Background: Gastric cancer (GC) is the second most prevalent cancer worldwide and the eighth most common cause of tumor-related death in Taiwan. Helminthostachys zeylanica, a flavonoid compound, has anti-inflammatory, immunomodulatory, and anticancer effects. We examined whether an extract of H. zeylanica (E1 and E2) has potential as a treatment for GC. Methods: We investigated the effects (pro-apoptosis, pro-autophagy, and antiproliferation ability) of H. zeylanica-E2 on cell viability in healthy gastric epithelial (GES-1) and GC cells (AGS and BGC823). H. zeylanica-E2 was toxic to GC cells but had little or no toxicity to normal cells. Results: In this study, H. zeylanica-E2 induced apoptosis through caspase 3/7, Bcl-2, Bax, cyclooxygenase-2 (COX-2), and cleaved poly (ADP-ribose) polymerase pathways in GC cells. In addition, it increased autophagy by stimulating autophagy-related protein (ATG)5, ATG7, LC3-I/LC3-II, and inhibiting COX-2 activity in GC cells. We also found that H. zeylanica-E2 exhibited antiproliferation ability through cell cycle arrest in G0/G1 and G2/M and suppressed the migration of GC cells. The anticancer effects of H. zeylanica-E2 in GC cells might be mediated partly through inhibition of tumor necrosis factor-α (TNF-α)-activated proinflammatory cytosolic phospholipase A2 (cPLA2)-COX-2-prostaglandin E2 (PGE2) pathway. Conclusions: Our results suggest that H. zeylanica-E2 has potential as a novel adjunctive agent for the treatment of GC.
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Affiliation(s)
- Ming-Ming Tsai
- Department of Nursing, Division of Basic Medical Sciences, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan and Department of General Surgery, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan
| | - Horng-Chyuan Lin
- Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Chin Yu
- Department of Surgery, New Taipei Municipal TuCheng Hospital, Chang Gung Memorial Hospital at Linkou, and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wan-Jung Lin
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Mei-Yi Chu
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Ching-Ching Tsai
- Department of Nursing, College of Nursing, Chang Gung University of Science and Technology, and Department of Cardiology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Ching-Yi Cheng
- Graduate Institute of Health Industry Technology, Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.,Department of Pulmonary Infection and Immunology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
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Epstein-Barr Virus-Encoded Latent Membrane Protein 2A Downregulates GCNT3 via the TGF-β1/Smad-mTORC1 Signaling Axis. J Virol 2021; 95:JVI.02481-20. [PMID: 33658337 PMCID: PMC8139646 DOI: 10.1128/jvi.02481-20] [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: 12/12/2022] Open
Abstract
Increasing evidence shows that Epstein-Barr virus (EBV) infection is closely related to various lymphoid and epithelioid malignancies. However, the underlying mechanisms are unclear. GCNT3 (core 2β-1,6-acetylglucosaminyltransferase) is a new type of core mucin synthase, and its expression in EBV-associated gastric cancer (EBVaGC) is lower than that in EBV-negative gastric cancer (EBVnGC). EBV-encoded latent membrane protein 2A (LMP2A) is a transmembrane protein with tumorigenic transformation properties. Here, we demonstrated that LMP2A inhibited the transcription of GCNT3 by inhibiting Smad2/3 and Smad4. LMP2A restrained the activation of the mTORC1 pathway by inactivating the TGF-β1/Smad pathway and then downregulated GCNT3 expression. The mTORC1-GCNT3 pathway promoted cell proliferation and migration and inhibited G0/G1 cell arrest. Related proteins involved in epithelial-mesenchymal transition (EMT) were downstream molecules of the TGF-β1/Smad-mTORC1-GCNT3 pathway. GCNT3 inhibited autophagy by inducing mTORC1 phosphorylation. These findings indicate that targeting the TGF-β1/Smad-mTORC1-GCNT3 axis may represent a novel therapeutic target in GC.ImportanceEpstein-Barr virus (EBV) is an opportunistic pathogen, and the latent membrane protein 2A (LMP2A) encoded by EBV plays a key role in ensuring the incubation period of EBV. Glycosylation modification is an important marker of cancer cells, and recent studies have reported that it is related to EBV. Our conclusions provide deeper theoretical support for the role of LMP2A and TGF/Smad-mTORC1-GCNT3 in EBVaGC and help to understand glycosylation abnormalities in cancer. Our results may provide novel therapeutic targets for the treatment of gastric cancer against the TGF/Smad-mTORC1-GCNT3 signaling cascade.
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Zhou X, Jiao D, Dou M, Zhang W, Hua H, Chen J, Li Z, Li L, Han X. Association of APC gene promoter methylation and the risk of gastric cancer: A meta-analysis and bioinformatics study. Medicine (Baltimore) 2020; 99:e19828. [PMID: 32312003 PMCID: PMC7220245 DOI: 10.1097/md.0000000000019828] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The methylation status of the adenomatous polyposis coli (APC) promoter has been shown to be associated with the occurrence of gastric cancer, but this finding remains controversial. The aim of this study was to investigate the relationship between methylation of the APC gene promoter and gastric cancer. METHODS We searched the Web of Science, EMBASE, Medline, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from the date of creation until August 1, 2019. According to the inclusion criteria, the relationship between the methylation status of the APC gene promoter and gastric cancer was investigated. The incidence of APC promoter methylation in the tissues or blood of patients with and without gastric cancer was compared. The results are expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed effects model or a random effects model to generate forest plots. We further validated the results using the MethHC database. RESULTS Eight studies (985 samples) were included. Our meta-analysis showed that the incidence of APC promoter methylation in patients with gastric cancer was higher than that of patients without gastric cancer (OR = 3.86, 95% CI 1.71-8.74, P = .001). Methylation of the APC promoter is associated with the incidence of gastric cancer, and it increases the risk of gastric cancer. CONCLUSION This study provides a new strategic direction for research on gastric cancer. Methylation of the APC promoter may be a potential biomarker for the diagnosis of gastric cancer, but the results of this work require further confirmation.
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Affiliation(s)
| | | | | | - Weijie Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hao Hua
- Department of Preventive Medicine, Division of Environmental Health, Keck School of Medicine of USC, Los Angeles, CA
| | | | | | - Lifeng Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Choi RSY, Lai WYX, Lee LTC, Wong WLC, Pei XM, Tsang HF, Leung JJ, Cho WCS, Chu MKM, Wong EYL, Wong SCC. Current and future molecular diagnostics of gastric cancer. Expert Rev Mol Diagn 2019; 19:863-874. [PMID: 31448971 DOI: 10.1080/14737159.2019.1660645] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 08/23/2019] [Indexed: 12/14/2022]
Abstract
Introduction: Gastric cancer (GC) is the fifth most common cancer and confers the second-highest mortality among other cancers. Improving the survival rates of GC patients requires prompt and accurate diagnosis and effective treatment which is often preceded by the poorly understood pathogenic mechanisms. Area covered: This literature review aims to summarize current understanding of genetic and molecular alterations that promote carcinogenesis including (1) activation of oncogenes, (2) overexpression of growth factors, receptors and matrix metalloproteinases, (3) inactivation of tumor suppressor genes, DNA repair genes, and cell adhesion molecules and (4) alterations of cell-cycle regulators that regulate biological characteristics of cancer cells. Moreover, the significance of molecular biomarkers such as micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) and advanced molecular techniques including droplet digital polymerase chain reaction (ddPCR), quantitative PCR (qPCR) and next-generation sequencing (NGS) are also discussed. Expert opinion: A GC-specific panel of biomarkers based on the NGS or ddPCR has the potential for diagnosis, prognosis, and monitoring treatment response in GC patients. Despite the requirements for validation in larger population in clinical studies, race-specific differences in the gene panel have also to be examined by performing the clinical trials in subjects with different races.
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Affiliation(s)
- Rachel Sin-Yu Choi
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Wing Yin Xenia Lai
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Lok Ting Claire Lee
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Wing Lam Christa Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Xiao Meng Pei
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Hin Fung Tsang
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Joel Johnson Leung
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - William Chi Shing Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital , Kowloon , Hong Kong Special Administrative Region, China
| | - Man Kee Maggie Chu
- Division of Life Science, The Hong Kong University of Science and Technology , Clear Water Bay , Hong Kong Special Administrative Region, China
| | - Elaine Yue Ling Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
| | - Sze Chuen Cesar Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University , Hong Kong , Hong Kong Special Administrative Region, China
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Yao J, Li X, Yan L, He S, Zheng J, Wang X, Zhou P, Zhang L, Wei G, Sun X. Role of HGF/c-Met in the treatment of colorectal cancer with liver metastasis. J Biochem Mol Toxicol 2019; 33:e22316. [PMID: 30897285 PMCID: PMC6617765 DOI: 10.1002/jbt.22316] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/27/2019] [Accepted: 02/12/2019] [Indexed: 12/12/2022]
Abstract
The system of hepatocyte growth factor (HGF) and its receptor c-Met plays a critical role in tumor invasive growth and metastasis. The mortality rate of colorectal cancer (CRC), one of the most commonly diagnosed malignancies, is increased by it gradual development into metastasis, most frequently in the liver. Overexpression of c-Met, the protein tyrosine kinase receptor for the HCF/scatter factor, has been implicated in the progression and metastasis of human colorectal carcinoma. In this study, we aimed to investigate the role of c-Met in CRC liver metastasis and illustrate the clinical impact of regulating HGF/c-Met signaling in patients with CRC liver metastasis. We found that (I) higher levels of c-Met expression (mRNA and Protein) in CRC liver metastasis than primary CRC by assessing the patient tissue samples; (II) a positive correlation of c-Met expression with tumor stages of CRC liver metastasis, as well as c-Met expression in CRC, live metastasis concurred with regional lymph node metastasis; (III) the clinical impact of downregulation of HGF/c-Met signaling on the reduction of proliferation and invasion in CRC liver metastasis. Therefore, we demonstrate that the regulation of HGF/c-Met pathways may be a promising strategy in the treatment of patients with CRC liver metastasis.
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Affiliation(s)
- Jian‐feng Yao
- Department of General SurgeryShaanxi Provincial People's HospitalXi'anShaanxiChina
- Department of General SurgeryThe First Affiliated Hospital, College of Medicine, Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Xiao‐jun Li
- Department of General SurgeryShaanxi Provincial People's HospitalXi'anShaanxiChina
| | - Li‐kun Yan
- Department of General SurgeryShaanxi Provincial People's HospitalXi'anShaanxiChina
| | - Sai He
- Department of General SurgeryThe First Affiliated Hospital, College of Medicine, Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Jian‐bao Zheng
- Department of General SurgeryThe First Affiliated Hospital, College of Medicine, Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Xiao‐rong Wang
- Department of General SurgeryThe First Affiliated Hospital, College of Medicine, Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Pei‐hua Zhou
- Department of General SurgeryThe First Affiliated Hospital, College of Medicine, Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Li Zhang
- Department of General SurgeryThe First Affiliated Hospital, College of Medicine, Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Guang‐bing Wei
- Department of General SurgeryThe First Affiliated Hospital, College of Medicine, Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Xue‐jun Sun
- Department of General SurgeryThe First Affiliated Hospital, College of Medicine, Xi'an Jiaotong UniversityXi'anShaanxiChina
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Ma YR, Siegal GP, Wei S. Reacquisition of E-cadherin expression in metastatic deposits of signet-ring cell carcinoma of the upper gastrointestinal system: a potential anchor for metastatic deposition. J Clin Pathol 2016; 70:528-532. [PMID: 27864451 DOI: 10.1136/jclinpath-2016-203959] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 10/18/2016] [Accepted: 10/27/2016] [Indexed: 01/06/2023]
Abstract
AIMS To examine the expression of E-cadherin in paired primary and metastatic signet-ring cell carcinomas (SRCC) of various organ systems in order to explore the potential role of the molecule in metastatic dissemination of this unique tumour type. METHODS Thirty-seven consecutive cases of SRCC from various organs with paired primary and metastatic tumorous tissue available were retrieved. The intensity of membranous E-cadherin expression was semiquantitatively scored on a scale of 0-3+. RESULTS Reduced E-cadherin expression was a distinct feature of primary SRCC and was observed in 78% of primary tumours. Interestingly, the E-cadherin reduction was less frequently seen in metastatic SRCC when compared with their primary counterparts, and was only found in 57% of tumours in lymph node metastases or at distant sites of relapse. Furthermore, the mean score of E-cadherin expression of primary SRCC was significantly lower than that of their metastatic counterparts (2.3 vs 1.8; p=0.008). When divided by organ systems, the reacquisition of E-cadherin expression in the metastatic deposits was most remarkable in the SRCC of upper gastrointestinal tract origin (2.3 vs 1.4; p=0.003), whereas no significant difference was observed in other organ systems. CONCLUSIONS While the reduction of E-cadherin in primary SRCC supports its pivotal role in epithelial-mesenchymal transition, a process crucial in tumour progression and metastatic dissemination, the re-expression of this molecule in metastatic SRCC cells implies a reversal to their epithelial phenotype (thus mesenchymal-epithelial transition) which, in turn, theoretically helps tumour cells to anchor and form cohesive metastatic deposits.
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Affiliation(s)
- Yihong R Ma
- Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Gene P Siegal
- Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Shi Wei
- Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
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Oya M, Yao T, Tsuneyoshi M. Numerical Chromosomal Aberration in NodePositive Early Gastric Carcinomas: Analysis by Fluorescence in Situ Hybridization and Immunohistochemical Staining. Int J Surg Pathol 2016. [DOI: 10.1177/106689699800600402] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Tissue from surgically resected early gastric carcinomas with nodal involvement (NI) and without nodal involvement (NNI) were examined by fluorescence in situ hybridization (FISH) by use of a set of alpha-satellite probes. Numerical gain was observed in seven cases (70%) by a probe of chromosome 17 and in three cases (30%) by a probe of chromosome 18 among the NI cases, whereas such a gain was not detected in any NNI cases examined. Cases with numerical aberration in chromosome 17 exhibited immunohistochemical positivity of oncogene or tumor suppressor gene products related to chromosome 17 more frequently than the cases lacking those aberrations. Numerical chromosomal aberration as well as DNA aneuploidy determined by FISH may be related to genetic instability and biological behavior in early gastric carcinomas.
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Affiliation(s)
| | - Takashi Yao
- Department of Pathology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
| | - Masazumi Tsuneyoshi
- Department of Pathology, Faculty of Medicine, Kyushu University, 3-1-Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Han JP, Hong SJ, Kim HK, Kim HS, Lee YN, Lee TH, Lee JS. Expression of immunohistochemical markers according to histological type in patients with early gastric cancer. Scand J Gastroenterol 2016; 51:60-6. [PMID: 26144872 DOI: 10.3109/00365521.2015.1065510] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE We compared the biological characteristics of early gastric cancer (EGC) using immunohistochemical (IHC) staining among histological types. MATERIALS AND METHODS IHC staining results were analyzed in 86 EGCs resected with endoscopic submucosal dissection to identify mucin phenotype and biological characteristics. RESULTS The histological type was classified as tubular adenocarcinoma (TAC), mixed adenocarcinoma (MAC), or poorly cohesive carcinoma (PCC). Significant differences in MUC-2 (34.4% vs. 10.7%, p < 0.05) and MUC-5AC (59.4% vs. 85.7%, p < 0.05) expression were observed between TAC and PCC. The poorly cohesive component of MAC showed stronger immunoreactivity to CD10 (46.2% vs. 14.3%, p < 0.05) but weaker reactivity to MUC-5AC (57.7% vs. 85.7%, p < 0.05), compared to that of PCC. E-cadherin and β-catenin expression levels significantly decreased in the poorly cohesive component of MAC (15.4% vs. 90.6%, p < 0.05; 7.7% vs. 90.6%, p < 0.05, respectively) and PCC (10.7% vs. 90.6%, p < 0.05; 14.3% vs. 90.6%, p < 0.05, respectively), compared to TAC. However, vascular endothelial growth factor expression significantly increased in the poorly cohesive component of MAC (42.3% vs. 9.4%, p < 0.05) and PCC (39.3% vs. 9.4%, p < 0.05), compared to TAC. CONCLUSION IHC analysis showed that EGC histological types differ in terms of mucin phenotype and biological characteristics. The poorly cohesive components showed decreased E-cadherin and β-catenin expression levels and increased vascular endothelial growth factor expression. These characteristics may contribute to the poor prognosis of patients with MAC and PCC.
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Affiliation(s)
- Jae Pil Han
- a 1 Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University College of Medicine , Bucheon, Korea
| | - Su Jin Hong
- a 1 Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University College of Medicine , Bucheon, Korea
| | - Hee Kyung Kim
- b 2 Department of Pathology, Soonchunhyang University College of Medicine , Bucheon, Korea
| | - Hyun Su Kim
- a 1 Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University College of Medicine , Bucheon, Korea
| | - Yun Nah Lee
- a 1 Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University College of Medicine , Bucheon, Korea
| | - Tae Hee Lee
- a 1 Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University College of Medicine , Bucheon, Korea
| | - Joon Seong Lee
- a 1 Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University College of Medicine , Bucheon, Korea
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Balgkouranidou I, Matthaios D, Karayiannakis A, Bolanaki H, Michailidis P, Xenidis N, Amarantidis K, Chelis L, Trypsianis G, Chatzaki E, Lianidou ES, Kakolyris S. Prognostic role of APC and RASSF1A promoter methylation status in cell free circulating DNA of operable gastric cancer patients. Mutat Res 2015; 778:46-51. [PMID: 26073472 DOI: 10.1016/j.mrfmmm.2015.05.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Revised: 04/18/2015] [Accepted: 05/09/2015] [Indexed: 12/12/2022]
Abstract
Gastric carcinogenesis is a multistep process including not only genetic mutations but also epigenetic alterations. The best known and more frequent epigenetic alteration is DNA methylation affecting tumor suppressor genes that may be involved in various carcinogenetic pathways. The aim of the present study was to investigate the methylation status of APC promoter 1A and RASSF1A promoter in cell free DNA of operable gastric cancer patients. Using methylation specific PCR, we examined the methylation status of APC promoter 1A and RASSF1A promoter in 73 blood samples obtained from patients with gastric cancer. APC and RASSF1A promoters were found to be methylated in 61 (83.6%) and 50 (68.5%) of the 73 gastric cancer samples examined, but in none of the healthy control samples (p < 0.001). A significant association between methylated RASSF1A promoter status and lymph node positivity was observed (p = 0.005). Additionally, a significant correlation between a methylated APC promoter and elevated CEA (p = 0.033) as well as CA-19.9 (p = 0.032) levels, was noticed. The Kaplan-Meier estimates of survival, significantly favored patients with a non-methylated APC promoter status (p = 0.008). No other significant correlations between APC and RASSF1A methylation status and different tumor variables examined was observed. Serum RASSF1A and APC promoter hypermethylation is a frequent epigenetic event in patients with early operable gastric cancer. The observed correlations between APC promoter methylation status and survival as well as between a hypermethylated RASSF1A promoter and nodal positivity may be indicative of a prognostic role for those genes in early operable gastric cancer. Additional studies, in a larger cohort of patients are required to further explore whether these findings could serve as potential molecular biomarkers of survival and/or response to specific treatments.
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Affiliation(s)
- I Balgkouranidou
- Department of Medical Oncology, Medical School, Democritus University of Thrace, Greece.
| | - D Matthaios
- Department of Medical Oncology, Medical School, Democritus University of Thrace, Greece
| | - A Karayiannakis
- Second Department of Surgery, Medical School, Democritus University of Thrace, Greece
| | - H Bolanaki
- Second Department of Surgery, Medical School, Democritus University of Thrace, Greece
| | - P Michailidis
- Department of Medical Oncology, Medical School, Democritus University of Thrace, Greece
| | - N Xenidis
- Department of Medical Oncology, Medical School, Democritus University of Thrace, Greece
| | - K Amarantidis
- Department of Medical Oncology, Medical School, Democritus University of Thrace, Greece
| | - L Chelis
- Department of Medical Oncology, Medical School, Democritus University of Thrace, Greece
| | - G Trypsianis
- Laboratory of Statistics, Medical School, Democritus University of Thrace, Greece
| | - E Chatzaki
- Department of Pharmacology, Medical School, Democritus University of Thrace, Greece
| | - E S Lianidou
- Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens, Greece
| | - S Kakolyris
- Department of Medical Oncology, Medical School, Democritus University of Thrace, Greece
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12
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Moradi MT, Salehi Z, Aminian K, Yazdanbod A. Effects of p53 codon 72 and MDM2 SNP309 polymorphisms on gastric cancer risk among the Iranian population. Asian Pac J Cancer Prev 2015; 15:7413-7. [PMID: 25227851 DOI: 10.7314/apjcp.2014.15.17.7413] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Development of gastric cancer (GC) is a multistep process that requires alterations in the expression of oncogenes and tumor suppressor genes, occurring over several decades. The p53 tumor suppressor protein is involved in cell-cycle control, apoptosis and DNA repair. One of the most important regulators of p53 is MDM2, which acts as a negative regulator in the p53 pathway. Based on the key role of p53 and MDM2 in tumor suppression, polymorphisms that cause change in their function might affect cancer risk. We therefore elevated associations of the polymorphisms of p53 (R72P) and MDM2 (SNP309) with GC in Iran. MATERIALS AND METHODS A total of 104 patients with gastric cancer and 100 controls were recruited. Genomic DNA was extracted from fresh gastric samples. Genotyping of the p53 and MDM2 genes was performed using allele specific PCR (AS-PCR). RESULTS There was no significant difference between the p53 codon 72 polymorphism distribution in control and patient groups (p=0.54), but the G allele of MDM2 was found to be over-represented in patients (p=0. 01, Odds Ratio=2. 08, 95% Confidence Interval= 1.37-4.34). CONCLUSIONS The p53 R72P seems not to be a potential risk factor for development of GC among Iranian patients, but our data suggest that MDM2 SNP309 might modify the risk related to GC.
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Affiliation(s)
- Mohammad-Taher Moradi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran E-mail :
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13
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Duan L, Ye L, Wu R, Wang H, Li X, Li H, Yuan S, Zha H, Sun H, Zhang Y, Chen X, Zhang Y, Zhou L. Inactivation of the Phosphatidylinositol 3‐Kinase/Akt Pathway is Involved in BMP9‐mediated Tumor‐suppressive Effects in Gastric Cancer Cells. J Cell Biochem 2015; 116:1080-9. [DOI: 10.1002/jcb.25063] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 12/18/2014] [Indexed: 01/23/2023]
Affiliation(s)
- Liang Duan
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Liwei Ye
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Rui Wu
- Department of Laboratory MedicineThe First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016,China
| | - Haiyan Wang
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Xueru Li
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Huan Li
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Shimei Yuan
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - He Zha
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Hui Sun
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Yunyuan Zhang
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Xian Chen
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Yan Zhang
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
| | - Lan Zhou
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of EducationCollege of Laboratory MedicineChongqing Medical UniversityChongqing 400016China
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14
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Tsai MM, Wang CS, Tsai CY, Chi HC, Tseng YH, Lin KH. Potential prognostic, diagnostic and therapeutic markers for human gastric cancer. World J Gastroenterol 2014; 20:13791-13803. [PMID: 25320517 PMCID: PMC4194563 DOI: 10.3748/wjg.v20.i38.13791] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/18/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human health. GC is frequently not diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for improving prognoses in patients with GC. Gastroscopy with biopsy is an appropriate method capable of aiding the diagnosis of specific early GC tumor types; however, the stress caused by this method together with it being excessively expensive makes it difficult to use it as a routine method for screening for GC on a population basis. The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identified and tested for their clinical relevance in the management of GC. Here, we review the serum-based tumor markers for GC and their clinical significance, focusing on discoveries from microarray/proteomics research. We also review tissue-based GC tumor markers and their clinical application, focusing on discoveries from immunohistochemical research. This review provides a brief description of various tumor markers for the purposes of diagnosis, prognosis and therapeutics, and we include markers already in clinical practice and various forthcoming biomarkers.
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15
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Otani K, Dong Y, Li X, Lu J, Zhang N, Xu L, Go MYY, Ng EKW, Arakawa T, Chan FKL, Sung JJY, Yu J. Odd-skipped related 1 is a novel tumour suppressor gene and a potential prognostic biomarker in gastric cancer. J Pathol 2014; 234:302-15. [PMID: 24931004 PMCID: PMC4277686 DOI: 10.1002/path.4391] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Revised: 05/26/2014] [Accepted: 06/10/2014] [Indexed: 01/12/2023]
Abstract
We report that the odd-skipped related 1 (OSR1) gene encoding a zinc-finger transcription factor was preferentially methylated in gastric cancer by genome-wide methylation screening. OSR1 expression was frequently silenced or down-regulated in gastric cancer cell lines. OSR1 expression was also significantly down-regulated at both mRNA and protein levels in primary gastric cancer tissues compared with adjacent normal tissues. The silencing or down-regulation of OSR1 was closely associated with promoter hypermethylation. Overexpression of OSR1 significantly inhibited cell growth, arrested the cell cycle, and induced apoptosis in the gastric cancer cell lines AGS, MKN28, and MGC803. Conversely, knockdown of OSR1 by OSR1-short hairpin RNA significantly enhanced cell growth, promoted the cell cycle, and inhibited apoptosis in the normal gastric epithelial cell line GES1. The dual-luciferase reporter assay revealed that OSR1 activated p53 transcription and repressed the T-cell factor (TCF)/lymphoid enhancer factor (LEF). Complementary DNA expression array and western blotting showed that OSR1 increased the expression of nuclear p53, p21, Fas, and death receptor-5, and suppressed the expression of cyclin D1 and cyclin-dependent kinase 4 in the p53 signalling pathway. In addition, OSR1 suppressed the expression of cytoplasmic β-catenin, TCF-1, and LEF1 in the Wnt/β-catenin signalling pathway. OSR1 methylation was detected in 51.8% of primary gastric cancer patients (85 of 164) by bisulphite genomic sequencing. Multivariate Cox regression analysis showed that OSR1 methylation was an independent predictor of poor survival. Kaplan–Meier survival curves revealed that OSR1 methylation was associated with shortened survival in TNM stage I–III patients. In conclusion, OSR1 acts as a functional tumour suppressor through the transcriptional activation of p53 and repression of TCF/LEF in gastric cancer. Detection of OSR1 methylation may serve as a potential biomarker of the early stage of gastric cancer. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Koji Otani
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shatin, Hong Kong; Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan
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16
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Protein kinase Cι is a new prognostic factor in gastric cancer. Surg Today 2014; 45:759-64. [DOI: 10.1007/s00595-014-1010-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 07/21/2014] [Indexed: 12/14/2022]
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17
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Tsai MM, Wang CS, Tsai CY, Chen CY, Chi HC, Tseng YH, Chung PJ, Lin YH, Chung IH, Chen CY, Lin KH. MicroRNA-196a/-196b promote cell metastasis via negative regulation of radixin in human gastric cancer. Cancer Lett 2014; 351:222-31. [PMID: 24933454 DOI: 10.1016/j.canlet.2014.06.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 05/25/2014] [Accepted: 06/04/2014] [Indexed: 12/24/2022]
Abstract
MicroRNAs (miRNAs) play an important role to contribute carcinogenesis. The aim of the current study was to identify useful biomarkers from miRNAs. Differential miRNA profiles were analyzed using the miRNA qRT-PCR-based assay. Two of the most upregulated miRNAs were selected and validated. The miR-196a/-196b levels were significantly increased in gastric cancer (GC) tissues (n=109). Overexpression of miR-196a/-196b was significantly associated with tumor progression and poorer 5-year survival outcomes. Overexpression of miR-196a/-196b enhances GC cell migration and invasion. Further, radixin was identified as a target gene of miR-196a/-196b. Elevated miR-196a/-196b expression in GC cells led to reduced radixin protein levels and vice versa. Notably, an inverse correlation between miR-196a/-196b and radixin mRNA and protein expression was observed in GC tissues with in situ hybridization and immunohistochemistry analyses. Together, miR-196a/-196b inhibitory oligonucleotides or overexpression of the radixin may thus have therapeutic potential in suppressing GC metastasis.
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Affiliation(s)
- Ming-Ming Tsai
- Department of Nursing, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital at Chiayi, Chiayi 613, Taiwan
| | - Chung-Ying Tsai
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Cheng-Yi Chen
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan; Department of Medical Research, Mackay Memorial Hospital, Taipei 251, Taiwan
| | - Hsiang-Cheng Chi
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Yi-Hsin Tseng
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Pei-Jung Chung
- Molecular Medicine Research Center, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Yang-Hsiang Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - I-Hsiao Chung
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Ching-Ying Chen
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan 333, Taiwan.
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Qiu T, Zhou X, Wang J, Du Y, Xu J, Huang Z, Zhu W, Shu Y, Liu P. MiR-145, miR-133a and miR-133b inhibit proliferation, migration, invasion and cell cycle progression via targeting transcription factor Sp1 in gastric cancer. FEBS Lett 2014; 588:1168-77. [PMID: 24613927 DOI: 10.1016/j.febslet.2014.02.054] [Citation(s) in RCA: 146] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 02/14/2014] [Accepted: 02/26/2014] [Indexed: 01/06/2023]
Abstract
MicroRNAs have recently emerged as key regulators of gastric cancers. Here we found that miR-145, miR-133a and miR-133b were down-regulated in gastric cancer tissues and cell lines. Overexpression of miR-145, miR-133a and miR-133b induced G1 cell cycle arrest and inhibited cell proliferation, migration and invasion in vitro. MiR-145, miR-133a and miR-133b targeted the transcription factor SP1, knockdown of which reduced the expression of MMP-9 and Cyclin D1 that were involved in cell growth and invasion. Thus, our findings demonstrated for the first time that miR-145, miR-133a and miR-133b suppressed the proliferation, migration, invasion and cell cycle progression of gastric cancer cells through decreasing expression of Sp1 and its downstream proteins.
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Affiliation(s)
- Tianzhu Qiu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Jian Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Yiping Du
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Jun Xu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Zebo Huang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Yongqian Shu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
| | - Ping Liu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
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Association between Genetic Instability and Helicobacter pylori Infection in Gastric Epithelial Dysplasia. Gastroenterol Res Pract 2012; 2012:360929. [PMID: 23346103 PMCID: PMC3546497 DOI: 10.1155/2012/360929] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Revised: 11/27/2012] [Accepted: 12/03/2012] [Indexed: 12/13/2022] Open
Abstract
Background. In gastric carcinogenesis, changes of DNA methylation appear to be an early molecular event, and the genome-wide methylation state is closely correlated with the level of long interspersed nucleotide element-1 (LINE-1) methylation. In this study, we measured LINE-1 methylation level according to genetic instability and evaluated the effect of Helicobacter pylori infection on genetic instability in gastric epithelial dysplasia. Methods. Total 100 tissue samples of gastric epithelial dysplasia were analyzed. Seven loci that linked to tumor suppressor genes were used to identify significant structural chromosomal aberrations. Microsatellite status was investigated for two different microsatellite marker loci (BAT25 and BAT26). Also, we measured LINE-1 methylation level by combined bisulfite restriction analysis (COBRA-LINE-1) method. Results. There were no significant differences of LINE-1 methylation level according to chromosomal/microsatellite instability and H. pylori state. In the dysplastic lesions with H. pylori infection, LINE-1 methylation level of MSI lesion was significantly lower than that of microsatellite stable (MSS) lesion (40.23 ± 4.47 versus 43.90 ± 4.81%, P < 0.01). Conclusions. In gastric epithelial dysplasia with H. pylori infection, MSI is correlated with reduced LINE-1 methylation level. Coexistence of H. pylori infection and MSI might be a driving force of gastric carcinogenesis.
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20
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Liu D, Zhang L, Shen Z, Tan F, Hu Y, Yu J, Li G. Clinicopathological significance of NMIIA overexpression in human gastric cancer. Int J Mol Sci 2012; 13:15291-15304. [PMID: 23203126 PMCID: PMC3509642 DOI: 10.3390/ijms131115291] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 10/16/2012] [Accepted: 11/07/2012] [Indexed: 01/09/2023] Open
Abstract
Altered expressions of nonmuscle myosin IIA (NMIIA) have been observed in certain types of cancers, but the impact of the alterations in gastric cancer (GC) remains unclear. The purpose of this study was to evaluate the expression of NMIIA at the mRNA and protein level in patients with GC and to assess its clinical significance. We investigated the expression of NMIIA in fresh, paired GC tissues by reverse transcriptase polymerase chain reaction (RT-PCR; n = 14) and Western blot analysis (n = 36). Simultaneously, we performed immunohistochemistry (IHC) on paraffin embedded specimens, including 96 GC specimens, 30 matched normal specimens and 30 paired metastatic lymph node samples. NMIIA is overexpressed in GC compared with the adjacent normal gastric epithelium (p < 0.001) and high-level NMIIA expression is significantly correlated with the depth of wall invasion, lymph node metastasis, distant metastasis and Tumor Node Metastasis (TNM) stage. Furthermore, elevated NMIIA expression is an independent prognostic factor in multivariate analysis using the Cox regression model (p = 0.021). These findings indicate that overexpression of NMIIA may contribute to the progression and poor prognosis of GC.
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Affiliation(s)
| | | | - Zhiyong Shen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; E-Mails: (D.L.); (L.Z.); (Z.S.); (F.T.); (Y.H.); (J.Y.)
| | - Fei Tan
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; E-Mails: (D.L.); (L.Z.); (Z.S.); (F.T.); (Y.H.); (J.Y.)
| | - Yanfeng Hu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; E-Mails: (D.L.); (L.Z.); (Z.S.); (F.T.); (Y.H.); (J.Y.)
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; E-Mails: (D.L.); (L.Z.); (Z.S.); (F.T.); (Y.H.); (J.Y.)
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China; E-Mails: (D.L.); (L.Z.); (Z.S.); (F.T.); (Y.H.); (J.Y.)
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Gomceli I, Demiriz B, Tez M. Gastric carcinogenesis. World J Gastroenterol 2012; 18:5164-5170. [PMID: 23066309 PMCID: PMC3468847 DOI: 10.3748/wjg.v18.i37.5164] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Revised: 04/30/2012] [Accepted: 05/05/2012] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the second most common cancer worldwide and the second most common cause of cancer-related deaths. Despite complete resection of gastric cancer and lymph node dissection, as well as improvements in chemotherapy and radiotherapy, there are still 700,000 gastric cancer-related deaths per year worldwide and more than 80% of patients with advanced gastric cancer die of the disease or recurrent disease within 1 year after diagnosis. None of the treatment modalities we have been applying today can influence the overall survival rates: at present, the overall 5-year relative survival rate for gastric cancer is about 28%. Cellular metaplasia due to chronic inflammation, injury and repair are the most documented processes for neoplasia. It appears that chronic inflammation stimulates tumor development and plays a critical role in initiating, sustaining and advancing tumor growth. It is also evident that not all inflammation is tumorigenic. Additional mutations can be acquired, and this leads to the cancer cell gaining a further growth advantage and acquiring a more malignant phenotype. Intestinalization of gastric units, which is called "intestinal metaplasia"; phenotypic antralization of fundic units, which is called "spasmolytic polypeptide-expressing metaplasia"; and the development directly from the stem/progenitor cell zone are three pathways that have been described for gastric carcinogenesis. Also, an important factor for the development of gastrointestinal cancers is peritumoral stroma. However, the initiating cellular event in gastric metaplasia is still controversial. Understanding gastric carcinogenesis and its precursor lesions has been under intense investigation, and our paper attempts to highlight recent progress in this field of cancer research.
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22
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Kubota T, Ohyama S, Hiki N, Nunobe S, Yamamoto N, Yamaguchi T. Endocrine carcinoma of the stomach: clinicopathological analysis of 27 surgically treated cases in a single institute. Gastric Cancer 2012; 15:323-30. [PMID: 22252152 DOI: 10.1007/s10120-011-0122-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Accepted: 11/26/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric endocrine carcinoma (EC) is an uncommon tumor of the stomach and the clinical features are not well known. Additionally, the classification and staging systems of this tumor are not yet unified worldwide. In this study, we reviewed 27 patients with gastric EC to evaluate the clinicopathological characteristics of this tumor. METHODS We retrospectively reviewed 27 patients with gastric EC among 6466 patients who had undergone gastrectomy between 1986 and 2008 at our institute. Clinicopathological features including immunohistochemistry of Ki-67 were investigated to evaluate the malignant potential of the tumor. Furthermore, survivals were compared between the 7th edition of the International Union Against Cancer (UICC)-TNM (7th TNM) classification for gastric cancer (GC) and the new TNM classification for foregut neuroendocrine tumors (NET). RESULTS The median survival of the patients was 19.0 months. The 5-year survival rate was 100% in pathological stage (pStage) I, 40% in pStage II, 38% in pStage III, and 11% in pStage IV according to the 7th TNM classification for GC. Survivals by stage showed great difference between the 7th TNM classification for GC and the new TNM classification for foregut NET, but each system correlated with survival. The Ki-67 labeling index was more than 20% in most of the patients. Univariate analysis revealed that maximum tumor diameter, tumor depth, lymph node metastasis, lymphatic invasion, pStage, and curability had significant correlations with survival. CONCLUSION Early detection and curative operations are essential for improving the prognosis of gastric EC. However, some adjuvant chemotherapies are required for advanced-stage tumors. Classification and staging systems may need to be unified worldwide for further analysis.
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Affiliation(s)
- Takeshi Kubota
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
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Fanelli MF, Chinen LTD, Begnami MD, Costa WL, Fregnami JHT, Soares FA, Montagnini AL. The influence of transforming growth factor-α, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer. Histopathology 2012; 61:153-61. [PMID: 22582975 DOI: 10.1111/j.1365-2559.2011.04139.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
AIMS Determination of prognostic parameters that are predictive of survival of gastric cancer (GC) may allow better identification of patients who could benefit from current chemotherapy regimens. To assess the correlation between tumour progression and epithelial-mesenchymal transition (EMT), we assayed the expression levels of selected molecules involved in EMT [CD44, transforming growth factor (TGF)-α, cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP)-7, MMP-9 and C-X-C chemokine receptor (CXCR4)], and correlated these with overall patient survival (OS) and disease stage. METHODS AND RESULTS Medical records and pathological biopsy results of 137 patients with GC were evaluated retrospectively. Spearman's correlation analysis showed that expression of CXCR4 was correlated significantly with the expression of all other proteins studied. In contrast, COX-2 expression correlated significantly with the expression of only MMP-7 (P = 0.011), MMP-9 (P = 0.015) and CXCR4 (P = 0.013). We observed significant negative correlations between OS and the expression of TGF-α (P = 0.017), COX-2 (P < 0.001), CXCR4 (P = 0.010), MMP-7 (P = 0.020) and MMP-9 (P = 0.015). On multivariate analysis, only COX-2 was an independent prognostic factor for OS [hazard ratio (HR) = 3.34; 95% confidence interval (CI): 1.43-9.75; P = 0.002). CONCLUSIONS COX-2, TGF-α, MMP-7, MMP-9 and CXCR4 are associated with poor OS in gastric cancer.
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Tsai MM, Lin PY, Cheng WL, Tsai CY, Chi HC, Chen CY, Tseng YH, Cheng YF, Chen CD, Liang Y, Liao CJ, Wu SM, Lin YH, Chung IH, Wang CS, Lin KH. Overexpression of ADP-ribosylation factor 1 in human gastric carcinoma and its clinicopathological significance. Cancer Sci 2012; 103:1136-44. [PMID: 22348287 DOI: 10.1111/j.1349-7006.2012.02243.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Revised: 02/13/2012] [Accepted: 02/15/2012] [Indexed: 12/29/2022] Open
Abstract
Gastric cancer is the sixth leading cause of cancer-related death in Taiwan, and the identification of related factors is essential to increase patient survival. ADP-ribosylation factor 1 (ARF1) was initially identified using 2-D electrophoresis combined with MALDI-time-of-flight mass spectrometry. ADP-ribosylation factor 1 belongs to the Ras superfamily or GTP-binding protein family and has been shown to enhance cell proliferation. In the current study, we evaluated the potential of ARF1 as a biomarker for gastric cancer detection. ADP-ribosylation factor 1 mRNA was upregulated in tumor tissues (compared with adjacent non-tumor tissues, n = 55) in approximately 67.2% of gastric cancer patients. Expression of ARF1 protein was additionally observed using Western blot and immunohistochemistry (IHC) analyses. The clinicopathological correlations of ARF1 were further evaluated. Elevated ARF1 expression was strongly correlated with lymph node metastasis (P = 0.008), serosal invasion (P = 0.046), lymphatic invasion (P = 0.035), and pathological staging (P = 0.010). Moreover, the 5-year survival rate for the lower ARF1 expression group (n = 50; IHC score < 90) was higher than that of the higher expression group (n = 60; IHC score ≥ 90) (P = 0.0228, log-rank test). To establish the specific function of ARF1 in human gastric cancer, isogenic ARF1-overexpressing cell lines were prepared. Our results showed that ARF1-overexpressing clones display enhanced cell proliferation, migration, and invasion. Furthermore, ARF1-overexpression might contribute to poor prognosis of patients. These findings collectively support the utility of ARF1 as a novel prognostic marker for gastric cancer and its role in cell invasion.
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Affiliation(s)
- Ming-Ming Tsai
- Department of Biochemistry, Chang-Gung University, Taoyuan, Taiwan
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Suh YS, Lee HJ, Jung EJ, Kim MA, Nam KT, Goldenring JR, Yang HK, Kim WH. The combined expression of metaplasia biomarkers predicts the prognosis of gastric cancer. Ann Surg Oncol 2011; 19:1240-9. [PMID: 22048633 DOI: 10.1245/s10434-011-2125-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND Our previous study indicated that gene expression profiling of intestinal metaplasia (IM) or spasmolytic polypeptide-expressing metaplasia (SPEM) can identify useful prognostic markers of early-stage gastric cancer, and seven metaplasia biomarkers (MUC13, CDH17, OLFM4, KRT20, LGALS4, MUC5AC, and REG4) were selectively expressed in 17-50% of gastric cancer tissues. We investigated whether the combined expression of these metaplasia biomarkers could predict the prognosis of advanced stage gastric cancer. METHODS The expression of seven metaplasia biomarkers was evaluated immunohistochemically using tissue microarrays comprised of 450 gastric cancer patients. The clinicopathologic correlations and the prognostic impact were analyzed according to the expression of multiple biomarkers. RESULTS MUC13, CDH17, LGALS4, and REG4 were significant prognostic biomarkers in univariate analysis. No expression of four markers was found in 56 cases (14.2%); 1 marker was seen in 67 cases (17%), 2 in 106 cases (27%), 3 in 101 cases (25.7%), and 4 in 63 cases (16%). Patients in which two or fewer proteins were expressed (group B) showed younger age, undifferentiated or diffuse type cancer, larger tumor size, larger number of metastatic lymph nodes, and more advanced stage than those in which three or more proteins were expressed (group A). In undifferentiated or stage II/III gastric cancer, the prognosis of group B was significantly poorer than that of group A by multivariate analysis. CONCLUSIONS The combined loss of expression of multiple metaplasia biomarkers is considered an independent prognostic indicator in undifferentiated or stage II/III gastric cancer.
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Affiliation(s)
- Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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26
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Song HR, Kweon SS, Kim HN, Piao JM, Yun WJ, Choi JS, Hwang JE, Yoon JY, Kim HR, Park YK, Kim SH, Choi YD, Shin MH. p53 codon 72 polymorphism in patients with gastric and colorectal cancer in a Korean population. Gastric Cancer 2011; 14:242-8. [PMID: 21461655 DOI: 10.1007/s10120-011-0034-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Accepted: 02/13/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND The common p53 codon 72 polymorphism has been investigated as a risk factor for cancer in different populations; however, the results have been inconsistent. This study investigated the risk of developing gastric or colorectal cancer associated with the p53 codon 72 polymorphism in a Korean population. METHODS We conducted a large-scale case-control study that included 2,213 gastric cancer patients; 1,829 colorectal cancer patients; and 1,700 healthy controls. Genotyping was performed with real-time polymerase chain reaction (PCR), using a TaqMan single-nucleotide polymorphism (SNP) genotyping assay. RESULTS The frequencies of Arg/Arg, Arg/Pro, and Pro/Pro genotypes of the p53 codon 72 polymorphism were 43.3, 42.0, and 13.0% in the gastric cancer patients; 40.5, 45.0, and 14.0% in the colorectal cancer patients; and 43.2, 45.6, and 11.2% in the controls, respectively. The Pro/Pro genotype was associated with an increased risk of gastric [age- and sex-adjusted odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.01-1.56, P = 0.04] and colorectal cancer (OR = 1.36, 95% CI = 1.07-1.72, P = 0.01). There were no significant interactions between the p53 codon 72 polymorphism and smoking or drinking. CONCLUSIONS Our results suggest that the Pro/Pro genotype is associated with modest increases in the risks of gastric cancer and colorectal cancer in a Korean population.
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Affiliation(s)
- Hye-Rim Song
- Department of Preventive Medicine, Chonnam National University Medical School, 5, Hak 1-dong, Dong-gu, Gwangju, 501-746, South Korea
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Telomere shortening occurs early during gastrocarcinogenesis. Med Oncol 2011; 29:893-8. [DOI: 10.1007/s12032-011-9866-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Accepted: 02/11/2011] [Indexed: 10/18/2022]
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Kim SH, Ahn BK, Nam YS, Pyo JY, Oh YH, Lee KH. Microsatellite instability is associated with the clinicopathologic features of gastric cancer in sporadic gastric cancer patients. J Gastric Cancer 2010; 10:149-54. [PMID: 22076179 PMCID: PMC3204495 DOI: 10.5230/jgc.2010.10.4.149] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2010] [Accepted: 09/15/2010] [Indexed: 12/13/2022] Open
Abstract
Purpose Replication error is an important mechanism in carcinogenesis. The microsatellite instability (MSI-H) of colorectal cancers is associated with the development of multiple cancers. The influence of MSI-H on the development of multiple gastric cancers in sporadic gastric cancer patients has not been defined. This study was performed to reveal the association between the clinicopathologic features and MSI in sporadic gastric cancers. Materials and Methods Between July 2004 and March 2009, the clinicopathologic characteristics, including MSI status, were evaluated in 128 consecutive patients with sporadic gastric cancers. None of the patients had hereditary non-polyposis colorectal cancer of familial gastric cancer. The markers that were recommended by the NCI to determine the MSI status for colorectal cancers were used. Results MSI-H cancers were found in 10.9% of the patients (14/128). Synchronous gastric cancers were shown in 4 patients (3.1%). Synchronous cancers were found in 2 of 14 patients with MSI-H gastric cancer (14.3%) and 2 of 114 patients with MSS gastric cancer (1.8%; P=0.059, Fisher's exact test). Among the patients with synchronous cancer 50% (2/4) had MSI-H cancer, but 9.7% of the patients (12/124) without synchronous cancer had MSI-H cancer. MSI-H (RR, 24.7; 95% CI, 1.5~398.9; P=0.024) was related with to synchronous gastric cancer, but age, gender, family history, histologic type, location, gross morphology, size, and stage were not related to synchronous gastric cancer. Conclusions MSI is associated with the intestinal-type gastric cancer and the presence of multiple gastric cancers in patients with sporadic gastric cancer. Special attention to the presence of synchronous and the development of metachronous multiple cancer in patients with MSI-H gastric cancer is needed.
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Affiliation(s)
- Shin Hyuk Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
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Zhou Y, Hu W, Zhuang W, Wu X. Interleukin-10 -1082 promoter polymorphism and gastric cancer risk in a Chinese Han population. Mol Cell Biochem 2010; 347:89-93. [PMID: 20953818 DOI: 10.1007/s11010-010-0616-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2010] [Accepted: 09/28/2010] [Indexed: 02/05/2023]
Abstract
Studies investigating the association between interleukin-10 (IL-10) -1082 promoter polymorphism and gastric cancer risk report conflicting results. Our recent meta-analysis suggests that the IL-10 -1082 promoter polymorphism may be associated with gastric cancer among Asians. The objective of this study was to investigate the association between IL-10 -1082 promoter polymorphism and gastric cancer risk in Chinese Han patients. We extracted the peripheral blood samples in 150 patients with gastric cancer and 150 controls. PCR-RFLP analysis was performed to detect IL-10 -1082 promoter polymorphism in these patients. Patients with gastric cancer had a significantly lower frequency of AA (OR = 0.45, 95% CI = 0.27, 0.76; P = 0.003) than controls. Patients with cardia gastric cancer had a significantly higher frequency of GG (OR = 2.17, 95% CI = 1.08, 4.38; P = 0.03) than those with noncardia gastric cancer. Patients with advanced gastric cancer had a significantly higher frequency of AA (OR = 5.21, 95% CI = 1.71, 15.87; P = 0.004) than those with early gastric cancer. When stratified by the Lauren's classification, histological differentiation of gastric cancer, no statistically significant results were observed. This study suggests that the IL-10 -1082 promoter polymorphism may be associated with gastric cancer in Chinese Han patients, and that difference in genotype distribution may be associated with the location and stage of gastric cancer.
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Affiliation(s)
- Yong Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 37 Guo Xue Rd, Chengdu, 610041, Sichuan Province, China
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Luo J, Zhu Y, Yang G, Gong L, Wang B, Liu H. Loss of Reprimo and S100A2 expression in human gastric adenocarcinoma. Diagn Cytopathol 2010; 39:752-7. [PMID: 20949468 DOI: 10.1002/dc.21461] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Accepted: 05/01/2010] [Indexed: 11/09/2022]
Abstract
Reprimo and S100A2 are two newly identified candidate tumor-suppressor genes, which play an important role in the regulation of p53-dependent cell cycle. In this study, we examined the expressions of Reprimo and S100A2 in surgical specimens of gastric adenocarcinoma and correlated these results with pathological and clinical parameters. Tissues were obtained from 100 gastric adenocarcinoma patients that underwent curative gastrectomy. Reprimo and S100A2 expressions were evaluated by immunohistochemical analysis. Loss of Reprimo and S100A2 expressions occurred in 65 and 52% of the patients, respectively. Loss of Reprimo expression was significantly correlated with the depth of tumor invasion (P = 0.000), lymphatic vessel invasion (P = 0.006), and lymph node metastasis (P = 0.000). Loss of S100A2 expression was significantly associated with histological type (P = 0.009), depth of invasion (P = 0.033), lymphatic vessel invasion (P = 0.01), and lymph node metastasis (P = 0.001). In addition, there was a significant positive association between the expressions of Reprimo and S100A2 (P < 0.01). The results suggest that loss of Reprimo and S100A2 expressions occurs frequently in gastric adenocarcinomas. The expressions of Reprimo and S100A2 may be potential biomarkers for gastric adenocarcinomas detection.
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Affiliation(s)
- Jun Luo
- Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
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31
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Zhou Y, Li N, Zhuang W, Wu X. p53 Codon 72 polymorphism and gastric cancer risk in a Chinese Han population. Genet Test Mol Biomarkers 2010; 14:829-33. [PMID: 20939739 DOI: 10.1089/gtmb.2010.0115] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND studies investigating the association between p53 codon 72 polymorphism and gastric cancer risk report conflicting results. Our recent meta-analysis suggests that the p53 codon 72 polymorphism may be associated with gastric cancer among Asians. AIM the objective of this study was to investigate the association between p53 codon 72 polymorphism and gastric cancer risk in Chinese Han patients. METHODS we extracted the peripheral blood samples from 150 patients with gastric cancer and 150 control subjects. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to detect p53 codon 72 polymorphism in these patients. RESULTS patients with gastric cancer had a significantly lower frequency of Arg/Arg (odds ratio [OR] = 0.48, 95% confidence interval [95% CI] = 0.28, 0.80; p = 0.005) than control subjects. Patients with cardia gastric cancer had a significantly higher frequency of Pro/Pro (OR = 2.26, 95% CI = 1.12, 4.55; p = 0.02) than those with noncardia gastric cancer. Patients with advanced gastric cancer had a significantly higher frequency of Arg/Arg (OR = 2.66, 95% CI = 1.06, 6.65; p = 0.03) than those with early gastric cancer. When stratified by the Lauren's classification, histological differentiation of gastric cancer, no statistically significant result was observed. CONCLUSION this study suggests that the p53 codon 72 polymorphism may be associated with gastric cancer in Chinese Han patients, and that difference in genotype distribution may be associated with the location and stage of gastric cancer.
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Affiliation(s)
- Yong Zhou
- Department of Gastrointestinal Surgery, Sichuan University, West China Hospital, Chengdu, China
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Namikawa T, Hanazaki K. Mucin phenotype of gastric cancer and clinicopathology of gastric-type differentiated adenocarcinoma. World J Gastroenterol 2010; 16:4634-4639. [PMID: 20872962 PMCID: PMC2951512 DOI: 10.3748/wjg.v16.i37.4634] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Revised: 04/07/2010] [Accepted: 04/14/2010] [Indexed: 02/06/2023] Open
Abstract
Differentiated adenocarcinoma of the stomach is classified into gastric or intestinal phenotypes based on mucus expression. Recent advances in mucin histochemistry and immunohistochemistry have highlighted the importance of such a distinction, and it is important clinically to distinguish between gastric- and intestinal-type differentiated adenocarcinoma. However, a clinical and pathological diagnosis of this type is often difficult in early gastric cancer because of histological similarities between a hyperplastic epithelium and low-grade atypia. Furthermore, determining tumor margins is often difficult, even with extensive preoperative examination. It is therefore critical to consider these diagnostic difficulties and different biological behaviors with high malignant potential when treating patients with gastric-type differentiated adenocarcinoma.
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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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Kim JS, Shin OR, Kim HK, Cho YS, An CH, Lim KW, Kim SS. Overexpression of protein phosphatase non-receptor type 11 (PTPN11) in gastric carcinomas. Dig Dis Sci 2010; 55:1565-1569. [PMID: 19690960 DOI: 10.1007/s10620-009-0924-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2009] [Accepted: 07/16/2009] [Indexed: 01/18/2023]
Abstract
BACKGROUND Tyrosine phosphorylation and dephosphorylation by protein tyrosine kinases and phosphatases (PTPs), respectively, play crucial roles in cellular signal transduction. Protein phosphatase non-receptor type 11 (PTPN11) is a positive signaling PTP that activates RAS and ERK signaling. Also, the PTPN11 binds with CagA of Helicobacter pylori in gastric epithelial cells. AIM The aim of this study was to explore whether alteration of PTPN11 protein expression is a feature of gastric cancer cells. METHODS We analyzed PTPN11 expression in 92 gastric cancer tissues by immunohistochemistry using a tissue microarray method. RESULTS The gastric cancers expressed PTPN11 in 78 (87%) specimens, while the epithelial cells in normal gastric mucosa did not display any PTPN11 immunoreactivity. The PTPN11 expression in the cancers was associated with the tubular morphology (versus signet ring cell type), the Lauren's intestinal type (versus diffuse type), and the advanced gastric cancer type (versus early gastric cancer type). CONCLUSION Our data indicate that gastric cancers display a higher expression of PTPN11 protein than the normal cells, suggesting that neo-expression of this positive signaling protein in the cells might play a role in the cancer development. Also, the higher expression of PTPN11 in tubular and intestinal types, where Helicobacter pylori has a definite role in the development of the cancers, suggest a possibility that PTPN11 might play a role in regulation in Helicobacter pylori pathogenesis the gastric cancers.
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Affiliation(s)
- Jin Soo Kim
- Department of Internal Medicine, College of Medicine, Uijongbu St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
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Kim MA, Jung EJ, Lee HS, Lee HE, Yang HK, Oh DY, Bang YJ, Kim WH. P-cadherin expression in gastric carcinoma: its regulation mechanism and prognostic significance. Hum Pathol 2010; 41:877-885. [PMID: 20233621 DOI: 10.1016/j.humpath.2009.04.031] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2008] [Revised: 04/24/2009] [Accepted: 04/28/2009] [Indexed: 11/28/2022]
Abstract
P-cadherin is a member of the cadherin family and is expressed in several solid tumors. This molecule was recently highlighted with the development of a new targeted compound being studied in a clinical trial on solid tumors. In the present study, we examined the protein and messenger RNA (mRNA) expression status of P-cadherin and its promoter methylation in gastric carcinoma cell lines and tissues. Of the 10 cell lines, 4 were found to express P-cadherin protein and mRNA, and the P-cadherin gene was found to be hypomethylated in its promoter region in these cell lines. Nonneoplastic gastric mucosal tissues from gastric carcinoma patients were negative for P-cadherin protein evaluated by immunohistochemistry and Western blotting and had a methylated P-cadherin promoter region. In carcinoma tissues, 70.8% (749/1058) of cases showed P-cadherin protein expression, and P-cadherin positive cases had a well or moderately differentiated histology according to the World Health Organization classification, intestinal-type histology by Lauren classification, and an earlier pT class. Furthermore, patients with P-cadherin expressing tumors had a favorable prognosis by univariate and multivariate survival analyses. In addition, P-cadherin protein expression was found to be significantly correlated with promoter hypomethylation. In summary, P-cadherin is silenced in nonneoplastic gastric mucosa, and P-cadherin expressing tumors constitute a subset of gastric carcinoma with intestinal-type histology and a favorable prognosis. In addition, our findings suggest that P-cadherin promoter methylation underlies the regulation of its expression. These findings may aid patient selection and the interpretation of P-cadherin targeted therapy and clinical trial results.
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Affiliation(s)
- Min A Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Korea
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36
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Kwon J, Lee JH, Jee YS, Park DJ, Kim HH, Lee HJ, Yang HK, Lee KU, Lee HS. Overexpression of p53, Mutation of hMLH1and Microsatellite Instability in Gastric Carcinomas: Clinicopathologic Implications and Prognosis. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2010. [DOI: 10.4174/jkss.2010.79.2.94] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Junsik Kwon
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ju-Hee Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ye Seob Jee
- Department of Surgery, Dankook University Hospital, Seoul, Korea
| | - Do-Jung Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk-Joon Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Han-Kwang Yang
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Kuhn Uk Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
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Tuan TF, Tsai ML, Yeh KC, Huang HC, Chung CT, Huang CL, Han CH, Chen CP, Wang MH, Shen CC, Lai YK, Lee WS, Hwang LL, Chen CT. Intravenous paclitaxel against metastasis of human gastric tumors of diffuse type. Cancer Chemother Pharmacol 2010; 66:773-83. [PMID: 20044750 DOI: 10.1007/s00280-009-1222-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Accepted: 12/13/2009] [Indexed: 10/20/2022]
Abstract
PURPOSE Gastric cancer is one of the leading cancerous diseases worldwide. It is diagnosed often at the advanced stage for which chemotherapy is the main treatment option. The prognosis remains poor for metastatic, especially the diffuse type, gastric cancers. We investigated the efficacy of intravenously administered paclitaxel treating metastases of locally disseminated gastric tumors of diffuse type. METHODS Transfection of green fluorescent proteins (GFP)-expressing plasmid into human gastric cancer MKN45 cells of diffuse type was performed, and MKN45-GFP cells constitutively expressing GFP were isolated. The MKN45-GFP cells were orthotopically inoculated into the mouse peritoneal cavity, and tumor growth and organ metastases were monitored. Liver metastases were harvested, re-inoculated, monitored for liver metastases again, and harvested for further inoculation. This in vivo selection procedure was repeated to isolate a subline with high metastatic abilities demonstrated by in vitro invasion abilities using Transwell((R)) system. By visualizing the GFP-expressing tumors, the effects of intravenously administered paclitaxel against the growing peritoneally disseminated and metastasized tumors in nude mice without laparotomy were measured. RESULTS An in vivo selected gastric cancer cell line MKN45-GFP-ip4 with high metastatic ability was established. Its invasion ability was inhibited by paclitaxel treatments in vitro. The growths of metastatic and intraperitoneally disseminated MKN45-GFP-ip4 tumors were significantly suppressed by intravenous paclitaxel treatments in nude mice. CONCLUSIONS We found that intravenous paclitaxel is active against the metastases of human gastric cancer of peritoneal diffuse type, which warrants further investigations on optimizing the perioperative regimens with intravenous paclitaxel therapy for gastric cancer in patients.
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Affiliation(s)
- Tsung-Fan Tuan
- Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli, Taiwan
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Park CH, Lee SM, Kim HS, Choi SK, Rew JS. A Polymorphism of the MMP-1, EGF, and IL-LB Gene Is Not Correlated with Gastric Carcinogenesis. Chonnam Med J 2010. [DOI: 10.4068/cmj.2010.46.1.32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Chang-Hwan Park
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Su-Mi Lee
- Department of Molecular Medicine Science, Chonnam National University Graduate School, Gwangju, Korea
| | - Hyun-Soo Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Sung-Kyu Choi
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Jong-Sun Rew
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
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Watari J, Moriichi K, Tanabe H, Sato R, Fujiya M, Miwa H, Das KM, Kohgo Y. Differences in genetic instability and cellular phenotype among Barrett's, cardiac, and gastric intestinal metaplasia in a Japanese population with Helicobacter pylori. Histopathology 2009; 55:261-9. [PMID: 19723140 PMCID: PMC4458565 DOI: 10.1111/j.1365-2559.2009.03370.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
AIMS Intestinal metaplasia is considered to be a precursor lesion in both Barrett's and intestinal-type gastric cancer. The aim was to clarify the differences in molecular pathology between specialized intestinal metaplasia (SIM) in Barrett's oesophagus (BO), cardiac (CIM) and gastric intestinal metaplasia (GIM). METHODS AND RESULTS Eighty-eight SIM cases with BO, 30 CIM cases and 52 GIM cases in patients with or without Helicobacter pylori infectionwere analysed for genetic instability and Das-1. Microsatellite instability and a loss of heterozygosity were evaluated at five microsatellite loci. The incidence of genetic instability was 55.7% in SIM, 40.0% in CIM and 23.1% in GIM, revealing a significant difference between SIM and GIM (P < 0.0005). For each microsatellite marker analysed, there were obvious differences in frequency among the three conditions. Das-1 reactivity was significantly higher in SIM than in CIM or GIM (P < 0.0001, both). Interestingly, both genetic instability and Das-1 reactivity in SIM showed a significantly higher incidence in patients with H. pylori infection than in those without (P < 0.005 and P < 0.01, respectively). CONCLUSIONS SIM is distinct from CIM and GIM, and the pathogenesis of SIM, like that of GIM, is associated to some degree with H. pylori infection in a Japanese population.
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Affiliation(s)
- Jiro Watari
- Department of Gastroenterology, Kushiro Medical Association Hospital, Kushiro, Japan.
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Hsu PI, Hsieh HL, Lee J, Lin LF, Chen HC, Lu PJ, Hsiao M. Loss of RUNX3 expression correlates with differentiation, nodal metastasis, and poor prognosis of gastric cancer. Ann Surg Oncol 2009; 16:1686-1694. [PMID: 19290488 DOI: 10.1245/s10434-009-0428-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2008] [Revised: 01/03/2009] [Accepted: 02/13/2009] [Indexed: 12/28/2022]
Abstract
BACKGROUND RUNX3 is a major growth regulator of gastric epithelial cells that is involved in gastric tumorigenesis in both humans and mice. In this study, we investigated the involvement of RUNX3 in tumor progression, and in the prognosis of human gastric cancer. METHODS We analyzed the extent of RUNX3 protein expression by immunohistochemistry in 95 primary gastric adenocarcinomas, and correlated expression levels with clinicopathological parameters. We examined the effects of pFlag/RUNX3 on cell growth, apoptosis, and caspase-3 expression in AGS and SNU1 gastric cancer cell lines by colony-forming assay, terminal deoxynucleotidyl transferase (TdT)-mediate deoxyuridine triphosphatase (dUTP) nick-end labeling (TUNEL) assay, and Western blot analysis, respectively. The pFlag/RUNX3 effects on AGS invasion and migration potentials were also evaluated. RESULTS RUNX3 expression was lost in 37 (39%) cases of gastric cancer. The expression of RUNX3 in diffuse- and mixed-type cancers was less frequent than expression in intestinal-type cancer (P < 0.001 and P = 0.001, respectively). In addition, the loss of RUNX3 expression was associated with lymph node metastasis (P = 0.02), and correlated with poor gastric cancer survival (P = 0.018). The growth of gastric cancer cells was suppressed after pFlag/RUNX3 transfection. The re-expression of RUNX3 resulted in the upregulation of caspase-3 and promoted apoptosis. Furthermore, Re-expression of RUNX3 induced significant inhibitions of AGS cell invasion and migration in vitro. CONCLUSIONS This work shows that loss of RUNX3 expression is highly associated with lymph node metastasis and poor prognosis of gastric cancer. The re-expression of RUNX3 may induce apoptosis and inhibit the growth as well as invasion/migration of cancer cells. These results indicate that the targeting of the RUNX3 pathway could represent a potential modality for treating gastric cancer.
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Affiliation(s)
- Ping-I Hsu
- Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Taiwan.
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41
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Yasui W, Oue N, Sentani K, Sakamoto N, Motoshita J. Transcriptome dissection of gastric cancer: identification of novel diagnostic and therapeutic targets from pathology specimens. Pathol Int 2009; 59:121-36. [PMID: 19261089 DOI: 10.1111/j.1440-1827.2009.02329.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Gastric cancer is the fourth most common malignancy in the world, and mortality due to gastric cancer is second only to that from lung cancer. 'Transcriptome dissection' is a detailed analysis of the entire expressed transcripts from a cancer, for the purpose of understanding the precise molecular mechanism of pathogenesis. Serial analysis of gene expression (SAGE) is a suitable technique for performing transcriptome dissection. Gastric cancers of different stages and histology were analyzed on SAGE, and one of the largest gastric cancer SAGE libraries in the world was created (GEO accession number GSE 545). Through SAGE, many candidate genes have been identified as potential diagnostic and therapeutic targets for the treatment of gastric cancer. Regenerating islet-derived family, member 4 (Reg IV) participated in 5-fluorouracil (5-FU) resistance and peritoneal metastasis, and its expression was associated with an intestinal phenotype of gastric cancer and with endocrine differentiation. GW112 expression correlated with advanced tumor stage. Measurement of Reg IV and GW112 levels in sera indicated a sensitivity of 57% for detection of cancer. SPC18 participated in tumor growth and invasion through transforming tumor growth factor-alpha upregulation. Palate, lung, and nasal epithelium carcinoma-associated protein (PLUNC) was a useful marker for gastric hepatoid adenocarcinoma. Expression of SOX9, HOXA10, CDH17, and loss of claudin-18 expression were associated with an intestinal phenotype of gastric cancer. Information obtained from transcriptome dissection greatly contributes to diagnosis and treatment of gastric cancer.
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Affiliation(s)
- Wataru Yasui
- Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
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42
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Karim S, Ali A. Correlation of p53 over-expression and alteration in p53 gene detected by polymerase chain reaction-single strand conformation polymorphism in adenocarcinoma of gastric cancer patients from India. World J Gastroenterol 2009; 15:1381-7. [PMID: 19294769 PMCID: PMC2658834 DOI: 10.3748/wjg.15.1381] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [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 study the alterations in p53 gene among Indian gastric cancer patients and to correlate them with the various clinicopathological parameters.
METHODS: A total of 103 gastric cancer patients were included in this study. The p53 alterations were studied by both immunohistochemical method as well as polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. We only studied four (exon 5, 6, 7, and 8) of the 11 p53 exons. The alterations in p53 were also correlated with respect to various clinicopathological parameters.
RESULTS: Among 103 cases, p53 over-expression and alteration were detected in 37 (35.92%) and 19 (18.44%) cases, respectively. Most of the p53 alterations were found at exon 5 (31.54%), followed by exon 6 (26.31%), exon 7 (21.04%) and exon 8 (21.04%). A significant correlation of p53 over-expression was found with p53 alteration (P = 0.000). Concordance between p53 alteration (as detected by SSCP) and over-expression [as detected by immunohistochemistry (IHC)] was found in 75% cases. We found that IHC-positive/SSCP-negative cases accounted for 21% of cases and IHC-negative/SSCP-positive cases accounted for remaining 4% cases.
CONCLUSION: Our results show that p53 gene mutations are significantly correlated with p53 protein over-expression, with 75% concordance in over-expression and alteration in the p53 gene, but 25% disconcordance also cautions against the assumption that p53 over-expression is always associated with a gene mutation. There may be other mechanisms responsible for stabilization and accumulation of p53 protein with no evidence of gene mutation that reflect an accumulation of a non-mutated protein, or a false negative SSCP result.
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43
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Cheng WL, Wang CS, Huang YH, Liang Y, Lin PY, Hsueh C, Wu YC, Chen WJ, Yu CJ, Lin SR, Lin KH. Overexpression of a secretory leukocyte protease inhibitor in human gastric cancer. Int J Cancer 2008; 123:1787-96. [DOI: 10.1002/ijc.23746] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Hsu PI, Huang MS, Chen HC, Hsu PN, Lai TC, Wang JL, Lo GH, Lai KH, Tseng CJ, Hsiao M. The significance of ANXA7 expression and its correlation with poor cellular differentiation and enhanced metastatic potential of gastric cancer. J Surg Oncol 2008; 97:609-614. [PMID: 18449914 DOI: 10.1002/jso.21046] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
BACKGROUND Annexin-A7 (ANXA7) exhibits biological and genetic properties expected of a tumor suppressor gene and may play a role in cancer progression. However, the ANXA7 expression in different histological subtypes of gastric adenocarcinomas and its correlation with invasive potentials has not been elucidated. METHODS Immunohistochemical staining of ANXA7 for 84 primary gastric adenocarcinomas was performed, and data was correlated with clinicopathological parameters of patients. RESULTS The ANXA7 expression was well correlated with the grade of differentiation of primary tumors. Its expression was detected in 100% (8/8), 64.9% (24/37), 66.7% (2/3), 31.9% (13/31), 0% (0/3), and 0% (0/2) of well-differentiated tubular, moderately-differentiated tubular, papillary, poorly differentiated, signet-ring cell, and mucinous adenocarcinoma, respectively. According to the Lauren's classification, the ANXA7 expression was higher in intestinal type than in diffuse type tumor (71.9% vs. 6.1%, P = 0.003). The loss of expression of ANXA7 expression was significantly related to distant metastasis (P = 0.04). However, there were no significant associations between the ANXA7 expression and survival of cancer patients (P = 0.159). CONCLUSIONS A striking correlation between ANXA7 expression and cell differentiation of gastric cancer was observed. The loss of expression of ANXA7 is associated with distant metastasis.
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Affiliation(s)
- Ping-I Hsu
- Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan
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45
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Zhou Y, Li N, Zhuang W, Liu GJ, Wu TX, Yao X, Du L, Wei ML, Wu XT. P53 codon 72 polymorphism and gastric cancer: a meta-analysis of the literature. Int J Cancer 2007; 121:1481-6. [PMID: 17546594 DOI: 10.1002/ijc.22833] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Studies investigating the association between p53 codon 72 polymorphism and gastric cancer risk report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline and Embase databases. This meta-analysis included 12 case-control studies, which included 1,665 gastric cancer cases and 2,358 controls. The combined results based on all studies showed that there was no significant difference in genotype distribution [Arg/Arg odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.79, 1.16; Pro/Pro (OR = 1.21, 95% CI = 0.92, 1.58); Pro/Arg (OR = 0.95, 95% CI = 0.79, 1.14)] between gastric cancer and noncancer patients. When stratifying for race, results were similar except that patients with gastric cancer had a significantly lower frequency of Arg/Arg (OR = 0.84, 95% CI = 0.72, 0.99) than noncancer patients among Asians. Stratified the various studies by the location, stage, Lauren's classification, and histological differentiation of gastric cancer, we found that (i) patients with cardia gastric cancer had a significantly higher frequency of Pro/Pro (OR = 3.20, 95% CI = 1.46,7.01) than those with noncardia gastric cancer among Asians; (ii) patients with advanced (stage III/IV) gastric cancer had a significantly higher frequency of Arg/Arg (OR = 1.48, 95% CI = 1.01, 2.16) than those with early (stage I/II) gastric cancer among Asians; (iii) patients with poor differentiation had a significantly lower frequency of Pro/Pro (OR = 0.13, 95% CI = 0.03, 0.64) than those with well differentiation among Caucasians. This meta-analysis suggests that the p53 codon 72 polymorphism may be associated with gastric cancer among Asians, and that difference in genotype distribution may be associated with the location, stage, and histological differentiation of gastric cancer.
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Affiliation(s)
- Yong Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
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46
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Watari J, Tanaka A, Tanabe H, Sato R, Moriichi K, Zaky A, Okamoto K, Maemoto A, Fujiya M, Ashida T, Das KM, Kohgo Y. K-ras mutations and cell kinetics in Helicobacter pylori associated gastric intestinal metaplasia: a comparison before and after eradication in patients with chronic gastritis and gastric cancer. J Clin Pathol 2007; 60:921-6. [PMID: 16997920 PMCID: PMC1994498 DOI: 10.1136/jcp.2006.041939] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2006] [Indexed: 01/10/2023]
Abstract
BACKGROUND Helicobacter pylori related gastric intestinal metaplasia (IM) is considered to be a precancerous lesion. AIMS To identify the effects of H pylori eradication on K-ras mutations, cell kinetics in IM and histological changes in patients with and without gastric cancers in a one-year prospective study. METHODS Patients included group A (n = 39), chronic gastritis, and group B (n = 53), intestinal-type early gastric cancer patients who had all undergone endoscopic mucosal resection (n = 25) or surgical resection (n = 28). K-ras codon 12 mutations in IM were examined, followed by DNA sequencing analysis. Proliferating and apoptotic cells were detected with anti-Ki-67 antibody and using the TUNEL method, respectively. RESULTS The incidence of K-ras mutations in the cancer was only 3.8%. The mutant K-ras in IM was observed more frequently in group A (46.2%) than in group B patients (1.9%) (p<0.005). After eradication, the K-ras mutations significantly declined to 12.8% in group A (p<0.005). The mutation pattern of K-ras codon 12 before eradication was that GGT was mainly changed to AGT (50%) in group A. AGT transformation was not affected by treatment. Apoptosis in IM showed an increase after H pylori eradication in both groups (p<0.05 in group A) although no histological improvement in IM was observed. The monocyte score was significantly higher in group A than in group B (p<0.05); the score improved significantly after eradication. CONCLUSIONS K-ras mutations in IM do not always play a role in gastric carcinogenesis but cell kinetics, especially apoptosis, in IM may contribute to it. There are early events in K-ras mutations which are influenced by H pylori infection; some mutations may also be selected by eradication. These unstable K-ras mutations in IM may be related to lymphocyte infiltration caused by H pylori infection.
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Affiliation(s)
- J Watari
- Division of Gastroenterology and Hepatology, Department of Medicine, Asahikawa Medical College, Asahikawa, Japan.
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Arai T, Takubo K. Clinicopathological and molecular characteristics of gastric and colorectal carcinomas in the elderly. Pathol Int 2007; 57:303-14. [PMID: 17539960 DOI: 10.1111/j.1440-1827.2007.02101.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The occurrence of malignant neoplasms increases with advancing age. Although aging and carcinogenesis are basically different processes, there are phenomena common to each such as accumulation of DNA damage and abnormal proteins. Gastric and colorectal carcinomas are representative tumors in which the prevalence and the number of patients increase significantly with age. Compared with gastric and colorectal cancers occurring in younger patients, those occurring in older patients have clinicopathological differences in tumor location, gender distribution, histological type, histological diversity, multiplicity, incidence of lymph node metastasis, and prognosis. In the elderly there are peculiar types of carcinoma such as medullary-type poorly differentiated colorectal adenocarcinoma and solid-type poorly differentiated gastric adenocarcinoma, both of which occur in older women. Methylation, apoptosis, and telomere dysfunction play important roles in the development of gastric and colorectal cancers in the elderly.
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Affiliation(s)
- Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Sakaecho, Tokyo, Japan.
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Mitani S, Kamata H, Fujiwara M, Aoki N, Okada S, Watanabe M, Tango T, Mori S. Missense mutation with/without nonsense mutation of the p53 gene is associated with large cell morphology in human malignant lymphoma. Pathol Int 2007; 57:430-6. [PMID: 17587242 DOI: 10.1111/j.1440-1827.2007.02119.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Mutations in p53 gene exons 5-9 were studied in 44 non-Hodgkin's lymphomas (NHL) consisting of 35 B-NHL and 9 T-NHL. Missense mutations were found in two diffuse large B-cell lymphomas (DLBL) and one peripheral T-cell lymphoma (unspecified). Double transversion missense and nonsense mutations were detected in one DLBL and one adult T-cell leukemia/lymphoma. Silent mutations were found in two DLBL. Detailed histomorphological study showed that cases harboring p53 missense mutation with/without nonsense mutation tended to have larger nuclei with much more prominent nucleoli. Cytomorphometric analysis was therefore conducted by measuring the gross area of 100 lymphoma cell nuclei in 44 cases and the results were compared between lymphomas harboring p53 missense mutation with/without nonsense mutation and lymphomas harboring p53 silent mutation or lacking mutation. It was found that the lymphomas harboring p53 missense mutation with/without nonsense mutation had a highly significantly larger nuclear gross area than lymphomas with silent p53 mutation or lacking mutation (two-sample t-test, P < 0.00001; Exact Wilcoxon rank-sum test, P < 0.00001). This result suggests that p53 mutation might induce enlargement of neoplastic cell nuclei by some molecular mechanism.
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Affiliation(s)
- Shoko Mitani
- Center for Professional Education, Kanagawa Prefectural University of Human Service, Yokohama, Japan.
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Yokoyama A, Shi BH, Kawai T, Konishi H, Andoh R, Tachikawa H, Ihara S, Fukui Y. Muc4 is required for activation of ErbB2 in signet ring carcinoma cell lines. Biochem Biophys Res Commun 2007; 355:200-3. [PMID: 17292332 DOI: 10.1016/j.bbrc.2007.01.133] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2007] [Accepted: 01/25/2007] [Indexed: 10/23/2022]
Abstract
Signet-ring cell carcinoma is one of the most malignant tumors, classified histologically as a poorly differentiated adenocarcinoma. The ErbB2/ErbB3 complex is often constitutively activated, which suggests that the ErbB2/ErbB3 signaling pathway may be important for malignancy of this tumor. However, the mechanism underlying this activation has not been understood. Here, we show that ErbB2 and Muc4 bind in signet ring carcinoma cells, which was not seen in highly differentiated adenocarcinoma cell lines. ErbB3 was suggested to be a substrate of ErbB2 because knockdown of ErbB2 resulted in less phosphorylation of ErbB3. Inhibition of expression of Muc4 at the cell surface by the treatment of the cells with benzyl-GalNac, an inhibitor of mucin secretion, blocked phosphorylation of ErbB3, suggesting that activity of ErbB2 depends on the expression of Muc4. These results supply the biochemical backgrounds in recent studies suggesting the contribution of Muc4 in the tumorigenesis.
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Affiliation(s)
- Atsushi Yokoyama
- Division of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
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Santoro R, Carboni F, Lepiane P, Ettorre GM, Santoro E. Clinicopathological features and prognosis of gastric cancer in young European adults. Br J Surg 2007; 94:737-42. [PMID: 17330827 DOI: 10.1002/bjs.5600] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Abstract
Background
The aims of this study were to define the clinicopathological features and prognosis of gastric cancer in young European adults.
Methods
Between 1990 and 2004, 603 patients with gastric cancer were enrolled in a prospective database. The findings for 51 (8·5 per cent) patients aged 45 years or less were compared with those of 457 aged between 46 and 75 years.
Results
In the younger group there were significantly more women (57 versus 36·3 per cent; P = 0·004), Laurén diffuse-type carcinomas (73 versus 42·7 per cent; P < 0·001), N2–3 lymph node metastases (59 versus 38·9 per cent; P = 0·005), stage IV disease (49 versus 35·7 per cent; P = 0·085) and resections that were non-curative (36 versus 18·5 per cent; P = 0·007) than in the older patients. Actuarial survival rates in younger patients at 5 and 10 years after resection were 40 and 32 per cent respectively, similar to those in older patients (P = 0·540). Unfavourable prognostic factors associated with poor 5-year survival were the degree of gastric wall invasion (T3–4 versus T1–2; P < 0·001), lymph node invasion (positive versus negative; P < 0·001), disease stage (III–IV versus I–II; P < 0·001) and curability of resection (non-curative versus curative; P < 0·001).
Conclusion
Gastric cancer in young adults tends to be more advanced; however, when matched for stage, the prognosis does not differ from that of older patients.
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Affiliation(s)
- R Santoro
- Department of Digestive Surgery and Liver Transplantation, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy.
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