Somatic mutations of the trefoil factor family 1 gene in gastric cancer

Park, Won Sang; Oh, Ro Ra; Park, Jik Young; Lee, Jong Heun; Shin, Min Sun; Kim, Hong Sug; Lee, Hun Kyung; Kim, Young Sil; Kim, Su Young; Lee, Sug Hyung; Yoo, Nam Jin; Lee, Jung Young

doi:10.1053/gast.2000.16483

Cited by 148 publications

(116 citation statements)

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“…Although GC is usually managed by surgery or chemotherapy, the prognosis is still poor, mainly because of tumor metastasis and chemotherapy resistance, and the overall 5-year survival rate is less than 15 % [3]. Numerous studies have reported that the causes of GC include genetic factors, such as p53, E-cadherin, c-Met, and trefoil factor 1 [4,5]. However, the molecular mechanisms underlying tumor metastasis and chemotherapy resistance, and affecting clinical outcome in GC remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance

Chen

Lian

et al. 2015

Gastric Cancer

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Background B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP) are involved in cancer metastasis and chemotherapeutic resistance, respectively. In this study, we evaluated the association between Bmi-1 and RKIP and outcome of gastric cancer through clinical data analysis and in vitro experiments. Methods Bmi-1 expression and RKIP expression were observed in 107 cases of gastric cancer through use of tissue microarray technology to identify their correlations with clinicopathological parameters, patient survival, and susceptibility to chemotherapy. The correlation was confirmed in gastric cancer cell lines, analyzed further by gene overexpression and silencing analysis, a cell invasion assay, and a chemosensitivity test.Results Positive expression of Bmi-1 was highly correlated with T classification and clinical stage. Diminished or lost expression of RKIP was significantly associated with T classification, lymph node metastasis, distant metastasis, and clinical stage. Bmi-1 is negatively and RKIP is positively related to patient survival. Positive expression of Bmi-1 and negative expression of RKIP are associated with poor patient survival and modest efficacy of postoperative chemotherapy. A meaningfully inverse association between Bmi-1 and RKIP was found in tissue microarray studies, and was verified further in gastric cancer cell lines. Moreover, gene overexpression and silencing analysis indicated that RKIP might be regulated by Bmi-1. Furthermore, the impacts of Bmi-1 on cell invasion and chemotherapy resistance were rescued by knockdown of RKIP. Conclusions Our study implies that detection of Bmi-1 and RKIP is valuable in predicting patient survival and therapeutic response in gastric cancer, and the inverse association between Bmi-1 and RKIP reveals the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance.Y. Chen, G. Lian, and G. Ou are contributed equally to this work.Electronic supplementary material The online version of this article

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Section: Introductionmentioning

confidence: 99%

Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance

Chen

Lian

et al. 2015

Gastric Cancer

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“…Stabilized b-catenin in this canonical Wnt pathway enters the cell nucleus and associates with members of the T-cell factor and lymphoid enhancer factor (TCF/LEF-1) family of transcription factors where it stimulates expression of Wnt/b-catenin target genes including regulators of cell growth and proliferation, modulators of cell death pathways and cell-cell communication (He et al, 1998;Van der Heyden et al, 1998;Mann et al, 1999;Tetsu and McCormick, 1999;Yamada et al, 2000;Zhang et al, 2001). This transforming activity of the Wnt/bcatenin pathway, which was initially delineated in the mammary epithelial cell line, C57MG, appears to be involved in the carcinogenesis of a number of human epithelial carcinomas (Kitaeva et al, 1997;Fukuchi et al, 1998;Miyoshi et al, 1998;Palacios and Gamallo, 1998;Chan et al, 1999;Gamallo et al, 1999;Kobayashi and Sagae, 1999;Koch et al, 1999;Mirabelli-Primdahl et al, 1999;Nhieu et al, 1999;Park et al, 1999;Wright et al, 1999;Jeng et al, 2000;Woo et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Wnt-5a has tumor suppressor activity in thyroid carcinoma

et al. 2005

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Stabilization of b-catenin by inhibition of its phosphorylation is characteristic of an activation of the canonical Wnt/b-catenin signaling pathway and is associated with various human carcinomas. It contrasts to an as yet incompletely characterized action of an alternative noncanonical Wnt signaling pathway on neoplastic transformation. The aim of the present study was to test the effects of a member of the noncanonical Wnt signaling pathway, Wnt-5a, in primary thyroid carcinomas and in thyroid carcinoma cell lines. Compared to normal tissue Wnt-5a mRNA expression was clearly increased in thyroid carcinomas. Immunohistochemically, a bellshaped response was observed with low to undetectable levels in normal tissue and in anaplastic tumors whereas differentiated thyroid carcinomas showed strong positive immunostaining for Wnt-5a. Transfection of Wnt-5a in a thyroid tumor cell line FTC-133 was able to reduce proliferation, migration, invasiveness and clonogenicity in these cells. These effects of Wnt-5a are associated with membranous b-catenin translocation and c-myc oncogene suppression and are mediated through an increase in intracellular Ca 2 þ release, which via CaMKII pathways promotes b-catenin phosphorylation. Specific inhibition of b-catenin phosphorylation by W-7, a calmodulin inhibitor, or by KN-93, a CaMKII inhibitor, supports these findings whereas PKC inhibitors were without effect. This interaction occurs downstream of GSK-3b as no Wnt-5a effect was seen on the Ser 9 phosphorylation of GSK-3b. Our data are compatible with the hypothesis that Wnt-5a serves as an antagonist to the canonical Wnt-signaling pathway with tumor suppressor activity in differentiated thyroid carcinomas.

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“…Genetic alternations involving proto-oncogenes (K-ras and b-catenin), tumor suppressor genes (p53 and APC), cell-cycle regulator genes (E-cadherin and p16), and mismatch repair genes (hMLH1 and hMSH2) play an important role in gastric carcinogenesis (Kihana et al, 1991;Becker et al, 1994;Rhyu et al, 1994;Akiyama et al, 1996;Gunther et al, 1998;Park et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas

et al. 2004

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Gastric carcinogenesis involves multiple genetic and epigenetic alterations. Epigenetic silencing of tumorrelated genes due to CpG island methylation (CIM) has been recently reported in gastric cancer, but the role in precursor lesions is not well understood. We analysed the methylation status of the tumor suppressor gene p16, the DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using methylation-specific polymerase chain reaction in 35 polypoid adenomas and 46 flat dysplasias unassociated with carcinoma, 34 early adenocarcinomas (T1N0M0) and associated adenomas/dysplasias, and corresponding adjacent non-neoplastic mucosa. The extent of CIM was defined by the fraction of methylated loci (methylation index), and compared with previously characterized genetic alterations (microsatellite instability (MSI) and APC gene mutation). We found that methylation of p16 was more frequent in adenocarcinoma-associated dysplasias/adenomas (29%) and adenocarcinomas (44%) as compared to flat dysplasias (4%) and adenomas (18%) unassociated with adenocarcinoma (P ¼ 0.001). The mean methylation index increased from normal/chronic gastritis (CG) mucosa (0.09) to intestinal metaplasia (IM) (0.16), flat dysplasias (0.40) or polypoid adenomas (0.41) unassociated with carcinoma, dysplasias/adenomas associated with carcinoma (0.44), and adenocarcinomas (0.44). There was no difference in frequencies of highlevel CpG island methylation (CIM-H, methylation index X0.5) among flat dysplasias (50%) and polypoid adenomas (51%) unassociated with carcinoma, dysplasias/adenomas associated with adenocarcinoma (47%), and adenocarcinoma (47%). CIM-H was present in 15% of IM, but not in normal/CG mucosa. There was a significant correlation between methylation of hMLH1 and high-level of microsatellite instability (MSI-H): methylation of hMLH1 was present in 71% of MSI-H tumors, but only 8% of MSI-low tumors and 13% of microsatellite-stable tumors (P ¼ 0.0001). There was no statistical difference between methylation index and APC mutation. Our results indicate that concurrent promoter methylation is an early and frequent event in gastric tumorigenesis, including both MSI-H and microsatellitestable neoplasms. Methylation of the p16 gene may contribute to the malignant transformation of gastric precursor lesions.

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Somatic mutations of the trefoil factor family 1 gene in gastric cancer

Cited by 148 publications

References 25 publications

Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance

Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance

Wnt-5a has tumor suppressor activity in thyroid carcinoma

Frequent CpG island methylation in precursor lesions and early gastric adenocarcinomas

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