Phosphorylated Smad2 in Advanced Stage Gastric Carcinoma

Shinto, Osamu; Yashiro, Masakazu; Toyokawa, Takahiro; Nishii, Takafumi; Kaizaki, Ryoji; Matsuzaki, Taro; Noda, Shinichi; Kubo, Naoshi; Tanaka, Hiroaki; Doi, Yukio; Ohira, Masaichi; Muguruma, Kazuya; Sawada, Tetsuji; Hirakawa, Kosei

doi:10.1186/1471-2407-10-652

Cited by 43 publications

(39 citation statements)

References 24 publications

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“…Activation of SMAD2 could induce migration of mouse squamous carcinoma cells and elevated levels of SMAD2 were required for induction of spindle-cell transformation and metastasis (33). Overexpression of SMAD2 was also suggested to be associated with metastasis and was correlated with poor prognosis of gastric cancers, especially diffuse-type gastric carcinoma (34). In our study SMAD2 was overexpressed and verified as a promising target gene, which was related to metastasis in gastric cancer cells.…”

Section: Discussionmentioning

confidence: 85%

microRNA-155 is downregulated in gastric cancer cells and involved in cell metastasis

Nie

Wang

et al. 2012

Oncol Rep

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Abstract. , an important multifunctional microRNA, has been implicated in the development of multiple solid tumors, yet, its role in gastric cancer cells has not been fully elucidated. In this study, we find that miR-155 was significantly downregulated in gastric cancer cell lines compared with an immortalized gastric epithelial cell line (GES-1). Overexpression of miR-155 in SGC-7901 and MKN-45 gastric cancer cells dramatically suppressed cell migration, invasion and adhesion in vitro. Overexpression of miR-155 significantly reduced the protein levels of SMAD2 and repressed the activity of a luciferase reporter containing one of the two predicted miR-155 binding sites in SMAD2 3'-UTR, indicating that SMAD2 may be a miR-155 target gene. miR-155 expression was also remarkably restored by a DNA demethylating agent (5-Aza-2-deoxycytidine) in SGC-7901 and MKN-45 gastric cancer cells. Taken together, these data suggest that miR-155 may function as a tumor suppressor to regulate gastric cancer cell metastasis by targeting SMAD2, and its downregulation in gastric cancer cells may be partly ascribed to DNA methylation. IntroductionGastric cancer remains the fourth most common malignancy and the second leading cause of cancer-related death in both genders worldwide, despite a substantial decrease in its rate (1,2). In 2008, more than 70% of new cases (713,000 cases) occurred in developing countries, and half the world total occured in Eastern Asia (mainly in China) (2). Despite a steady decline in mortality, the prognosis of patients with advanced gastric cancer is still very disappointing (3), mainly due to poor understanding of the mechanisms underlying its development. microRNAs (miRNAs) are endogenous, small (18-25 nucleotides), non-coding RNAs that play important roles in gene expression by targeting 3'UTR of cellular transcripts, resulting mRNA cleavage or translational inhibition (4,5). By these mechanisms, miRNAs have been shown to be involved in mediating processes in tumorigenesis such as cell cycle regulation, differentiation, apoptosis, invasion and metastasis (6,7). Dysregulated expression of miRNAs is now considered as a common characteristic of all human tumors (8). The aberrant expression of miRNAs in human cancers and their role in tumor formation might define miRNAs as oncogenes or tumor suppressors.miR-155, processed from an exon of a non-coding RNA transcribed from the B-cell integration cluster (BIC), has been a typical multifunctional miRNA (9,10). Accumulating evidence has demonstrated that miR-155 is involved in numerous biological processes including haematopoiesis, inflammation, immunity and carcinogenesis (10,11). Several lines of evidence indicate that dysregulation of miR-155 is linked to various solid tumors, including breast, colon, cervical, thyroid, pancreatic and lung cancer (12-18). The frequently detected overexpression of miR-155 in these tumors indicates a major role of an oncogene; however, possible tumor suppressor functions have also been reported (19-21). Although miR-155 has bee...

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Section: Discussionmentioning

confidence: 85%

microRNA-155 is downregulated in gastric cancer cells and involved in cell metastasis

Nie

Wang

et al. 2012

Oncol Rep

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“…In our findings, BLM induces phosphorylation of Smad2/3 and activates the Smad signaling pathway to prevent the malignant progression of gastric cancer cells. It has been reported that Smad proteins, such as phosphorylated Smad3, are the intracellular signaling effectors for the mediation of intracellular signaling of TGF-β, and the expression of it provides significant prognostic power for gastric cancer patients [27]. Kim et al [28] reported that the prognosis of patients with Smad4-positive gastric carcinomas was significantly better than that of patients with a negative tumor.…”

Section: Discussionmentioning

confidence: 99%

Bleomycin Suppresses the Proliferation and the Mobility of Human Gastric Cancer Cells Through the Smad Signaling Pathway

Liu

Nie

Shao

et al. 2016

Cell Physiol Biochem

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Background/Aims:Extensive studies have demonstrated that Bleomycin (BLM) is a glycopeptide antibiotic that has been used as an anticancer chemotherapeutic reagent. It can induce both single-and double-strand DNA damage, inhibit synthesis of DNA, suppress proliferation, and induce apoptosis in cancer cells. Smad signaling transducers are considered as important molecules in tumor development and progression, and may closely be related to the biological behaviors of some malignant carcinomas, including gastric cancer. Methods: The effects of different concentrations of BLM on the proliferation, cell cycle, apoptosis, migration, and invasion on gastric cancer cell lines MKN45 and AGS were assayed by using CCK-8 assay, Annexin V/PI double staining, PI staining, and transwell assay. Western blot and Immunohistochemistry were applied to analyze the potential mechanism(s). Results: BLM treatment resulted in a low proliferation, high apoptosis, low migration and invasion in MKN45 and AGS cells. Furthermore, the possible mechanisms underlying that Smad3 activity could be changed after binding with BLM, and subsequently the Smad signaling pathway had a cascade response. Conclusion: These results highlight BLM as an exciting theme for gastric cancer treatment, which may represent an effective clinical therapeutic reagent for gastric cancer patients.

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“…The association between a high level of p-Smad2 and a malignant phenotype and poor prognosis in patients with advanced carcinoma (51) suggests that targeting mutant p53 may amend the balance between Smad2 and Smad3 signaling for late-stage cancers.…”

Section: Discussionmentioning

confidence: 99%

Mutant p53 Promotes Tumor Cell Malignancy by Both Positive and Negative Regulation of the Transforming Growth Factor β (TGF-β) Pathway

Liu

et al. 2015

Journal of Biological Chemistry

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Background:The molecular mechanisms by which mutant p53 deregulates the TGF-␤ pathway remain obscure. Results: Mutant p53 disrupts the Smad3/Smad4 complex by occupying the MH2 domain in Smad3 upon ERK activation. Conclusion: Mutant p53 achieves gain of function by attenuating and cooperating with the TGF-␤ pathway via targeting Smad3. Significance: We discovered a new mechanistic mode explaining the cross-talks among the mutant p53, TGF-␤, and ERK pathways.

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Phosphorylated Smad2 in Advanced Stage Gastric Carcinoma

Cited by 43 publications

References 24 publications

microRNA-155 is downregulated in gastric cancer cells and involved in cell metastasis

microRNA-155 is downregulated in gastric cancer cells and involved in cell metastasis

Bleomycin Suppresses the Proliferation and the Mobility of Human Gastric Cancer Cells Through the Smad Signaling Pathway

Mutant p53 Promotes Tumor Cell Malignancy by Both Positive and Negative Regulation of the Transforming Growth Factor β (TGF-β) Pathway

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