Genetic and Epigenetic Down-regulation of MicroRNA-212 Promotes Colorectal Tumor Metastasis via Dysregulation of MnSOD

Meng, Xiangqi; Wu, Jiangxue; Pan, Ci; Wang, Hui; Ying, Xiaofang; Zhou, Yi; Yu, Hongyan; Zuo, Yufang; Pan, Zhizhong; Liu, Ran‐yi; Huang, Wenlin

doi:10.1053/j.gastro.2013.04.004

Cited by 117 publications

(100 citation statements)

References 39 publications

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“…Dysregulation of miRNAs in diseases is frequently due to epigenetic changes in the miRNA genome (28,29). Previous studies of miRNA genomic sequences have indicated that promoter hypermethylation of miRNAs occurs frequently as a result of the aberrant expression of DNMTs, histone deacetylases, and methyl-CpG-binding proteins (29)(30)(31). In the present study, we found that miR-126 was downregulated in ECs and that its downregulation was induced by promoter hypermethylation of its host gene.…”

Section: Discussionsupporting

confidence: 57%

DNMT1–MicroRNA126 Epigenetic Circuit Contributes to Esophageal Squamous Cell Carcinoma Growth via ADAM9–EGFR–AKT Signaling

Liu

Jiang

et al. 2015

Clinical Cancer Research

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Purpose: MicroRNAs (miRNA) are involved in and are controlled by epigenetic regulation, and thereby form a reciprocal regulatory circuit. Using next-generation sequencing (NGS)-based miRNA profiling, this study aimed to discover esophageal squamous cell carcinoma (ESCC)-specific miRNAs and miRNArelated epigenetic modulations.Experimental Design: NGS-based miRNA profiles were generated for four pairs of ESCC tissues and adjacent normal tissues. In situ hybridization was used to assess miRNA expression and its correlation with prognosis. miRNA-related DNA methylations were identified using bisulfite genomic sequencing, and the role of DNA methyltransferase 1 (DNMT1) was investigated using RNA interference. miRNA targets were screened by mRNA sequencing, and functional validation was performed in vitro and in vivo.Results: NGS-based miRNA profiling identified 78 differentially expressed miRNAs in ESCC. Among them, microRNA126-3p (miR-126) was significantly downregulated, and its downregulation correlated with poor ESCC prognosis. Downregulation of miR-126 was due to promoter hypermethylation of its host gene, Egfl7. DNMT1 was aberrantly upregulated in ESCC and responsible for the hypermethylation of Egfl7. Intriguingly, DNMT1 was suppressed by overexpression of miR-126, indicating the existence of a regulatory feedback circuit. ADAM9 was identified as a key target of miR-126. Ectopic expression of miR-126 or silencing of ADAM9 reduced ESCC cell proliferation and migration by inhibiting epidermal growth factor receptor-AKT signaling.Conclusions: Our results indicate that miR-126 is a potential prognostic indicator for ESCC and suggest that a novel "DNMT1-miR-126 epigenetic circuit" is involved in ESCC progression. Consequently, miR-126-based epigenetic modulations may provide a basic rationale for new approaches to antitumor therapeutics.

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Section: Discussionsupporting

confidence: 57%

DNMT1–MicroRNA126 Epigenetic Circuit Contributes to Esophageal Squamous Cell Carcinoma Growth via ADAM9–EGFR–AKT Signaling

Liu

Jiang

et al. 2015

Clinical Cancer Research

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“…At the advanced stages, most patients also develop liver, lung, or peritoneal metastases (28). Therefore, we used 2 models (hepatic and lung metastasis) to simulate colorectal cancer metastasis (29). Sirt7 was a significant metastasis facilitator in human colorectal cancers.…”

Section: Discussionmentioning

confidence: 99%

“…We found that Sirt7 reintroduction into colorectal cancer cells promoted EMT, as shown by the decreased expression of the epithelial markers E-cadherin and b-catenin and the enhanced expression of the mesenchymal markers fibronectin and vimentin. The ERK signaling pathway has been shown to upregulate Snail and slug, leading to the downregulation of E-cadherin (29,33). To test whether Sirt7 promotes EMT through the MAPK pathway, we used the ERK inhibitor PD98059 in migration assays.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Sirt7 Exhibits Oncogenic Property and Serves as a Prognostic Factor in Colorectal Cancer

et al. 2014

Clinical Cancer Research

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119

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Purpose: Sirtuins play an important role in cancer development. Sirt7, as a member of this family, is frequently overexpressed in certain carcinomas, but the oncogenic mechanism is seldom reported. In this study, Sirt7 was characterized for its role in colorectal cancer aggressiveness and underlying molecular mechanisms.Experimental Design: Quantitative PCR, Western blotting, and immunohistochemistry were performed to study Sirt7 expression in a cohort of colorectal cancer tissues and non-tumor tissues and cells. A series of in vitro and in vivo assays was performed to elucidate the function of Sirt7 in colorectal cancer and its underlying mechanisms. Association between the Sirt7 signature and survival was examined using Kaplan-Meier analysis and log-rank tests.Results: The Sirt7 protein level significantly correlated with tumor stage (P ¼ 0.029), lymph node metastasis (P ¼ 0.046), and poor patient survival (P < 0.05). Sirt7 knockdown significantly inhibited colorectal cancer cell proliferation, colony formation, and motility. Ectopic Sirt7 expression promoted colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Moreover, Sirt7 enhanced MAPK pathway activity concomitantly with p-ERK and p-MEK upregulation. In Sirt7-overexpressing cells, the mesenchymal markers vimentin and fibronectin were upregulated, and the epithelial markers E-cadherin and b-catenin were downregulated, which was linked to enhanced invasion by colorectal cancer cells.Conclusion: Our findings suggest that Sirt7 plays an important role in the development and progression of human colorectal cancer and functions as a valuable marker of colorectal cancer prognosis. Clin Cancer Res; 20(13); 3434-45. Ó2014 AACR.

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“…We found that 15 of 30 papers (50%) reported at least one statistically significant result-effect estimate or difference between marker expression-stratified survival curves-that supported a role for EMT markers measured in primary colorectal cancer tumors in predicting patient outcomes (19,20,29,34,36,37,40,42,(44)(45)(46)(47)(48)(49)(50). This is impressive given that the 30 studies had relatively small sample sizes (mean, 213.3 subjects; range, 10-566, with 80% having less than 260 subjects).…”

Section: Quality and Limitations Of Studiesmentioning

confidence: 79%

“…One study reported that subjects with high expression of miR-19b and miR-194 had shorter survival than those with low expression (46). The other study found shorter survival for subjects whose tumors had low expression of miR-212 compared with those with high expression (47).…”

Section: Mirnasmentioning

confidence: 99%

The Potential for Markers of Epithelial–Mesenchymal Transition to Improve Colorectal Cancer Outcomes: A Systematic Review

Busch¹,

McGraw

Sandler³

2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Epithelial-mesenchymal transition (EMT) is thought to be an important mechanism of cancer cell metastasis. Clinical measurement of EMT markers in primary tumors could improve risk stratification and treatment decisions by identifying patients who potentially have metastatic disease. To evaluate the potential of EMT markers that could be used for risk stratification for patients with colorectal cancer, we conducted a systematic review of studies (N ¼ 30) that measured at least one of a selection of EMT markers in primary tumors and patient outcomes. Fifteen of 30 studies (50%) reported at least one statistically significant result supporting a role for one of the selected EMT markers in identifying patients at risk for worse outcomes. Importantly, however, we identified design inconsistencies that limited inferences and prevented meta-analysis of data. We offer a number of recommendations to make future studies more informative and standardized, including consistent sampling of different parts of the primary tumor, larger sample sizes, and measurement of both protein and RNA expression of a given EMT marker in the same tumors. Strengthening the literature per our recommendations could facilitate translating EMT markers to clinical use. Cancer Epidemiol Biomarkers Prev; 23(7); 1164-75. Ó2014 AACR.

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Genetic and Epigenetic Down-regulation of MicroRNA-212 Promotes Colorectal Tumor Metastasis via Dysregulation of MnSOD

Cited by 117 publications

References 39 publications

DNMT1–MicroRNA126 Epigenetic Circuit Contributes to Esophageal Squamous Cell Carcinoma Growth via ADAM9–EGFR–AKT Signaling

DNMT1–MicroRNA126 Epigenetic Circuit Contributes to Esophageal Squamous Cell Carcinoma Growth via ADAM9–EGFR–AKT Signaling

Overexpression of Sirt7 Exhibits Oncogenic Property and Serves as a Prognostic Factor in Colorectal Cancer

The Potential for Markers of Epithelial–Mesenchymal Transition to Improve Colorectal Cancer Outcomes: A Systematic Review

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