Detection of <i>miR-34a</i> Promoter Methylation in Combination with Elevated Expression of c-Met and β-Catenin Predicts Distant Metastasis of Colon Cancer

Siemens, Helge; Neumann, Jens; Jackstadt, René; Mansmann, Ulrich; Horst, David; Kirchner, Thomas; Hermeking, Heiko

doi:10.1158/1078-0432.ccr-12-1703

Cited by 132 publications

(107 citation statements)

References 46 publications

(58 reference statements)

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“…The analysis of human CRC samples suggests that the IL-6R/STAT3/miR-34a loop is also manifest in primary human colorectal tumors with mesenchymal characteristics and might represent a useful prognostic marker for cancer progression. In line with these findings, we recently showed that the loss of miR-34a expression by epigenetic silencing in primary tumors is associated with increased lymph node infiltration and metastasis in colon cancer patients (57). Besides STAT3 and IL-6R, which are already established targets for cancer treatment, our results suggest that restoring miR-34a function using mimetics may have therapeutic potential for the treatment of invasive CRCs.…”

Section: Discussionsupporting

confidence: 86%

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

Rokavec¹,

Öner²,

Li³

et al. 2014

J. Clin. Invest.

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618

434

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Members of the miR-34 family are induced by the tumor suppressor p53 and are known to inhibit epithelialto-mesenchymal transition (EMT) and therefore presumably suppress the early phases of metastasis. Here, we determined that exposure of human colorectal cancer (CRC) cells to the cytokine IL-6 activates the oncogenic STAT3 transcription factor, which directly represses the MIR34A gene via a conserved STAT3-binding site in the first intron. Repression of MIR34A was required for IL-6-induced EMT and invasion. Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, as a conserved, direct miR-34a target. The resulting IL-6R/STAT3/miR-34a feedback loop was present in primary colorectal tumors as well as CRC, breast, and prostate cancer cell lines and associated with a mesenchymal phenotype. An active IL-6R/ STAT3/miR-34a loop was necessary for EMT, invasion, and metastasis of CRC cell lines and was associated with nodal and distant metastasis in CRC patient samples. p53 activation in CRC cells interfered with IL-6-induced invasion and migration via miR-34a-dependent downregulation of IL6R expression. In Mir34a-deficient mice, colitis-associated intestinal tumors displayed upregulation of p-STAT3, IL-6R, and SNAIL and progressed to invasive carcinomas, which was not observed in WT animals. Collectively, our data indicate that p53-dependent expression of miR-34a suppresses tumor progression by inhibiting a IL-6R/STAT3/miR-34a feedback loop.

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Section: Discussionsupporting

confidence: 86%

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

Rokavec¹,

Öner²,

Li³

et al. 2014

J. Clin. Invest.

Self Cite

618

434

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“…miR-15a and AP4 expression shows an inverse correlation in primary colon cancer. A, 94 samples of right-sided colon cancer, which have been described previously (2,48), were subjected to qRT-PCR analysis of miR-15a expression. Expression of AP4 has previously been determined using immunohistochemistry (2) and was correlated with miR-15a expression.…”

Section: Discussionmentioning

confidence: 99%

p53-Induced miR-15a/16-1 and AP4 Form a Double-Negative Feedback Loop to Regulate Epithelial–Mesenchymal Transition and Metastasis in Colorectal Cancer

et al. 2014

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The transcription factor AP4 mediates epithelial-mesenchymal transition (EMT) in colorectal cancer but its control in this setting is not fully understood. Here, we report the definition of a double-negative feedback loop involving AP4 and miR-15a/16-1 that regulates EMT and metastatic progression. In colorectal cancer cells, AP4 was downregulated by DNA damage in a p53-dependent manner. AP4 downregulation by p53 was mediated indirectly by the tumor-suppressive microRNAs miR-15a and miR-16-1, which targeted the 3 0 untranslated region (3 0 -UTR) of AP4 mRNA, induced mesenchymal-epithelial transition (MET), and inhibited colorectal cancer cell migration and invasion. The downregulation of AP4 was necessary for induction of MET and cell cycle arrest by miR-15a/16-1. In tumor xenoplants, ectopic miR-15a/16-1 suppressed formation of lung metastases. Furthermore, AP4 directly suppressed expression of miR-15a/16-1. In clinical specimens of colorectal cancer, miR-15a levels inversely correlated with AP4 protein levels shown previously to correlate with distant metastasis and poor survival. In summary, our results define a double-negative feedback loop involving miR-15a/16-1 and AP4 that stabilizes epithelial and mesenchymal states, respectively, which may determine metastatic prowess. Cancer Res; 74(2); 532-42. Ó2013 AACR.

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“…124 miR-34a methylation may be a powerful predictive marker of liver metastasis in colorectal cancer. 125 Downregulation of miR-203 in metastatic breast cancer cells, caused by hypermethylation of its promoter, increases cell invasion and migration in vitro. 97 Hypermethylation mediates the silencing of miR-124, thereby promoting pancreatic cancer metastasis.…”

Section: Biomarkers For Cancer Prognosismentioning

confidence: 99%

Mutual regulation of microRNAs and DNA methylation in human cancers

Wang¹,

Wu²,

Claret

2017

Epigenetics

117

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microRNAs (miRNAs) and DNA methylation are the 2 epigenetic modifications that have emerged in recent years as the most critical players in the regulation of gene expression. Compelling evidence has indicated the roles of miRNAs and DNA methylation in modulating cellular transformation and tumorigenesis. miRNAs act as negative regulators of gene expression and are involved in the regulation of both physiologic conditions and during diseases, such as cancer, inflammatory diseases, and psychiatric disorders, among others. Meanwhile, aberrant DNA methylation manifests in both global genome changes and in localized gene promoter changes, which influences the transcription of cancer genes. In this review, we described the mutual regulation of miRNAs and DNA methylation in human cancers. miRNAs regulate DNA methylation by targeting DNA methyltransferases or methylation-related proteins. On the other hand, both hyper-and hypo-methylation of miRNAs occur frequently in human cancers and represent a new level of complexity in gene regulation. Therefore, understanding the mechanisms underlying the mutual regulation of miRNAs and DNA methylation may provide helpful insights in the development of efficient therapeutic approaches.

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Detection of miR-34a Promoter Methylation in Combination with Elevated Expression of c-Met and β-Catenin Predicts Distant Metastasis of Colon Cancer

Cited by 132 publications

References 46 publications

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

p53-Induced miR-15a/16-1 and AP4 Form a Double-Negative Feedback Loop to Regulate Epithelial–Mesenchymal Transition and Metastasis in Colorectal Cancer

Mutual regulation of microRNAs and DNA methylation in human cancers

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