Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1

Abstract

Previous studies have demonstrated that microRNA (miRNA) expression is altered in human cancer. However, the molecular mechanism underlying these changes in miRNA expression remains unclear. In this study, we investigated the epigenetic modification of miR-124 genes and the potential function of miR-124 in pancreatic cancer. Using pyrosequencing analysis, we found that miR-124 genes (including miR-124-1, miR-124-2 and miR-124-3) are highly methylated in pancreatic cancer tissues compared with in non-cancerous tissues. Hypermethylation mediated the silencing of miR-124, which was a frequent event in pancreatic duct adenocarcinoma (PDAC). Furthermore, miR-124 downregulation was significantly associated with worse survival of PDAC patients. Functional studies showed that miR-124 inhibited cell proliferation, invasion and metastasis. Furthermore, we characterized Rac1 as a direct target of miR-124, and miR-124 interacted with the 3'-untranslated region of Rac1, which we showed to be a putative tumor promoter in pancreatic cancer. Thus, the miR-124-mediated downregulation of Rac1 led to the inactivation of the MKK4-JNK-c-Jun pathway. Therefore, our study demonstrates that miR-124 is a tumor suppressor miRNA that is epigenetically silenced in pancreatic cancer. Our findings suggest a previously unidentified molecular mechanism involved in the progression and metastasis of pancreatic cancer.

Role of miR-124 and miR-141 in the regulation of vascular reactivity and the relationship to RhoA and Rac1 after hemorrhage and hypoxia

“…The Table 3. Changes in miRNAs in superior mesenteric arteries after hypoxia effects of the mutant 3=-UTR control of RhoA and Rac1 were also investigated in this experiment (22).…”

Mutual regulation of microRNAs and DNA methylation in human cancers

“…97 Hypermethylation mediates the silencing of miR-124, thereby promoting pancreatic cancer metastasis. 126,127 Downregulation of miR-212 due to promoter hypermethylation promotes EMT as well as cell migration and invasion in vitro and promotes the formation of intrahepatic and pulmonary colorectal cancer metastasis in vivo. 128 In contrast, miR-135b, which promotes NSCLC metastasis in vivo, is regulated by DNA demethylation.…”

miR-124 Regulates Amadori-Glycated Albumin-Induced Retinal Microglial Activation and Inflammation by Targeting Rac1

“…23,[28][29][30] Interestingly, some studies have shown that miR-124 directly controls Rac1 expression by binding to the 3 0 -UTR of Rac1 mRNA. 40,41 MicroRNA-124 acts as a tumor suppressor in MG-63 and U2OS The soluble TNF-a release and TNF-a mRNA were inhibited by overexpression of miR-124. In contrast, the ectopic expression of mutated 3 0 -UTR Rac1 significantly abrogated the effect of downregulated TNF-a production induced by miR-124.…”

“…40 Furthermore, miR-124 also inhibits cell proliferation, invasion, and metastasis by directly controlling Rac1 in pancreatic cancer. 41 Therefore, to investigate the possible mechanism through which miRNAs are involved in the inflammatory action of AGA, the expression of miRNAs that have been found to either regulate Rac1 expression or undergo inflammatory response was examined by qRT-PCR. We found that miR-124 expression decreased by nearly 5-fold in the presence of AGA, whereas the levels of other miRNAs were not affected.…”