MicroRNA‐27b suppresses tumor progression by regulating ARFGEF1 and focal adhesion signaling

Abstract

The non‐receptor tyrosine kinase c‐Src is frequently activated during progression of colon cancers. In this study, we found that among the c‐Src‐regulated microRNAs (miRNAs), miR‐27b is also repressed by activation of K‐Ras/H‐Ras. Inhibitor studies suggested that the phosphatidylinositol 3‐kinase pathway is involved in the repression of miR‐27b. MicroRNA‐27b was repressed in various colon cancer cell lines and tumor tissues. Re‐expression of miR‐27b in human colon cancer HCT116 cells caused morphological changes and suppressed tumor growth, cell adhesion, and invasion. We also identified ARFGEF1 and paxillin as novel targets of miR‐27b, and found that miR‐27b‐mediated regulation of ARFGEF1 is crucial for controlling anchorage‐independent growth, and that of paxillin is important for controlling cell adhesion and invasion. Re‐expression of miR‐27b suppressed the activation of c‐Src induced by integrin‐mediated cell adhesion, suggesting that repression of miR‐27b may contribute to c‐Src activation in cancer cells. These findings show that miR‐27b functions as a tumor suppressor by controlling ARFGEF1 and the paxillin/c‐Src circuit at focal adhesions.

The regulatory role of microRNAs in angiogenesis‐related diseases

“…145 In the bladder, prostate and colon tumours, miR-27b plays anti-tumour and anti-angiogenesis roles. 147,149 These contrary results may be because the effects of miR-27b in different diseases are context-dependent. The intricacy of miRNA-dependent gene expression is extended deeper by the fact that more than one miRNA can cooperatively target the same mRNA and each miRNA can target numerous mRNAs.…”

“…Moreover, a recent study indicated that miR‐27b effectively represses migration and tube formation of ovarian cancer cells, and angiogenesis in vivo by inhibiting VE‐cadherin 145. In the bladder, prostate and colon tumours, miR‐27b plays anti‐tumour and anti‐angiogenesis roles 147, 149. These contrary results may be because the effects of miR‐27b in different diseases are context‐dependent.…”

Promising therapeutic role of miR-27b in tumor

“…Followed by activation of the c-Src/AKT oncogenic pathway, miR-27b is repressed and down-regulated in human colon cancer cells. MiR-27b targets and directly reduces ARFGEF1 and paxillin, thus elevated ARFGEF1 and paxillin activating AKT and c-Src in turn, resulting in AKT/miR-27b/ ARFGEF1 and c-Src/miR-27b/paxillin positive feedback circuits 33 (Figure 1). …”

“…58 MiR-27b inhibits the formation of focal adhesions and cell motility abilities including invasion and migration in colon cancer HCT116 cells through targeting paxillin and silencing paxillin gene expression accompanied by reduced activation of c-Src signaling. 33 MiR-27b-induced cell invasive/metastatic potential of both glioma and hepatocellular carcinoma (HCC) is directly mediated by Spry2 suppression, thereby the miR-27b/Spry2 axis may as a promising molecular target for glioma and HCC metastasis. 59,60 The up-regulated miR-27b in BRC cells alters cell migration and invasion abilities by influencing Nischarin expression and inducing PAK signaling activation.…”

Upregulation of microRNA‑18b induces phosphatase and tensin homolog to accelerate the migration and invasion abilities of ovarian cancer

“…Multiple miRNAs function as potential tumor suppressors or oncogenes due to their fundamental roles in diverse cellular processes of various types of human cancer, including proliferation, migration, invasion and apoptosis (6)(7)(8)(9)(10)(11). Currently, numerous miRNAs including miR-126 (12), miR-137 (13), miR-145 (14), miR-148a (15) and miR-498 (16) have been demonstrated as tumor suppressor genes in OC.…”