Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133

Abstract

Tumor relapse after therapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive treatment. We have previously identified a CSC population derived from HCC that is characterized by CD133. Despite our growing knowledge of the importance of this subset of cells in driving HCC, the regulatory mechanism of CD133 is not known. Epigenetic changes are believed to be essential in the control of cancer and stem cells. Here, we report the epigenetic regulation of CD133 by miR-142-3p. The interaction between CD133 and miR-142-3p was identified by in silico prediction and substantiated by luciferase reporter analysis. Expression of CD133 was found to be inversely correlated with miR-142-3p in HCC clinical samples as well as in cell lines. Importantly, lower miR-142-3p expression in HCC was significantly associated with worst survival. Functional studies with miR-142-3p stably transduced in HCC cells demonstrated a diminished ability to self-renew, initiate tumor growth, invade, migrate, induce angiogenesis and resist chemotherapy. Rescue experiments whereby CD133 and miR-142-3p is simultaneously overexpressed compensated the deregulated ability of the cells to confer these features. Thus, miR-142-3p directly targets CD133 to regulate its ability to confer cancer and stem cell-like features in HCC.

Oncogenic microRNA-142-3p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma

“…In clinical application, the reduced expression of miR-142-3p in hepatocellular carcinoma and its overexpression in esophageal squamous cell carcinoma was significantly associated with reduced survival, suggesting that miR-142-3p may function as a prognostic predictor (24,31). Serum miR-142-3p was identified to be associated with a high recurrence risk in patients with early-stage lung adenocarcinoma, and was a putative serum marker for risk assessment (40).…”

“…miRNAs target numerous genes, including HIF, mTOR, VEGF and VHL, through translational inhibition or the induction of mRNA degradation, which suggests that miRNAs function as important factors in RCC initiation and development (36,37). Previous studies have reported that miR-142-3p is dysregulated in various types of cancer (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), and may therefore function as a biomarker. The expression of miR-142-3p in RCC has not yet been validated by qPCR.…”

“…Previous microarray chip studies have demonstrated that miR-142-3p is overexpressed in RCC tissues compared with adjacent normal or benign kidney tissues (18)(19)(20)(21). It has also been reported that miR-142-3p is dysregulated in malignancies of the breast (22), thyroid (23), liver (24), stomach (25), lung (26), blood (27,28), colorectum (29), testes (30), esophagus (31), head and neck (32), and bone (33). The present study establishes the oncogenic role of miR-142-3p in RCC, demonstrating how it regulates cell migration, proliferation and apoptosis.…”

miR-142 acts as a tumor suppressor in osteosarcoma cell lines by targeting Rac1

“…miR-142 has been found to be downregulated in several types of cancers, including hepatic cancer (17), squamous cell lung cancer (18) and human acute lymphoblastic leukemia (19), and acts as a tumor suppressor. It was reported that lower miR-142 expression in hepatocellular carcinoma was significantly associated with poor survival (17).…”

“…It was reported that lower miR-142 expression in hepatocellular carcinoma was significantly associated with poor survival (17). Rac1 expression is frequently upregulated in several types of cancers, including hepatic cancer (14) and breast cancer (20).…”