Downregulation of microRNA-138 enhances the proliferation, migration and invasion of cholangiocarcinoma cells through the upregulation of RhoC/p-ERK/MMP-2/MMP-9

Abstract

microRNAs (miRs) play an important role in tumor initiation and progression in many types of cancer, including cholangiocarcinoma (CC). miR-138 dysregulation is frequently observed in a variety of tumors. In the present study, miR-138 was found to be downregulated in CC tissues by quantitative real-time RT-PCR. Furthermore, its potential target molecule, Ras homolog gene family, member C (RhoC) protein, was found to be highly expressed in CC tissues examined by western blot analysis. Luciferase reporter assay further demonstrated that miR-138 directly targeted RhoC. We found that the introduction of miR-138 mimics to RBE and QBC939 CC cells could reduced RhoC mRNA and protein expression, and suppressed the proliferation, G1/S transition, migration and invasion of CC cells. However, transfection with a miR-138 inhibitor induced an inverse effect in CC cells. The expression of phosphorylated extracellular signal-regulated kinase (p-ERK), matrix metalloproteinase (MMP)-2 and MMP-9 decreased following transfection with miR-138, and increased following transfection with miR-138 inhibitor in CC cells. In conclusion, RhoC upregulation induced by miR-138 downregulation promotes the malignant progression of CC cells and the underlying mechanisms of this effect involve the increase in the expression of p-ERK/MMP-2/MMP-9. Consequently, miR-138/RhoC is a potential target for the clinical diagnosis and treatment of CC.

MiR‐138/peroxisome proliferator‐activated receptor β signaling regulates human hypertrophic scar fibroblast proliferation and movement in vitro

“…4 MiR-138 acts as a tumor suppressor in various types of cancer, including non-small cell lung cancer, 11 head and neck squamous cell carcinoma, 12 and cholangiocarcinoma. 13 MiR-138 was found to be downregulated in cholangiocarcinoma tissues. The introduction of miR-138 mimics to cholangiocarcinoma cells and may suppress proliferation, G1/S transition, migration and invasion.…”

“…The introduction of miR-138 mimics to cholangiocarcinoma cells and may suppress proliferation, G1/S transition, migration and invasion. 13 Moreover, in head and neck squamous cell carcinoma, it was found that overexpressed miR-138 attenuated the downstream signaling cascade, extracellular signal-regulated kinase (1/2), leading to cancer progression and survival. 12 MiR-138 has been recognized as a potential tumor suppressor because it regulates PDK1 expression in non-small cell lung cancer cells, which are independent prognostic factors for overall survival in non-small cell lung cancer cells patients.…”

Circular RNA participates in the carcinogenesis and the malignant behavior of cancer

“…As a result, the RhoC/p-ERK/MMP-2/ MMP-9 pathway is upregulated, which causes enhanced proliferation, migration and invasion of cholangiocarcinoma cells. 64 In addition, miR-138 could target directly the Twist basic helix-loop-helix transcription factor 2 gene (TWIST2) and reduce its function, which inhibits migration and invasion in colorectal cancer. 65 Besides, miR-138 is ovarian cancer-specific, where it functions to inhibit ovarian cancer cell growth by blocking the proliferating cell nuclear antigen (PCNA) and Bcell lymphoma-2 (Bcl ¡ 2) pathway.…”

Noncoding RNAs and Their Potential Therapeutic Applications in Tissue Engineering

“…Although little is known about the role of miRNAs in regulating cholangiocyte proliferation and function [215], several studies implicated specific miRNAs in the pathogenesis of cholangiocarcinoma. For example, the overexpression of miR-31 in cholangiocarcinoma cells altered RAS/MAPK signaling [216], and miR-138 can regulate cholangiocarcinoma proliferation, cell-cycle control, and migration, possibly by directly targeting RhoC [217]. miR-506 regulates the expression of anion exchanger 2 (AE2), and the suppression of miR-506 leads to improved AE2 function in primary biliary cirrhosis cholangiocytes [82].…”