MicroRNA‐486‐5p, which is downregulated in hepatocellular carcinoma, suppresses tumor growth by targeting PIK3R1

Abstract

Deregulated microRNAs and their roles in carcinogenesis and cancer progression have attracted much attention. In previous studies conducted in our laboratory, the Illumina Solexa massively parallel signature sequencing of miRNomes in nontumor and hepatocellular carcinoma (HCC) tissues revealed that miR-486-5p was significantly downregulated in HCC, but its role in HCC development remains unknown. In this study, miR-486-5p levels in HCC tissues and matched control tissues, and in seven HCC cell lines (QGY-7701, QGY-7703, QGY-7404, SMMC-7721, Huh7, HepG2, and PCL/PRF/5) and human normal liver cells (HL-7702), were tested by real-time quantitative RT-PCR. We found that the level of miR-486-5p was significantly decreased in HCC tissue and in all seven HCC cell lines. Overexpression of miR-486-5p markedly suppressed HCC cell proliferation, migration and invasion in vitro, and inhibited HCC growth in vivo. Mechanistically, miR-486-5p was confirmed to directly target PIK3R1 expression, thereby suppressing phosphatidylinositol 3-kinase-AKT pathway activation, by dual luciferase reporter assay and real-time quantitative RT-PCR and western blot analysis. In addition, PIK3R1 knockdown mimicked the effects of miR-486-5p overexpression by inhibiting HCC growth, migration, and invasion. Furthermore, correlation analysis, Kaplan-Meier estimates and Cox proportional hazard models showed an inverse correlation between miR-486-5p and PIK3R1, as well as a shorter time to recurrence after HCC resection, in patients with lower miR-486-5p expression. Hence, we conclude that miR-486-5p, which is frequently downregulated in HCC, inhibits HCC progression by targeting PIK3R1 and phosphatidylinositol 3-kinase-AKT activation. DatabaseThe Solexa sequencing data are available in GEO database (www.ncbi.nlm.nih.gov/geo/) under accession number GSE21279.Abbreviations DFS, disease-free survival; FACS, fluorescence-activated cell sorting; GSK3b, glycogen synthase kinase-3b; HCC, hepatocellular carcinoma; miRNA, microRNA; MPSS, massively parallel signature sequencing; PI3K, phosphatidylinositol 3-kinase; qRT-PCR, quantitative RT-PCR; SD, standard deviation.

miR-486-5p regulates the migration and invasion of colorectal cancer cells through targeting PIK3R1

“…It was previously demonstrated that the overexpression of miR-486-5p may inhibit cell proliferation, migration and invasion, and decrease tumor growth via targeting PIK3R1 and AKT in hepatocellular carcinoma (25). The results of the present study indicated that the overexpression of miR-486-5p, as simulated using the transfection of miR-486-5p mimics, inhibited cell migration and invasion.…”

“…microRNAs (miRNAs/miRs) are small, non-coding RNAs of [19][20][21][22][23][24][25] nucleotides that may negatively regulate gene expression at a transcriptional or post-transcriptional level (5). Additionally, the expression profiles of miRNAs may be more accurate in classifying subtypes of tumors compared with mRNA expression profiles (6).…”

MicroRNA-486-5p enhances hepatocellular carcinoma tumor suppression through repression of IGF-1R and its downstream mTOR, STAT3 and c-Myc

“…2). This corroborates a recent study performed on Chinese patients in which miR-486-5p was also downregulated in HBV-induced HCC tissues (33).…”

“…3-5). These results are in line with those of a recent study performed on QGY-7701 and QGY-7703 HCC cell lines, which reported that miR-486-5p also repressed the migration and induced apoptosis of those types of cells (33).…”

“…This could be a direct or indirect effect of miR-486-5p on the downstream mediators, as bioinformatically, miR-486-5p was predicted to target the 3'-UTR of STAT3. By contrast, miR-486-5p was recently found to target an upstream regulator of PI3K/AKT/mTOR known as p85α, thus inhibiting the activation of the PI3K/AKT/mTOR pathway and its interlocked RAS/RAF/MAPK signaling cascade, and indirectly acting as a repressor for mTOR and c-Myc transcription (33,38). It is important to note that due to the limited efficacy of IGF-1R inhibitors as a single therapy in HCC and the compensatory activation of downstream signaling pathways resulting in drug resistance (9-13), a combination of agents targeting multiple molecules in IGF-axis, known as vertical blockade, were previously evaluated in several preclinical studies, and synergistic anti-cancer efficacy was demonstrated (39,40).…”