MicroRNA-182 targets protein phosphatase 1 regulatory inhibitor subunit 1C in glioblastoma

Abstract

Glioblastoma (GBM) is an incurable cancer, with mean post-diagnosis survival time of 14-16 months. Metagenomic analysis by The Cancer Genome Atlas (TCGA) program has identified microRNA-182-5p (miR-182-5p or miR-182) as the only miRNA associated with favorable disease prognosis and temozolomide (TMZ) susceptibility. Previous reports have indicated that miR-182 down regulates expression of BCL2L12, c-MET, and HIF2A. However, other messenger RNA (mRNA) targets of miR-182 have not been validated which would explain its association with a favorable disease prognosis. In situ analysis revealed that protein phosphatase 1 regulatory inhibitor subunit 1C (PPP1R1C) is a putative target of miR-182. PPP1R1C protein and RNA expression as assessed by tissue microarray and quantitative real time PCR, respectively, was inversely correlated to miR-182 expression in glioblastoma patients and in the metastatic glioblastoma cell line U87-MG. Reporter assays using PPP1R1C 3′ untranslated region (UTR) showed that miR-182 can interact with the wild-type but not a miR-182-5-seed mutant. Ectopic expression of miR-182 mimic in the U87-MG cell line significantly decreased proliferation as well as suppressed in vitro migration and invasion. Opposite observations were made when the non-malignant neuronal cell line HCN-2 was transfected with anti-miR-182 antagomir. The miR-182 mimic or siRNA targeting PPP1R1C induced TMZ susceptibility indicating that decreased susceptibility to TMZ in GBM patients might be attributed to high expression of PPP1R1C. Inverse correlation of PPP1R1C mRNA and miR-182 levels in 20 GBM patients confirmed the same. Cumulatively, our results indicate that loss of miR-182 leads to increased expression of PPP1R1C which in part explain disease progression and resistance to TMZ therapy.

Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for hepatocellular carcinoma

“…miR-182 promotes tumorigenesis in a variety of tumors and is one of the most frequently studied cancer-associated miRNAs [36]. In glioblastoma, miR-182-5p targets protein phosphatase 1 regulatory inhibitor subunit 1C [37]. By downregulating RAB27A expression, miR-182-5p improves the migration, mitosis, viability, and invasion capabilities of human gastric cancer cells [37].…”

“…In glioblastoma, miR-182-5p targets protein phosphatase 1 regulatory inhibitor subunit 1C [37]. By downregulating RAB27A expression, miR-182-5p improves the migration, mitosis, viability, and invasion capabilities of human gastric cancer cells [37]. Inhibiting miR-182-5p by regulating CASP9 expression confers pro-apoptotic and anti-proliferative effects in human breast cancer [38].…”

lncRNA PCAT19 promotes the proliferation of laryngocarcinoma cells via modulation of the miR‐182/PDK4 axis

“…miR‐182 was also correlated with cell mitotic arrest in renal cancer cells . In glioblastoma, miR‐182 has been shown to promote tumor invasion, disease progression, and resistance to the temozolomide therapy . The reasons may attribute to the different target genes of miR‐182, which largely relied on the tumor types and gene profiles.…”

miR-182-5p Promotes Growth in Oral Squamous Cell Carcinoma by Inhibiting CAMK2N1

“…Several studies have highlighted the role of miR-182-5p in the development of different cancers [13,14]. In glioblastoma, miR-182-5p targets protein phosphatase 1 regulatory inhibitor subunit 1C [20]. miR-182-5p promotes the progression of hepatocellular carcinoma by repressing FOXO3a expression [21].…”