MicroRNA-192 targeting retinoblastoma 1 inhibits cell proliferation and induces cell apoptosis in lung cancer cells

Abstract

microRNAs play an important roles in cell growth, differentiation, proliferation and apoptosis. They can function either as tumor suppressors or oncogenes. We found that the overexpression of miR-192 inhibited cell proliferation in A549, H460 and 95D cells, and inhibited tumorigenesis in a nude mouse model. Both caspase-7 and the PARP protein were activated by the overexpression of miR-192, thus suggesting that miR-192 induces cell apoptosis through the caspase pathway. Further studies showed that retinoblastoma 1 (RB1) is a direct target of miR-192. Over-expression of miR-192 decreased RB1 mRNA and protein levels and repressed RB1-3′-UTR reporter activity. Knockdown of RB1 using siRNA resulted in a similar cell morphology as that observed for overexpression of miR-192. Additionally, RB1-siRNA treatment inhibited cell proliferation and induced cell apoptosis in lung cancer cells. Analysis of miRNA expression in clinical samples showed that miR-192 is significantly downregulated in lung cancer tissues compared to adjacent non-cancerous lung tissues. In conclusion, our results demonstrate that miR-192 is a tumor suppressor that can target the RB1 gene to inhibit cell proliferation and induce cell apoptosis in lung cancer cells. Furthermore, miR-192 was expressed at low levels in lung cancer samples, indicating that it might be a promising therapeutic target for lung cancer treatment.

Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma

“…Song et al (18) also found that miR-192 overexpression suppresses cell proliferation in colon cancer cell lines through induction of p53-dependent cell cycle arrest at both the G1 and G2 phases. In lung cancer cells, miR-192 was found to inhibit cell proliferation through targeting RB1 (19). Our results are highly inconsistent with these previous studies.…”

“…The growth-promoting effects of miR-192 overexpression were also observed in the in vitro colony formation assay and in vivo xenograft tumor model. This inconsistency with previous reports (18,19,23) may reflect the effects on the functional consequences of manipulating miRNA. Similar to miR-192, miR-17-5p is able to act as both an oncogene and a tumor suppressor in different types of cancer cells (24).…”

“…RB1 was found to be a target of miR-192, which mediates an effect on cell apoptosis through the caspase pathway (19). miR-192 inhibits nucleotide excision repair by targeting ERCC3 and ERCC4 in HepG2.2.15 cells (27).…”

MicroRNA deep-sequencing reveals master regulators of follicular and papillary thyroid tumors

“…39 Thus, further studies are required to elucidate the role of this miRNA family in thyroid tumorigenesis. However, the tumor suppressive role of miR-192 has been robustly functionally demonstrated, [40][41][42] and is consistent with our current observation. In this regard, the value of the tumor set 2 was limited for validation, as the time of follow-up was shorter.…”

miRNA Landscape in Stage I Epithelial Ovarian Cancer Defines the Histotype Specificities

“…This positive feedback loop TP53-miR-192/194-MDM2 confers the status of tumor suppressor to the miR-192/194 cluster. Recently, the importance of this circuit has been further strengthened by the identification of new oncogenes among the downregulated target genes of these miRNAs (14,28,29). In our analysis, PSME3 and CUL4A are promising miR-192/194 targets, being among the miR-194 anticorrelated predicted target genes and proteins that physically associate with MDM2 and part of the TP53 degradation pathway.…”