Co-targeting of IGF1R/mTOR pathway by miR-497 and miR-99a impairs hepatocellular carcinoma development

Abstract

Persistent activation of IGF1R/mTOR signaling pathway plays crucial role in the development of hepatocellular carcinoma (HCC). Therefore, our goal was to elucidate microRNAs (miRNAs) targeting IGF1R/mTOR and the therapeutic potential of single or dual miRNA on HCC development. In this study, we found that miR-497 and miR-99a that target the 3′-UTR of both IGF1R and mTOR were down-regulated in HCC human tissues and cell lines. Functional assay revealed that ectopic expression of miR-497 or miR-99a in HCC cells resulted in a significant inhibition on tumor growth and invasiveness in vitro and tumor development in vivo via repressing the expression of IGF1R and mTOR. Such inhibitory effect on tumor growth is reversed by application of IGF1 ((IGF1R ligand) or MHY1485 (mTOR agonist) in vitro. Furthermore, we found that simultaneous over-expression of both miR-497 and miR-99a exhibited much stronger inhibitory effects on tumor growth than their individual effect, which is still correlated with significantly stronger repression of IGF1R and mTOR. Overall, our results suggest that miR-497 and miR-99a both function as tumor-suppressive miRNAs by suppressing IGF1R/mTOR signaling pathway. The synergistic actions of these two miRNAs partly correlated with IGF1R and mTOR levels, which may represent new strategies for the molecular treatment of HCC.

Role of microRNAs in the main molecular pathways of hepatocellular carcinoma

“…miR-187, miR-497, miR-99a, miR-592: IGF-1R activation, through the PI3K/Akt/mTOR axis, is responsible for cell proliferation, migration and invasion in HCC[ 27 ]. IGF-1R is a target of miR-187, miR-497, miR-99a and miR-592[ 28 - 30 ]. miR-187 was found downregulated in HCC tissues and cell lines: as reported by Han et al[ 29 ], the restoration of miR-187 leads to a significant arrest of HCC growth.…”

“…miR-187 was found downregulated in HCC tissues and cell lines: as reported by Han et al[ 29 ], the restoration of miR-187 leads to a significant arrest of HCC growth. miR-497 and miR-99a target the 3′-UTR of both IGF-1R and mTOR and were shown to be down-regulated in HCC human tissues and cell lines: the co-transfection with both miRNAs slowed cell proliferation and the tumor growth in HCC cell lines and in xenograft models[ 28 ]. Wang and colleagues demonstrated that miR-592 was significantly downregulated in HCC tissues and cell lines and that its low expression was associated with lymph node metastases[ 30 ].…”

Identification and Validation of Circulating Micrornas as Prognostic Biomarkers in Pancreatic Ductal Adenocarcinoma Patients Undergoing Surgical Resection

“…Decreased expression of miR-99a-5p was found to predict worse survival in lung adenocarcinoma [27], cervical cancer [28], and breast cancer [29]. MiR-99a-5p was found to play important tumor-suppressive roles, including inhibition of cell proliferation and tumorigenesis by suppressing mTOR signaling pathway and downregulation of insulin-like growth factor 1 receptor [30], and also inhibition of migration and invasion of cancer cells by decreasing MTMR3 protein (Myotubularin-related protein 3) in oral cancer [31].…”

Effects of miR-99a on the migration and proliferation of glioma cells

“…It has recently been reported that miR-99a may regulate tumor cell proliferation through mTOR, AKT1 and FGFR3 [20][21][22], but detailed studies on the mechanisms of action remain lacking. In this study, MTT assay showed that up-regulating miR-99a inhibited the proliferation of glioma cells, but knocking it down promoted their proliferation.…”