MicroRNA-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer

Abstract

Past studies have shown that amplified insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1-R) signalling has an important role in colorectal cancer (CRC) development, progression and resistance to treatment. In this report, we demonstrate that downregulation of microRNA-497 (miR-497) as a result of DNA copy number reduction is involved in upregulation of IGF1-R in CRC cells. MiR-497 and miR-195 of the miR-15/16/195/424/497 family that share the same 3′ untranslated region (3′UTR) binding seed sequence and are predicted to target IGF1-R were concurrently downregulated in the majority of CRC tissues relative to paired adjacent normal mucosa. However, only overexpression of miR-497 led to suppression of the IGF1-R 3′UTR activity and downregulation of the endogenous IGF1-R protein in CRC cells. This was associated with inhibition of cell survival, proliferation and invasion, and increased sensitivity to apoptosis induced by various stimuli including the chemotherapeutic drugs cisplatin and 5-fluorouracil, and the death ligand tumour necrosis factor-related apoptosis-inducing ligand. The biological effect of miR-497 on CRC cells was largely mediated by inhibition of phosphatidylinositol 3-kinase/Akt signalling, as overexpression of an active form of Akt reversed its impact on cell survival and proliferation, recapitulating the effect of overexpression of IGF1-R. Downregulation of miR-497 and miR-195 appeared to associate with copy number loss of a segment of chromosome 17p13.1, where these miRs are located at proximity. Similarly to miR-195, the members of the same miR family, miR-424 that was upregulated, and miR-15a, miR-15b and miR-16 that were unaltered in expression in CRC tissues compared with paired adjacent normal mucosa, did not appear to have a role in regulating the expression of IGF1-R. Taken together, these results identify downregulation of miR-497 as an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.

MicroRNA-497 regulates cell proliferation in hepatocellular carcinoma

“…The current study focused on miRNA-497, which was previously demonstrated to exhibit decreased expression in numerous tumor types, and which may function as a tumor suppressor (12)(13)(14)(15)(16)(17)(18)(19)(20). The results confirmed that the expression levels of miRNA-497 are decreased in HCC tumor tissues or HCC-derived cell lines compared with adjacent non-cancerous tissues or normal human L02 hepatocytes.…”

“…IGF-1R mRNA and protein expression are increased in HCC and are closely associated with the progression of malignant tumors (34,35). To date, studies have demonstrated that miR-497 targets IGF-1R and has a tumor suppressive role in human cervical cancer (20) and in colorectal cancer (12). However, whether miR-497 functions as a tumor suppressor by directly targeting IGF-1R in HCC remains unclear.…”

“…Many of these miRNAs act as tumor suppressors and/or oncogenes, and are involved in cell activities that include development, differentiation, proliferation, apoptosis, metabolism and immunity (7,10,11). Recently, an increasing number of studies have revealed that microRNA-497 (miR-497) levels are decreased in tumors, and that it functions as a tumor suppressor in a number of types of human cancer, including colorectal, gastric, cervical and breast cancers, adrenocortical carcinoma and melanoma (12)(13)(14)(15)(16)(17)(18)(19)(20). Similarly, a study by Furuta et al (21) indicated that miR-497 targets multiple cell cycle regulators and suppresses cell cycle progression in vitro.…”

Coactivator-associated arginine methyltransferase 1 promotes cell growth and is targeted by microRNA-195-5p in human colorectal cancer

“…24 Moreover, the sequence of mature miR-195-5p is conserved across mammalian species. 25 Previous studies have shown aberrant miR-195-5p expression in multiple cancers, including breast cancer, 26 hepatocellular carcinoma, 27 colorectal cancer, 28,29 gastric cancer, 30 and non-small cell lung cancer (NSCLC). 31 However, the biological function of miR-195-5p in colorectal cancer, to our knowledge, remains unclear.…”

MicroRNAs that Potentially Regulate SOS1 Expression in Colon Cancer

“…Notably, eight miRNAs (miR-124, -195, -28-3p, -30a, -378, -378c, -422a, -497) were predicted to target the 3'UTR region on SOS1 mRNA using the Targetscan software. The downregulations of these miRNAs have been previously reported in various independent colon cancer researches [24]- [29].…”