MiR-30e inhibits tumor growth and chemoresistance via targeting IRS1 in Breast Cancer

Abstract

MicroRNA-30e (miR-30e) is downregulated in various tumor types. However, its mechanism in inhibiting tumor growth of breast cancer remains to be elucidated. In this study, we found that miR-30e was significantly downregulated in tumor tissues of breast cancer (BC) patients and cell lines, and overexpression of miR-30e inhibited cell proliferation, migration and invasion. To understand the potential mechanism of miR-30e in inhibiting tumor growth, we showed that miR-30e blocked the activation of AKT and ERK1/2 pathways, and the expression of HIF-1α and VEGF via directly targeting IRS1. Moreover, miR-30e regulates cell proliferation, migration, invasion and increases chemosensitivity of MDA-MB-231 cells to paclitaxel by inhibiting its target IRS1. MiR-30e also inhibited tumor growth and suppressed expression of IRS1, AKT, ERK1/2 and HIF-1α in mouse xenograft tumors. To test the clinical relevance of these results, we used 40 pairs of BC tissues and adjacent normal tissues, analyzed the levels of miR-30e and IRS1 expression in these tissues, and found that miR-30e levels were significantly inversely correlated with IRS1 levels in these BC tissues, suggesting the important implication of our findings in translational application for BC diagnostics and treatment in the future.

The interplay between HIF-1α and noncoding RNAs in cancer

“…Wang et al suggested that lncRNA CPS1-IT1 could serve as an Hsp90 cochaperone, and this interaction in turn reduces the binding affinity between Hsp90 and HIF-1α, leading to transcriptional inactivation of HIF-1α and diminished EMT of hepatocellular carcinoma cells [135]. In addition, the lncRNA-mediated regulation of the mTOR/HIF-1α/P-gp signaling pathway marked by increased HIF-1a mRNA [146] miR-23b glioma promotes proliferation and migration, inhibits apoptosis post-translational activation via VHL [147] miR-145 colorectal cancer inhibits proliferation, migration and invasion post-translational inhibition via Akt/ERK axis [148] miR-30e breast cancer inhibits proliferation, migration and invasion post-translational inhibition via IIRS1/Akt/ERK axis [149] miR-26a hepatocellular cancer inhibits angiogenesis post-translational inhibition via PIK3C2α/Akt axis [150] miR-99a breast cancer inhibits migration, invasion, sphere formation post-translational inhibition via mTOR signals [151] lncRNA ENST00000480739…”

MiR-30a-5p promotes cholangiocarcinoma cell proliferation through targeting SOCS3

“…The miR-30 family, which contains five members of distinct pre-mature miRNAs (miR-30a, -30b, -30c, -30d, -30e), has been proved to play diverse roles in regulating essential aspects of tumorigenesis, metastasis, chemo-resistance and clinical prognosis in several types of human cancers [11,12]. A large number of reports have demonstrated that miR-30a-5p, as a member of the mir-30 family, was down-regulated and associated with tumorigenesis and progression of prostate cancer, hepatocellular carcinoma, breast tumor and some other cancers [13][14][15].…”

MiR-126 enhances cisplatin chemosensitivity in hepatocellular carcinoma cells by targeting IRS1

“…To mechanistically determine the role of miR-126 in HCC development and progression, we predicted the target genes of miR-126 using the bioinformatics algorithm TargetScan website. MiR-126 has a putative binding site from 106~112 bp within the 3′-UTR region of IRS1 gene (Figure 2 a), whose product (IRS1 protein) was reported to promote tumor growth and chemoresistance [13][14][15]. To verify this speculation, we transfected miR-126 mimics into two HCC cell lines HCCLM3 and MHCC-97H, and found that both mRNA and protein levels of IRS1 were significantly inhibited upon miR-126 overexpression (Figure 2 b and c).…”