MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis

Abstract

MiR-145 can regulate cell apoptosis, proliferation, neural development and stem cell differentiation. Previous studies indicate that miR-145 is downregulated in human colon cancer cells. However, the molecular mechanisms of miR-145 used to regulate colon carcinogenesis and angiogenesis remain to be clarified. Here, we show that the expression of miR-145 is downregulated in colon and ovarian cancer tissues and cell lines. MiR-145 inhibits p70S6K1 post-transcriptional expression by binding to its 3′-UTR. The angiogenic factors hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF), which are downstream molecules of p70S6K1, are decreased by miR-145 overexpression. P70S6K1 rescues miR-145-suppressed HIF-1 and VEGF levels, tumorigenesis and tumor angiogenesis. Furthermore, the miR-145 level is inversely correlated with the amount of p70S6K1 protein in colon cancer tissues. Taken together, these studies suggest that miR-145 serves as a tumor suppressor which downregulates HIF-1 and VEGF expression by targeting p70S6K1, leading to the inhibition of tumor growth and angiogenesis. The miR-145 rescue could be a rationale for therapeutic applications in colon cancer in the future.

miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3

“…The expression of miR-145 was shown to reduce the expression of differentiation markers, decrease cell proliferation, and induce cell cycle arrest and apoptosis consistent with data from other cancers (Xu et al 2012, Zhang et al 2013. miR-145 also regulated the expression of VEGF in vivo and in vitro.…”

miRNA-145 Targets v-ets Erythroblastosis Virus E26 Oncogene Homolog 1 to Suppress the Invasion, Metastasis, and Angiogenesis of Gastric Cancer Cells

“…In 2003, Michael and colleagues reported the consistently reduced miR-145 levels at the adenomatous and cancer stages of colorectal neoplasm, suggesting its potential role in the tumorigenesis of colon (13). Since then, aberrant miR-145 expression has been documented in diverse cancer specimens and cell lines (14)(15)(16). In this study, we noted the downregulation of miR-145 in gastric cancer tissues compared with normal gastric mucosa, which was consistent with previous findings (17).…”

“…Recently, downregulated miR-145 expression has been identified in diverse tumor types, such as colon cancer (14), prostate cancer (15), and breast cancer (16). Ectopic expression of miR-145 leads to significant growth inhibition in several kinds of cancer, including colon cancer (14) and breast cancer (16).…”

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

“…Sun et al (21) suggested that wogonoside induces autophagy through regulating the mitogen-activated protein kinase-mTOR signaling pathway in MDA-MB-231 cells. P70S6K, the kinase of 40S ribosomal small subunit protein S6 and one of the downstream targets in the PI3K/Akt/mTOR signaling pathway, directly phosphorylates 40S ribosomal protein S6 to promote the translation of mRNA essential in the Gl-S stage of the cell cycle, as well as the expression of proteins associated with cell growth and differentiation, thus serving an important role in the regulation of cell growth and proliferation (29,30). The mTOR/P70S6K signaling pathway serves an essential role in cell growth, differentiation, proliferation, migration and survival (29).…”