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

TLDR

MiR‑145 regulates cell apoptosis, proliferation, neural development, and stem cell differentiation. The study aims to clarify how miR‑145 modulates colon carcinogenesis and angiogenesis. MiR‑145 suppresses p70S6K1 expression post‑transcriptionally by binding to its 3′‑UTR. In colon and ovarian cancers, miR‑145 is downregulated; its overexpression reduces HIF‑1 and VEGF by targeting p70S6K1, while p70S6K1 overexpression rescues these effects and promotes tumorigenesis and angiogenesis, establishing miR‑145 as a tumor suppressor that inhibits growth and angiogenesis and indicating therapeutic potential.

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.