P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis

Abstract

The pathway involving the tumor suppressor gene TP53 can regulate tumor angiogenesis by unclear mechanisms. Here we show that p53 regulates hypoxic signaling through the transcriptional regulation of microRNA-107 (miR-107). We found that miR-107 is a microRNA expressed by human colon cancer specimens and regulated by p53. miR-107 decreases hypoxia signaling by suppressing expression of hypoxia inducible factor-1β (HIF-1β). Knockdown of endogenous miR-107 enhances HIF-1β expression and hypoxic signaling in human colon cancer cells. Conversely, overexpression of miR-107 inhibits HIF-1β expression and hypoxic signaling. Furthermore, overexpression of miR-107 in tumor cells suppresses tumor angiogenesis, tumor growth, and tumor VEGF expression in mice. Finally, in human colon cancer specimens, expression of miR-107 is inversely associated with expression of HIF-1β. Taken together these data suggest that miR-107 can mediate p53 regulation of hypoxic signaling and tumor angiogenesis.

Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24

“…During the process of preparing this report, an independent study reported that human ARNT in a colon carcinoma cell line HCT116 was down-regulated by miR-107 (Yamakuchi et al, 2010). It was reported that the miR-107-mediated regulation of ARNT affected the colon cancer tumor growth through the regulation of vascular endothelial growth factor, a target gene of HIF.…”

MicroRNA-149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma

“…p53 has previously been shown to transcriptionally regulate a number of miRNAs such as miR-34a, miR-34b, miR-34c, and miR-107, and can also modulate miRNA biogenesis independently of transcription (18)(19)(20)(21)(22)(23). These have been proposed to contribute to its tumor suppressing function in some cancers (35)(36)(37).…”

“…Although a number of miRNAs have been shown to be important components of the p53 tumor suppressor network in various cell types (18)(19)(20)(21)(22)(23), the potential interaction between miRNAs and p53 in melanoma cells, in which the expression of p53 may result in distinct biological consequences, have not be established. We report here that p53 mediates a prosurvival pathway by upregulation of miRNA-149* (miR-149*) that in turn targets glycogen synthase kinase-3α (GSK3α), leading to stabilization of Mcl-1 in melanoma cells under ER stress.…”

The MicroRNA miR-199a-5p Down-regulation Switches on Wound Angiogenesis by Derepressing the v-ets Erythroblastosis Virus E26 Oncogene Homolog 1-Matrix Metalloproteinase-1 Pathway

“…miR-27b, a miR facilitating breast cancer cell invasiveness (35), promotes angiogenesis in endothelial cells by targeting angiostatic protein semaphorin 6A (36). miR-107, a miR down-regulated by hypoxia, attenuates cell migration (37,38) and blocks VEGF-dependent angiogenesis by targeting hypoxia-inducing factor (HIF)-1␤ (39). The current study, together with findings from previous reports, reinforces the concept that miR-199a-5p not only inhibits cell migration (9,13,16) but also exerts potent angiostatic effect on endothelial cells by targeting a discrete subset of gene(s).…”