title: MicroRNA-382 induced by HIF-1α is an angiogenic miR targeting the tumor suppressor phosphatase and tensin homolog.
abstract: Recent studies have revealed that microRNAs (miRs) play important roles in the regulation of angiogenesis. In this study, we have characterized miR-382 upregulation by hypoxia and the functional relevance of miR-382 in tumor angiogenesis. miRs induced by hypoxia in MKN1 human gastric cancer cells were investigated using miRNA microarrays. We selected miR-382 and found that the expression of miR-382 was regulated by HIF-1α. Conditioned media (CM) from MKN1 cells transfected with a miR-382 inhibitor (antagomiR-382) under hypoxic conditions significantly decreased vascular endothelial cell (EC) proliferation, migration and tube formation. Algorithmic programs (Target Scan, miRanda and cbio) predicted that phosphatase and tensin homolog (PTEN) is a target gene of miR-382. Deletion of miR382-binding sequences in the PTEN mRNA 3'-untranslated region (UTR) diminished the luciferase reporter activity. Subsequent study showed that the overexpression of miR-382 or antagomiR-382 down- or upregulated PTEN and its downstream target AKT/mTOR signaling pathway, indicating that PTEN is a functional target gene of miR-382. In addition, PTEN inhibited miR-382-induced in vitro and in vivo angiogenesis as well as VEGF secretion, and the inhibition of miR-382 expression reduced xenograft tumor growth and microvessel density in tumors. Taken together, these results suggest that miR-382 induced by hypoxia promotes angiogenesis and acts as an angiogenic oncogene by repressing PTEN.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea School of Life Sciences and Biotechnology, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea.
authors.forename: Jin-Kyung
authors.initials: JK
authors.lastname: Seok
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea School of Life Sciences and Biotechnology, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea.
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea School of Life Sciences and Biotechnology, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea lym@knu.ac.kr.
authors.forename: You-Mie
authors.initials: YM
authors.lastname: Lee
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013274:Stomach Neoplasms / Q000098:blood supply / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C555413:MIRN382 microRNA, human; D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase