title: Stabilization of Snail by HIF-1α and TNF-α is required for hypoxia-induced invasion in prostate cancer PC3 cells.
abstract: Hypoxia has been involved in the development of tumor by regulating the expression of invasiveness-associated genes. However, the specific function of hypoxia in cancer cell invasion is still unclear. The aim of the present study was to determine the role of hypoxia in invasion of prostate cancer PC3 cells and to investigate the underlying mechanisms. We found that hypoxia significantly increased the invasive activity of PC3 cells, via up-regulation of the expression of hypoxia inducible factor 1α (HIF-1α) and the autocrine production of tumor necrosis factor α (TNF-α). More important, TNF-α cooperated with HIF-1α in promoting stabilization of Snail, a transcriptional repressor of E-cadherin expression, which lead to the up-regulation of invasiveness-associated genes MMP-9, fibronectin and vimentin. Snail silencing by specific siRNA significantly inhibited hypoxia-induced invasion of PC3 cells, indicating an essential role of Snail in conferring the malignant phenotype to cancer cells under hypoxic conditions. In conclusion, our data demonstrate that hypoxia promoted the invasiveness of prostate cancer PC3 cells via HIF-1α- and TNF-α-induced stabilization of Snail, suggesting a signaling mechanism involving HIF-1α/TNF-α/Snail that mediates invasiveness hypoxic tumor cells in the absence of neoangiogenesis.
authors.affiliation: Department of Urology, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lv
authors.forename: Jingdong
authors.initials: J
authors.lastname: Yuan
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Chuanhua
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhineng
authors.initials: Z
authors.lastname: Zhu
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Guosong
authors.initials: G
authors.lastname: Jiang
authors.forename: Fuqing
authors.initials: F
authors.lastname: Zeng
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002465:Cell Movement; D002470:Cell Survival; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D005353:Fibronectins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; D020780:Matrix Metalloproteinase 9