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.

Hypoxia-Induced Signaling Promotes Prostate Cancer Progression: Exosomes Role as Messenger of Hypoxic Response in Tumor Microenvironment

“…45 Hypoxia also increased the invasiveness of PCA cells through HIF-1α- and TNFα-mediated stabilization of EMT promoter Snail. 46 We have also observed an increase in HIF-1α expression in hypoxic PCA cells associated with activation of several lipogenesis-related molecules and lipid accumulation. 23 Huss et al have reported that angiogenic switch in TRAMP (transgenic adenocarcinoma mouse prostate transgenic model) mice is driven in part by HIF-1α early in PCA progression.…”

The Effect and Mechanism of Celecoxib in Hypoxia-Induced Survivin Up-Regulation in HUVECs

“…In some experiments, 5 μM PGE 2 was added to hypoxic-treated HUVECs for 24 hrs in the presence of 65 μM of celecoxib. To study the effect of HIF-1α on survivin expression, HUVECs were pre-incubated Immunocytochemistry method 1 × 10 4 HUVECs with or without hypoxic treatment were seeded on coverslips placed in wells of six-well plates. The experimental protocol followed the instruction of the strep avidin-biotin complex method (Beijing Zhongshan Golden Bridge Biotechnology, Beijing, China).…”

“…Under hypoxic conditions, it has been found that HIF-1α over-expression stimulates the transcription of its downstream target genes involved in neovascularization, promoting glucose metabolism and cell proliferation. The inhibition of HIF-1α activity distinctly slows tumor growth and activates radiochemotherapic sensitivity in tumor cells [3,4].…”

Association of interleukin-6 (-174 G/C) polymorphism with the prostate cancer risk: A meta-analysis

“…The study by Woo et al (19) observed that tumor infiltrating B-cells were increased in prostate cancer tissue. The Lv et al (20) study suggested that hypoxia promoted the invasiveness of prostate cancer PC3 cells via hypoxia-inducible factor-1α-and tumor necrosis factor-α-induced stabilization of Snail. McDonald et al (21) investigated the associations between systemic inflammatory markers and serum prostate-specific antigen (PSA) in 3,164 healthy males and found that elevated serum PSA (194 males, 6.1% of the total) was significantly associated with plasma fibrinogen, suggesting that the markers of systemic inflammation were associated with elevated PSA in males without a known prostate disease.…”