Abstract
MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally repress expression of target genes via imperfect base-pairing with the 3′-untranslated region (3′-UTR). The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays important roles in physiology and pathology. Constitutive over-expression of HIF-1α is observed in many types of cancers including prostate carcinoma, but the mechanisms underlying this event remain largely unknown. Here we investigated the expression of miR199b and HIF-1α in normal prostate tissue, prostate cancer tissues and prostate carcinoma (PCa) cell lines LNCaP, PC-3 and DU145.We found that miR-199b expression level was decreased in prostate cancer while HIF-1α was significantly over-expressed. Furthermore, we postulated the posttranscriptional regulation of HIF-1α by miR199b through bioinformatics analysis, and herein we experimentally demonstrated that miR199b negatively regulated HIF-1α by targeting its 3′-untranslated region. Artificial over-expression of miR199b by using adenoviral vectors in prostate cancer PC-3 and DU145 cells significantly down-regulated HIF-1α, together with reduced cell growth and increased cell death.
Highlights
Prostate cancer is the most commonly diagnosed cancer in men in the United States and in the majority of European countries [1,2]
Over-expression of hypoxia-inducible factor-1α (HIF-1α) is implicated in the pathogenesis of many cancers including prostate carcinoma [4,5,9], in which it is associated with advanced clinical stage and chemo-resistance [10]
We examined the downstream target genes including Bcl-xl, VEGF and proly hydroxylases (PHD)-2, which are regulated by HIF-1α
Summary
Prostate cancer is the most commonly diagnosed cancer in men in the United States and in the majority of European countries [1,2] It progresses from a localized, androgen-dependent disease to an advanced, invasive and metastatic stage with the loss of androgen-dependent [3]. Once the androgen-independent phase develops, prostate cancer is always fatal. For this reason, unconventional strategies targeting novel molecular mechanisms are eagerly required. Over-expression of HIF-1α could be hypoxia-dependent, human prostate cancer cells can express functional HIF-1α protein excessively under normoxic conditions, the mechanisms of which remain largely unknown [12]. Artificial over-expression of miR199b in prostate cancer cells may significantly impair the HIF-1α expression under normoxic and hypoxia-mimicking conditions, together with reduced cell growth and increased cell apoptosis. Our findings will help to further understand the functions of miRNAs in cancer and suggest that miR-199b may be employed as therapeutic for prostate cancer
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