Abstract
To investigate the involvement of hsa-miRNA-195-5p (miR-195) in progression and prognosis of human prostate cancer. qRT-PCR was performed to detect miR-195 expression in both prostate cancer cell lines and clinical tissue samples. Its clinical significance was statistically analyzed. The roles of miR-195 and its candidate target gene, ribosomal protein S6 kinase, 70 kDa, polypeptide 1 (RPS6KB1) in prostate cancer progression were confirmed on the basis of both in vitro and in vivo systems. miR-195 downregulation in prostate cancer tissues was significantly associated with high Gleason score (P = 0.001), positive metastasis failure (P < 0.001), and biochemical recurrence (BCR, P < 0.001). Survival analysis identified miR-195 as an independent prognostic factor for BCR-free survival of prostate cancer patients (P = 0.022). Then, we confirmed the tumor suppressive role of miR-195 through prostate cancer cell invasion, migration, and apoptosis assays in vitro, along with tumor xenograft growth, angiogenesis, and invasion in vivo according to both gain-of-function and loss-of-function experiments. In addition, RPS6KB1 was identified as a novel direct target of miR-195 through proteomic expression profiling combined with bioinformatic target prediction and luciferase reporter assay. Moreover, the reexpression and knockdown of RPS6KB1 could respectively rescue and imitate the effects induced by miR-195. Importantly, RPS6KB1 expression was closely correlated with aggressive progression and poor prognosis in prostate cancer patients as opposed to miR-195. Furthermore, we identified MMP-9, VEGF, BAD, and E-cadherin as the downstream effectors of miR-195-RPS6KB1 axis. The newly identified miR-195-RPS6KB1 axis partially illustrates the molecular mechanism of prostate cancer progression and represents a novel potential therapeutic target for prostate cancer treatment.
Highlights
Clinical behavior of prostate cancer (PCa) ranges from indolent tumors with no or little clinical significance to aggressive metastatic and lethal diseases [1]
We confirmed the tumor suppressive role of miR-195 through PCa cell invasion, migration and apoptosis assays in vitro, along with tumor xenografts growth, angiogenesis and invasion in vivo according to both gain-of-function and loss-of-function experiments
RPS6KB1 expression was closely correlated with aggressive progression and poor prognosis in PCa patients as opposed to miR-195
Summary
Clinical behavior of prostate cancer (PCa) ranges from indolent tumors with no or little clinical significance to aggressive metastatic and lethal diseases [1]. MicroRNAs (miRNAs) represent the best characterized class of small (19–25 nt in length) non-coding RNA transcripts that are endogenously expressed in animal and plant cells [5,6,7] Due to their important roles in the regulation of genes that are involved in many physiological processes, including cell development, proliferation, differentiation, and apoptosis, it is not of a surprise that miRNAs are involved in the initiation and progression of various human diseases such as cancer [8]. Up to now, its roles in PCa are still unclear
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