Purpose To investigate the involvement of hsa-microRNA-195-5p (miR-195) in progression and prognosis of human prostate cancer (PCa). Experimental Design qRT-PCR was performed to detect miR-195 expression in both PCa 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, 70kDa, polypeptide 1 (RPS6KB1) in PCa progression were confirmed based on both in vitro and in vivo systems. Results MiR-195 downregulation in PCa 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 PCa patients (P=0.022). Then, 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. Additionally, 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 re-expression 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 PCa 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. Conclusion The newly identified miR-195-RPS6KB1 axis partially illustrates the molecular mechanism of PCa progression and represents a novel potential therapeutic target for PCa treatment.
As a member of helix-loop-helix protein family, transcription factor 12 functions as either an oncogene or a tumor suppressor in various human cancers. However, there are no reports on its involvement in prostate cancer. To investigate clinical relevance of transcription factor 12 in prostate cancer and to evaluate its roles in malignant phenotypes of this cancer in vitro and in vivo, we here examined expression patterns of transcription factor 12 protein in 50 prostate cancer tissue specimens by immunohistochemistry. Then, associations of transcription factor 12 expression with various clinicopathological characteristics and patients' prognosis of prostate cancer were evaluated. Its involvements in cancer cell proliferation, migration, invasion, and tumor growth were determined by in vitro and in vivo experiments. As a result, the positive immunostaining of transcription factor 12 protein was localized in cytoplasm and/or nucleus of prostate cancer cells. Its expression levels were decreased with prostate cancer Gleason score increased. Statistically, the decreased expression of transcription factor 12 protein more frequently occurred in prostate cancer patients with high Gleason score, positive metastasis, prostate-specific antigen failure, and short biochemical recurrence-free survival (all p < 0.05). Importantly, multivariate analysis showed that the status of transcription factor 12 expression was an independent predictor of biochemical recurrence-free survival in prostate cancer. Functionally, enforced expression of transcription factor 12 suppressed cell proliferation, migration, and invasion in vitro and inhibited tumor growth in vivo. In conclusion, transcription factor 12 protein may be a novel molecule which plays a critical role in prostate cancer progression and patients' prognosis, suggesting it might be a promising therapeutic target for prostate cancer therapy.
Tumor-adjacent normal (TAN) tissues, which constitute tumor microenvironment and are different from healthy tissues, provide critical information at molecular levels that can be used to differentiate aggressive tumors from indolent tumors. In this study, we analyzed 52 TAN samples from the Cancer Genome Atlas (TCGA) prostate cancer patients and developed a 10-gene prognostic model that can accurately predict biochemical recurrence-free survival based on the profiles of these genes in TAN tissues. The predictive ability was validated using TAN samples from an independent cohort. These 10 prognostic genes in tumor microenvironment are different from the prognostic genes detected in tumor tissues, indicating distinct progression-related mechanisms in two tissue types. Bioinformatics analysis showed that the prognostic genes in tumor microenvironment were significantly enriched by p53 signaling pathway, which may represent the crosstalk tunnels between tumor and its microenvironment and pathways involving cell-to-cell contact and paracrine/endocrine signaling. The insight acquired by this study has advanced our knowledge of the potential role of tumor microenvironment in prostate cancer progression.
Background: As the seventh most common urologic carcinoma worldwide, approximately 430,000 patients are diagnosed with bladder cancer (BC) every year. Increasing evidence indicates that long noncoding RNAs (lncRNAs) play crucial roles in the progression of BC. Objectives: This study is aimed to explore the function and mechanism of CASC9 in BC. Methods: Bioinformatics analysis and experiments including RT-qPCR, luciferase reporter, Cell Counting Kit-8 assay, Western blot, RNA immunoprecipitation assay, and TU-NEL staining were applied to explore the function and mechanism of CASC9 in BC tissues and cell lines. Results: Our study demonstrated that CASC9 was upregulated in BC tissues and cell lines. Moreover, we found that CASC9 knockdown notably decreased proliferation while increased apoptotic rate in BC cells. Mechanistically, bioinformatics prediction and following experiments indicated that CASC9 worked as a competing endogenous RNA (ceRNA) of CBX2 through sponging miR-497-5p. Meanwhile, we recognized that CASC9 and miR-497-5p negatively regulated each other in a mutual way. Furthermore, we found that miR-497-5p shared binding site with CBX2. In addition, miR-497-5p could negatively regulated CBX2, while CASC9 could positively regulated CBX2. Rescue assays reveled that CBX2 overexpression could reversed the reduction of cell proliferation or the enhancement of cell apoptosis induced by CASC9 suppression. Conclusions: Our study manifests the first evidence that CASC9 serves as an oncogene in BC and accelerates cell proliferation by modulating miR-497-5p/CBX2 axis. The present study may provide a cogitable target for BC therapy.
Voltage-gated chloride ion channels (CLCs) are transmembrane proteins that maintain chloride ion homeostasis in various cells. Accumulating studies indicated CLCs were related to cell growth, proliferation, and cell cycle. Nevertheless, the role of CLCs in prostate cancer (PCa) has not been systematically profiled. The purpose of this study was to investigate the expression profiles and biofunctions of CLCs genes, and construct a novel risk signature to predict biochemical recurrence (BCR) of PCa patients. We identified five differentially expressed CLCs genes in our cohort and then constructed a signature composed of CLCN2 and CLCN6 through Lasso-Cox regression analysis in the training cohort from the Cancer Genome Atlas (TCGA). The testing and entire cohorts from TCGA and the GSE21034 from the Gene Expression Omnibus (GEO) were used as internal and independent external validation datasets. This signature could divide PCa patients into the high and low risk groups with different prognoses, was apparently correlated with clinical features, and was an independent excellent prognostic indicator. Enrichment analysis indicated our signature was primarily concentrated in cellular process and metabolic process. The expression patterns of CLCN2 and CLCN6 were detected in our own cohort based immunohistochemistry staining, and we found CLCN2 and CLCN6 were highly expressed in PCa tissues compared with benign tissues and positively associated with higher Gleason score and shorter BCR-free time. Functional experiments revealed that CLCN2 and CLCN6 downregulation inhibited cell proliferation, colony formation, invasion, and migration, but prolonged cell cycle and promoted apoptosis. Furthermore, Seahorse assay showed that silencing CLCN2 or CLCN6 exerted potential inhibitory effects on energy metabolism in PCa. Collectively, our signature could provide a novel and robust strategy for the prognostic evaluation and improve treatment decision making for PCa patients.
<p>Supplementary Figure and Table Legends. List of supporting information</p>
<p>Supplementary Tab S1-S9. Supplementary Tab. S1. Follow-up clinicopathological information of patients from MGH cohort; Supplementary Tab. S2. ligonucleotide Sequence for all the primers used in the study; Supplementary Tab.S3. The antibodies used in this study; Supplementary Tab.S4. Associations of miR-195 and RPS6KB1 protein expression with clinicopathological features of prostate cancer (PCa) patients; Supplementary Tab.S5. Prognostic value of miR-195 expression for the biochemical recurrence-free survival in univariate and multivariate analysis by Cox Regression; Supplementary Tab. S6 Differentially expressed proteins detected by iTRAQ; Supplementary Tab. S7 Canonical pathways analysis by IPA; Supplementary Tab. S8 Diseases and bio functions analysis by IPA; Supplementary Tab.S9. Prognostic value of RPS6KB1 expression for the biochemical recurrence-free survival in univariate and multivariate analysis by Cox Regression.</p>
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