Dataset Information

MiR-4638-5p inhibits castration resistance of prostate cancer through repressing Kidins220 expression and PI3K/AKT pathway activity.

ABSTRACT: MicroRNAs (miRNAs) are short, conserved segments of non-coding RNA which play a significant role in prostate cancer development and progression. To identify miRNAs associated with castration resistance, we performed miRNA microarray analysis comparing castration resistant prostate cancer (CRPC) with androgen dependent prostate cancer (ADPC). We identified common underexpression of miR-4638-5p in CRPC compared to ADPC samples, which were further confirmed by quantitative PCR analysis. The role of miR-4638-5p in prostate cancer androgen-independent growth has been demonstrated both in vitro and in vivo. We also identified Kidins220 as a target gene directly regulated by miR-4638-5p and shRNA-mediated knockdown of Kidins220 phenocopied miR-4638-5p restoration. Subsequently, we revealed that Kidins220 activates PI3K/AKT pathway, which plays a key role in CRPC. Loss of miR- 4638-5p may lead to CRPC through the activity of Kidins220 and PI3K/AKT pathway. Furthermore, we found that miR-4638-5p, through regulating Kidins220 and the downstream activity of VEGF and PI3K/AKT pathway, influences prostate cancer progression via angiogenesis. The identification of miR-4638-5p down-regulation in CRPC and the understanding of the functional role of miR-4638-5p and its downstream genes/pathways have the potential to develop biomarkers for CRPC onset and to identify novel targets for novel forms of treatments of this lethal form of PCa.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5216953 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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MiR-4638-5p inhibits castration resistance of prostate cancer through repressing Kidins220 expression and PI3K/AKT pathway activity.

Wang Yang Y Shao Ning N Mao Xueying X Zhu Minmin M Fan Weifei W Shen Zhixiang Z Xiao Rong R Wang Chuncai C Bao Wenping W Xu Xinyu X Yang Chun C Dong Jian J Yu Deshui D Wu Yan Y Zhu Caixia C Wen Liting L Lu Xiaojie X Lu Yong-Jie YJ Feng Ninghan N

Oncotarget 20160701 30

MicroRNAs (miRNAs) are short, conserved segments of non-coding RNA which play a significant role in prostate cancer development and progression. To identify miRNAs associated with castration resistance, we performed miRNA microarray analysis comparing castration resistant prostate cancer (CRPC) with androgen dependent prostate cancer (ADPC). We identified common underexpression of miR-4638-5p in CRPC compared to ADPC samples, which were further confirmed by quantitative PCR analysis. The role of ...[more]

PMID: 27329728

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Project description:Biochemical recurrence (BCR) is a cause of concern in advanced prostate cancer (PCa). Thus, novel diagnostic biomarkers are required to improve clinical care. However, research on PCa immunotherapy is also scarce. Hence, the present study aimed to explore promising BCR-related diagnostic biomarkers, and their expression pattern, prognostic value, immune response effects, biological functions, and possible molecular mechanisms were evaluated. GEO datasets (GSE46602, GSE70768, and GSE116918) were downloaded and merged as the training cohort, and differential expression analysis was performed. Lasso regression and SVM-RFE algorithm, as well as PPI analysis and MCODE algorithm, were then applied to filter BCR-related biomarker genes. The CIBERSORT and estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) methods were used to calculate the fractions of tumor-infiltrating immune cells. GO/DO enrichment analyses were used to identify the biological functions. The expression of latent transforming growth factor β-binding protein 2 (LTBP2) was determined by RT-qPCR and western blotting. The role of LTBP2 in PCa was determined by CCK-8, Transwell, and the potential mechanism was investigated by KEGG and GSEA and confirmed by western blotting. In total, 44 BCR-related differentially expressed genes (DEGs) in the training cohort were screened. LTBP2 was found to be a diagnostic biomarker of BCR in PCa and was associated with CD4+ T-cell infiltration and response to anti-PD-1/PD-L1 immunotherapy. Subsequently, using the ESTIMATE algorithm, it was identified that LTBP2 was associated with the tumor microenvironment and could be a predictor of the clinical benefit of immune checkpoint blockade. Finally, the expression and biological function of LTBP2 were evaluated via cellular experiments. The results showed that LTBP2 was downregulated in PCa cells and inhibited PCa proliferation and metastasis via the PI3K/AKT signaling pathway in vitro. In conclusion, LTBP2 was a promising diagnostic biomarker of BCR of PCa and had an important role in CD4+ T-cell recruitment. Moreover, it was associated with immunotherapy in patients with PCa who developed BCR, and it inhibited PCa proliferation and metastasis via the PI3K/AKT signaling pathway in vitro.

Dataset Information

MiR-4638-5p inhibits castration resistance of prostate cancer through repressing Kidins220 expression and PI3K/AKT pathway activity.

Publications

MiR-4638-5p inhibits castration resistance of prostate cancer through repressing Kidins220 expression and PI3K/AKT pathway activity.

Similar Datasets

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