Abstract
Prostate cancer is a major health problem worldwide. MiR-183 is an oncomiR and a candidate biomarker in prostate cancer, affecting various pathways responsible for disease initiation and progression. We sought to discover the most relevant processes controlled by miR-183 through an unbiased transcriptomic approach using prostate cell lines and patient tissues to identify miR-183 responsive genes and pathways. Gain of function experiments, reporter gene assays, and transcript and protein measurements were conducted to validate predicted functional effects and protein mediators. A total of 135 candidate miR-183 target genes overrepresenting cell adhesion terms were inferred from the integrated transcriptomic analysis. Cell attachment, spreading assays and focal adhesion quantification of miR-183-overexpressing cells confirmed the predicted reduction in cell adhesion. ITGB1 was validated as a major target of repression by miR-183 as well as a mediator of cell adhesion in response to miR-183. The reporter gene assay and PAR-CLIP read mapping suggest that ITGB1 may be a direct target of miR-183. The negative correlation between miR-183 and ITGB1 expression in prostate cancer cohorts supports their interaction in the clinical set. Overall, cell adhesion was uncovered as a major pathway controlled by miR-183 in prostate cancer, and ITGB1 was identified as a relevant mediator of this effect.
Highlights
We demonstrated that miR-183 reduces the number of focal adhesions, the main surface complexes in which ITGB1 mediates adhesion to the extracellular matrix (ECM)
Positive associations between miR-183 expression and PSA level at diagnosis and prior to radical prostatectomy and shorter time until recurrence were found in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort (Table 1)
The results indicate that a negative regulation of ITGB1 by miR-183 may operative in prostate cancer patient tissue, as well as in cell lines, and might contribute
Summary
Prostate cancer (PrCa) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related deaths in men worldwide [1]. The disease frequently evolves slowly, a minority of patients will progress to an aggressive form that is resistant to androgen deprivation therapy. Despite the international efforts to improve diagnosis and treatment, no significant reduction in the mortality rate has been reached. MicroRNAs (miRNAs) are endogenous small non-coding RNAs (19–22 nt) that are able to modulate protein levels through their sequence-specific interactions with complementary target mRNAs [2,3]. MiRNA regulation has a wide impact in human gene expression [2,4] MicroRNAs (miRNAs) are endogenous small non-coding RNAs (19–22 nt) that are able to modulate protein levels through their sequence-specific interactions with complementary target mRNAs [2,3]. miRNA regulation has a wide impact in human gene expression [2,4]
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