Caveolin-1 involvement in prostate cancer

Caveolin-l (Cav-l) is an important component of plasma membrane caveolae and orchestrates cell signalling in the regulation of proliferation and apoptosis. Unlike many cancers, prostate cancer cells demonstrate elevated levels of cav-l expression which has been linked to Gleason scoring and aggression. A loss of cav-l, with siRNA, in an advanced prostate cancer cell line (PC-3) caused a significant increase in PI positive cells combined with reduced proliferation. Both Akt and ERK signalling showed altered functioning under these conditions and may orchestrate these effects. Such an effect was not observed in benign prostate epithelial cells (PrEC) implicating cav-l as an important protein in the control of cellular viability in malignant but not benign prostate cells. To investigate possible causes of elevated cav-l expression in malignant prostate cells, miRNAs predicted to target the cav-l 3 'UTR were analyzed in both benign and malignant prostate cell lines. In PC-3 cells both miR-30a-3p and miR-203 expression was significantly reduced and miR-I06a and miR-93 increased when compared to benign PrEC cells. Over-expression ofmiR-30a-3p, miR-93, miR-203 but not miR-I06a in PC-3 cells caused significant reduction in cav-l protein expression. This points to a role for these miRNAs in the regulation of cav-l in prostate cancer cells. Interestingly cav-l knockdown in PC-3 cells increased expression of miR-124 and miR-124 up-regulation reduced cav-l protein and mRNA expression, suggesting that the two molecules are linked. Androgen stimulation of LNCaP cells implicate an androgen response element may be involved in the transcriptional regulation of miR-124. In summary, these results suggest changes in miRNA expression with oncogenic transformation may result in over- expression of cav-l which promotes cell survival and proliferation, hence promoting cancer progression. Whether the effects of these miRNAs on cav-l are direct and occur at an early or late stage in the development of the malignancy needs to be determined but it is clear that miRNA expression profiles are becoming increasingly important potential biomarkers in the early diagnosis of many cancers.EThOS - Electronic Theses Online ServiceGBUnited Kingdo