[1950] The microRNA-Kallikrein Axis of Interaction: A New Dimension in the Pathogenesis of Prostate Cancer

Nicole MA White, Youssef M Youssf, Klaus Jung, Annika Fendler, Carsten Stephan, Manal Gabril, George M Yousef. St. Michael's Hospital, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada; University Hospital Charite, Berlin, Germany

Background: Kallikrein-related peptidases (KLKs) are a family of serine proteases that are being actively investigated as clinical markers for cancer. Their dysregulation in many cancers, including prostate cancer (PCa), has been reported. microRNAs (miRNAs) are short non-coding RNA molecules that negatively regulate expression of their target genes. miRNAs have been shown to be dysregulated in a number of cancers, including PCa.
Design: Our objective was to elucidate the interaction between miRNAs and KLKs and their potential involvement in PCa pathogenesis. We compiled a comprehensive list of miRNAs dysregulated in PCa by combining data from our miRNA microarray in addition to a literature search. Target prediction analysis was preformed for the dysregulated miRNAs. We also analyzed the expression of dysregulated miRNAs with their target KLK expression by quantitative real-time PCR in PCa patients. Furthermore, we examined the effect of ectopic miRNA expression on KLK expression and biological functions in a PCa cell line model.
Results: There were a total of 55 miRNAs dysregulated in PCa that were predicted to target KLKs. In addition, we found seven miRNAs (miR-1, miR-140, miR-143, miR-17-5p, miR-21, miR-24 and miR-331-3p) that could target more than one KLK. Target prediction analysis identified that 27 of these miRNAs could target KLKs. We examined 12 pairs of PCa tissue and normal matched tissue from the same patient and found that there was an inverse correlation expression pattern between these dysregulated miRNAs and their target KLKs. When miR-143 showed decreased expression, its target KLK2 had increased expression and vice versa. This relationship was also shown for miR-331-3p and its target KLK4. The interaction between miRNAs and KLKs was also shown in a cell line model. When DU-145 cells were transfected with miR-331-3p, expression of KLK4 was decreased. Furthermore, transfection of miR-143 or miR-331-3p decreased cell growth when compared to untransfected controls.
Conclusions: Our analysis shows that miRNAs that are dysregulated in PCa can target KLKs. Furthermore, our data supports an interaction between miRNAs and KLKs in PCa both in vivo and in vitro, suggesting that miRNAs regulate KLK expression in PCa. The miRNA-KLK axis of interaction presents a new element in the pathogenesis of PCa.
Category: Pathobiology

Wednesday, March 21, 2012 9:30 AM

Poster Session V # 268, Wednesday Morning

 

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