Abstract C23: MicroRNA-106b targets caspase-7 and is associated with recurrence in human prostate cancer

Previously, we found several microRNA (miR) of the polycistronic miR-106b-25 cluster to be elevated in prostate cancer. This cluster is a homolog to the prototypical oncomiR-1 (miR-17-92) and is thought to act as a super-oncogene when co-amplified with its host gene minichromosome complex maintenance component 7 (MCM7). In this study we validated our previous findings in an independent prostate cancer dataset and further found that miR-106b is elevated in metastatic tissues and associated with disease recurrence. Genome-wide analysis of miR-106b-25 correlated transcripts revealed enrichment of focal adhesion and ECM-receptor interaction genes. Further, we found miR-106b target enrichment in transcripts that were protective against recurrence, suggesting that miR-106b targets collectively have a functionally protective role in the recurrence of prostate cancer. In cell based assays, overexpression of miR-106b increased proliferation, adhesion-free survival, soft agar survival, and adhesion to ECM components (laminin, and collagen type I and IV). In addition, microarray analysis showed that miR-106b down-regulated transcripts were enriched for miR-106b targets sites and cell death pathways genes. When we compared genes that were related to recurrence, altered by miR-106b, and predicted to have miR-106b 3′UTR target sites we identified CASP7, a central executioner of apoptosis. Corroborating these findings we found that the expression of CASP7 was consistently reduced in primary human prostate tumors and metastatic lesions across multiple prostate cancer datasets, and is by itself a candidate predictor of disease recurrence. Western blot analysis in RWPE-1, 22Rv1, and LNCaP prostate cells showed that miR-106b was capable of reducing CASP7 protein levels. Direct targeting of the CASP7 3′UTR by miR-106b was confirmed using wild-type and mutant 3′UTR luciferase reporter assays. This research reveals a novel oncogenic role for the miR-106b-25 cluster in prostate cancer and, for the first time, indentifies CASP7 as a direct target of miR-106b. Future work is aimed at understanding the role of miR-106b-dependent regulation of CASP7 and the possible utility of targeting miR-106b as novel therapy for prostate cancer. Citation Format: Robert S. Hudson, Tiffany H. Dorsey, Ming Yi, Dominic Esposito, Robert M. Stephens, Carlo M. Croce, Stefan Ambs. MicroRNA-106b targets caspase-7 and is associated with recurrence in human prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C23.