MicroRNA-Mediated Gene Regulation in Prostate Cancer

miRNAs are a class of small non-coding RNAs that regulate gene expression post-transcriptionally. Aberrant expression of miRNAs has been observed in various cancers. Extensive studies in the past decade have identified a number of oncogenic and tumor suppressive miRNAs. The purpose of this dissertation was to identify the miRNAs that are involved in the progression of prostate cancer.

Androgen and androgen receptor signaling is essential for prostate development and function as well as the growth of prostate cancer. Therefore, it is worth examining the regulation of miRNAs by androgen in prostate cancer cells. We identified a cluster of miRNAs, miR-99a/let-7c/miR-125b, that is repressed by androgen. Repression of the miR-99a/let-7c/miR-125b cluster by androgen results in upregulation of their target genes, including IGF1R, suggesting another method of gene induction by androgen through downregulating miRNAs. Further study demonstrated that ectopic expression of the miR- 99a/let-7c/miR-125b-2 cluster inhibits androgen-induced cell proliferation by targeting IGF1R, highlighting the potential tumor suppressive functions of miR-99a/let-7c/miR- 125b-2 cluster.

A common feature of prostate cancer progression is the transition from androgendependence to a castration resistant state. At this stage, prostate cancer cells become resistant to androgen manipulation and can survive and proliferate under the constraint of androgen deprivation. To identify the miRNAs that are important for the progression of prostate cancer, we examined the miRNA expression profile in the androgen dependent prostate cancer cell line LNCaP and its castration resistant derivative cell line, C4-2. We found that the miR-99 family of miRNAs was downregulated in C4-2 cells compared to its parental LNCaP cells. This downregulation was also seen in other advanced prostate cancer cells lines relative to their parental cell lines as well as in prostate tumors compared to normal prostate tissues. Further study showed that the miR-99 family inhibits the proliferation of prostate cancer cells and decreases the expression of PSA, suggesting their potential roles as tumor suppressors.

Taken together, this dissertation has identified a cluster of miRNAs and a miRNA family that possess tumor suppressive functions in prostate cancer. Our study, together with other studies, suggests that these miRNAs may be used as novel diagnostic and therapeutic methods for prostate cancer.