Abstract 4001: Lin28/miR-let-7c axis controls the growth and tumorigenicity of prostate cancer cells

Abstract

Abstract Introduction: MicroRNAs (miRNA) are small ∼22 nt non-coding RNAs that regulate gene expression by binding to and inducing degradation of target mRNAs. Deregulated expression of several miRNAs has been found in prostate cancer cells. Let-7 is an evolutionarily conserved family of miRNAs that have been shown to regulate expression of several oncogenes like HMGA2, RAS and Myc. Expression of members of the let-7 family has been shown to be downregulated in many human cancers including lung, breast, ovarian and prostate. In this study, we examined the relative expression levels of let-7c and its master regulator, Lin28 in prostate cancer cells and clinical specimens. We also examined the role of the let-7/Lin28 axis in controlling proliferation in prostate cancer cells. Methods: Expression levels of Let-7c and Lin28 in prostate cancer cells and clinical specimens were measured by real-time qRT-PCR, Northern and Western blotting. Prostate cancer cell lines with stable expression of let-7c or Lin28 were generated and their growth characteristics, clonogenic ability and colony forming abilities in soft agar were examined. Expression of let-7c was downregulated in LNCaP cells using antisense oligonucleotides and effects on growth were examined. Lentiviruses containing let-7c were injected into tumors generated by implantation of prostate cancer cells in nude mice and tumor volumes were measured. Results: Expression levels of let-7c were found to be downregulated in castration-resistant prostate cancer cells and clinical specimens. These levels were found to be inversely correlated to expression levels of Lin28. Overexpression of let-7c reduced prostate cancer cell growth, clonogenic ability and ability to form colonies in soft agar, while downregulation of let-7c resulted in increased cell growth. Conversely, overexpression of Lin28 enhanced prostate cancer cell growth and clonogenic ability. In addition, intratumoral injection of lentiviruses containing let-7c reduced tumor volumes significantly in vivo in nude mice compared to control viruses. Conclusions: Levels of miR-let-7c are reduced in CRPC compared to androgen-dependent prostate cancer. Levels of Lin28, which regulates processing of let-7c into its mature form, are elevated in CRPC. Overexpression of let-7c reduces prostate cancer cell growth and tumorigenic ability. These results suggest that miR-let-7c is a tumor suppressor and may be developed as a therapeutic agent against CRPC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4001. doi:10.1158/1538-7445.AM2011-4001