Abstract B061: Alternative RNA splicing and prostate cancer aggressiveness

Abstract

Abstract Prostate cancer (PCa) is the most common cancer in men in the United States. Aggressive pathology, metastasis, and drug resistance of cancer cells are the most important prognostic factors for patients with PCa. African Americans (AAs) suffer disproportionately from PCa, with higher aggressiveness, progression, and mortality. A recently published analysis involving our laboratory reported more than 2,500 alternatively RNA spliced (ARS) genes between AA and white PCa biopsy tissue specimens. Subsequent analysis revealed that, among the race-related ARS genes in PCa tissue, 19 are also ARS in breast, lung, and liver cancer. Several of the genes that are ARS across multiple tumor types are important for cancer aggressiveness, including CD44, FN1, and LMO7. We designed PCR primers to further explore the expression of LMO7 variants in preclinical models of white and AA PCa, and found that a LMO7 variant that skips exons 10, 11, and 12 is predominantly expressed in VCaP (white) and MDA PCA 2b (AA) PCa cell lines. In addition, we detected a unique race-related LMO7 splicing event that excludes exons 10 and 11, but preserves exon 12. This event is detected in MDA PCA 2b cells, but not in VCaP cells. Importantly, both of these LMO7 splicing events are in-frame and are not frameshifts leading to truncated or extended C-terminal proteins. These LMO7 variants translate to proteins of 1297 amino acids (missing 344 amino acids coded by skipped exons 10, 11, and 12) and 1287 amino acids (missing 334 amino acids coded by skipped exons 10 and 11), which differ from the full-length LMO7 variant that translates to a protein of 1631 amino acids. Interestingly, the enrichment of these variants in cancer cells suggests an important regulatory role for the amino acids encoded by the skipped exons. Further work to study the impact of LMO7 variants as well as other candidate RNA splice variants on PCa aggressiveness is ongoing, using gene overexpression, gene depletion, and splicing manipulation by siRNA or CRISPR-cas, followed by assessment of resulting alterations in growth, migration, invasion, and drug sensitivity. In summary, we have identified genes that undergo race-related ARS in multiple tumor types and novel ARS events that may functionally contribute to increased tumor aggressiveness, including that of PCa in AA men. Citation Format: Muthana Al Abo, Steven R. Patierno, Jennifer A. Freedman. Alternative RNA splicing and prostate cancer aggressiveness [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B061.