Characterization of unique PMEPA1 gene splice variants (isoforms d and e) from RNA Seq profiling provides novel insights into prognostic evaluation of prostate cancer
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Shashwat Sharad1,2,3,*, Allissa Amanda Dillman1,3, Zsófia M. Sztupinszki4, Zoltan Szallasi4,5,6, Inger Rosner1,2,7, Jennifer Cullen1,2,3, Shiv Srivastava1, Alagarsamy Srinivasan1,3 and Hua Li1,2,*
1 Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, Maryland, 20814, USA
2 John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, Maryland, 20814, USA
3 Henry Jackson Foundation for the Advancement of Military Medicine (HJF), Bethesda, Maryland, 20817, USA
4 Danish Cancer Society Research Center, Copenhagen, 2100, Denmark
5 Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA
6 SE-NAP Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, 1085, Hungary
7 Urology Service, Walter Reed National Military Medical Center, Bethesda, Maryland, 20814, USA
* These authors contributed equally to this work
|Hua Li,||email:||[email protected]|
|Shashwat Sharad,||email:||[email protected]|
Keywords: prostate cancer; PMEPA1; gene isoform; splice variant; TGF-β
Received: October 17, 2019 Accepted: December 02, 2019 Published: January 28, 2020
Prostate cancer is a disease with heterogeneity of multiple gene transcriptomes and biological signaling pathways involved in tumor development. The prostate transmembrane protein, androgen induced 1 (PMEPA1), a multifunctional protein played critical roles in prostate tumorigenesis. The pleiotropic nature of PMEPA1 in modulating androgen and TGF-β signaling as well as splice variants mechanisms for functional regulations of cancer-associated genes prompted us to investigate the biological roles of PMEPA1 isoforms in prostate cancer. In addition to 4 reported PMEPA1 isoforms (a, b, c and d), one novel isoform PMEPA1-e was identified with RNA Seq analysis of hormone responsive VCaP, LNCaP cells and human prostate cancer samples from The Cancer Genome Atlas (TCGA) dataset. We analyzed the structures, expressions, biological functions and clinical relevance of PMEPA1-e isoform and less characterized isoforms c and d in the context of prostate cancer and AR/TGF-β signaling. The expression of PMEPA1-e was induced by androgen and AR. In contrast, PMEPA1-d was responsive to TGF-β and inhibited TGF-β signaling. Both PMEPA1-d and PMPEA1-e promoted the growth of androgen independent prostate cancer cells. Although PMEPA1-c was responsive to TGF-β, it was found to have no impacts on cell growth and androgen/TGF-β signaling. The TCGA data analysis from 499 patients showed higher expression ratios of PMEAP1-b versus -d or -e strongly associated with enhanced Gleason score. Taken together, our findings first time defined the prostate tumorigenesis mediated by PMEPA1-d and -e isoforms, providing novel insights into the new strategies for prognostic evaluation and therapeutics of prostate tumor.
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