Analysis of <i>PMEPA1</i> Isoforms (<i>a</i> and <i>b</i>) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer.

Dysfunctions of androgen/TGF-β signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (<i>PMEPA1</i>) inhibits androgen and TGF-β signaling via a negative feedback loop. The loss of <i>PMEPA1</i> confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of <i>PMEPA1</i> in prostate and other cancers propelled us to investigate isoform specific functions in prostate cancer (PCa). One hundred and twenty laser capture micro-dissection matched normal prostate and prostate tumor tissues were analyzed for correlations between quantitative expression of <i>PMEPA1</i> isoforms and clinical outcomes with Q-RT-PCR, and further validated with a The Cancer Genome Atlas (TCGA) RNA-Seq dataset of 499 PCa. Cell proliferation was assessed with cell counting, plating efficiency and soft agar assay in androgen responsive LNCaP and TGF-β responsive PC3 cells. TGF-β signaling was measured by SMAD dual-luciferase reporter assay. Higher <i>PMEPA1</i>-<i>a</i> mRNA levels indicated biochemical recurrence (<i>p</i> = 0.0183) and lower <i>PMEPA1</i>-<i>b</i> expression associated with metastasis (<i>p</i> = 0.0173). Further, lower <i>PMEPA1</i>-<i>b</i> and a higher ratio of <i>PMEPA1</i>-<i>a</i> vs. -<i>b</i> were correlated to higher Gleason scores and lower progression free survival rate (<i>p</i> < 0.01). TGF-β-responsive <i>PMEPA1</i>-<i>a</i> promoted PCa cell growth, and androgen-responsive <i>PMEPA1</i>-<i>b</i> inhibited cancer cell proliferation. <i>PMEPA1</i> isoforms -<i>a</i> and -<i>b</i> were shown to be promising candidate biomarkers indicating PCa aggressiveness including earlier biochemical relapse and lower disease specific life expectancy via interrupting androgen/TGF-β signaling.

Chen Y, Cullen J, Dobi A, Kuo C, Li H, Petrovics G, Ravindranath L, Rosner IL, Sharad S, Sreenath TL, Srinivasan A, Srivastava S, Szallasi Z, Sztupinszki ZM


Cancers (Basel), 2019, 11 (12)

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