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.
Abstact
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.
Authors
- 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