Abstract
Dysfunctions of androgen/TGF-β signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-β signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of PMEPA1 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 PMEPA1 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 PMEPA1-a mRNA levels indicated biochemical recurrence (p = 0.0183) and lower PMEPA1-b expression associated with metastasis (p = 0.0173). Further, lower PMEPA1-b and a higher ratio of PMEPA1-a vs. -b were correlated to higher Gleason scores and lower progression free survival rate (p < 0.01). TGF-β-responsive PMEPA1-a promoted PCa cell growth, and androgen-responsive PMEPA1-b inhibited cancer cell proliferation. PMEPA1 isoforms -a and -b 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.
Highlights
Prostate cancer is a commonly diagnosed malignancy in United States with an estimated 31,620 deaths in 2019 [1]
Our results revealed that the isoform specific functions of Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) and aberrant expressions of PMEPA1-a and -b correlated with biochemical recurrence and metastasis, respectively, serving as a potential biomarker for prostate cancer progression
All these findings highly suggested a differential role played by PMEPA1 isoforms (a and suggested a differential role played by PMEPA1 isoforms in prostate cancer progression via distinct signaling pathways as well as that the interplay of these two isoforms might contribute to b) in prostate cancer progression via distinct signaling pathways as well as that the interplay of these cancer progression collectively
Summary
Prostate cancer is a commonly diagnosed malignancy in United States with an estimated 31,620 deaths in 2019 [1]. The underlying etiology of lethal prostate cancer including CRPC and metastasis is still not fully understood, it has been shown that alterations of androgen receptor (AR) mediated signaling, including AR splice variants and transforming growth factor-β (TGF-β) signaling, contribute to prostate tumorigenesis and disease progression [2,3,4,5,6]. The Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) gene was originally identified by our group as an androgen responsive gene with abundance in the prostate [7,8,9]. Our earlier study showed that PMEPA1 degraded the AR protein via the E3 ubiquitin ligase NEDD4 mediated proteasome-ubiquitin pathway, and the PMEPA1 gene suppressed androgen signaling by, for example, decreasing the expression of the androgen responsive gene PSA/KLK3 in hormone responsive prostate cancer cells [10]. PMEPA1 was reported to be induced by TGF-β and PMEPA1 protein inhibited
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