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Characterization of unique PMEPA1 gene splice variants (isoforms d and e) from RNA Seq profiling provides novel insights into the prognostic evaluation of prostate cancer


FOR IMMEDIATE RELEASE
2020-01-29

The cover for issue 4 of Oncotarget features Figure 8, "Model for biological function categorization of PMEPA1 isoforms (c, d, and e) in the context of prostate cancer," by Sharad, et al.

In addition to 4 reported PMEPA1 isoforms, one novel isoform PMEPA1-e was identified with RNA Seq analysis of hormone-responsive VCa P, LNCa P cells and human prostate cancer samples from The Cancer Genome Atlas dataset.

The researchers 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- signaling.

The expression of PMEPA1-e was induced by androgen and AR.

Taken together, their findings first 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.

Figure 8: Model for biological function categorization of PMEPA1 isoforms (c, d and e) in the context of prostate cancer. Our study suggested a model where evaluation of PMEPA1 isoforms revealed a potentially new mechanism of prostate cancer cell adaptation from androgen dependent to hormone independent, TGF-β controlled cell growth. PMEPA1-e were androgen responsive whereas the PMEPA1 isoform c and d were TGF-β responsive and only isoform d inhibited TGF-β signaling.

Dr. Hua Li and Dr. Shashwat Sharad from the Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences as well as the Walter Reed National Military Medical Center, Bethesda, Maryland, USA said in their Oncotarget article, "Prostate cancer is the most commonly diagnosed male malignancy and second leading cause of cancer-related deaths in the USA."

It was shown that the methylation of PMEPA1 gene promoter accounted for the silencing of PMEPA1 in prostate cancer cells in vitro and in vivo.

PMEPA1 was also reported as a TGF- regulated gene in the context of both prostate cancer and non-prostate solid tumors including colon, lung and breast cancers.

Further, a recent study showed that the loss of membrane-anchored PMEPA1 protein facilitated metastasis of prostate cancer via activating TGF- signaling by sequestering SMAD2/3 in proteasome independent way.

Cumulatively, these findings underscored the multi-function features of the PMEPA1 gene and further suggested its expressions and biological functions were dependent on the cellular context centering androgen and TGF- signaling.

The alternative splicing variant mechanism had also been shown to be important for diversifying functions of tumor-associated genes.

Further, earlier studies from their and other groups explored PMEAP1 gene isoforms in the initiation and development of prostate tumors via interrupting AR and/or TGF- signaling.

Here, the Oncotarget authors focused on defining the expressions, regulations and biological behaviors/functions of understudied PMEPA1 isoforms in the context of both androgen and TGF- signaling, and further exploration of the clinical significances and relevance of these isoforms in prostate tumor.

The Li/Sharad Research Team concluded in their Oncotarget study that gene isoform ratio could potentially predict the gene functional consequences and disease progression.

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Full text - https://doi.org/10.18632/oncotarget.27406

Correspondence to - Hua Li - hli@cpdr.org and Shashwat Sharad - ssharad@cpdr.org

Keywords - prostate cancer, PMEPA1, gene isoform, splice variant, TGF-β



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