前胸腺素α在人類膀胱泌尿上皮癌能夠增強PTEN表現及鍵結TRIM21共同調節Keap1/Nrf2 訊息表現
蔡育賢1、周詠欽2、蔡欣孜1、蕭璦莉3、吳昭良4、蔡宗欣5
國立成功大學醫學院附設醫院泌尿部1；嘉義基督教醫院泌尿科2；國立成功大學醫學院為免所3；生化所4；台南市立安南醫院 泌尿科5
Prothymosin-α enhances PTEN expression and binds with TRIM21 to regulate Keap1/Nrf2 signaling in human bladder cancerr
Yuh-Shyan Tsai1, Yeong-Chin Jou2, Hsin-Tzu Tsai1, Ai-Li Shiau3, Chao-Liang Wu4, Tzong-Shin Tzai5
1Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
2Department of Urology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
3Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan.
4Department of Biochemistry and Molecular biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
5Department of Urology, An-Nan Hospital, China Medical University, Tainan, Taiwan
Purpose:
Prothymosin-a (PTMA) is a small, acidic protein that is usually transported into the nucleus and involves many cellular and immunologic functions. Previous studies demonstrated that nuclear translocation may influence its biological potential in some immune cells. However, the role of PTMA protein expression remains elusive in cancer. In this study, we explored the effect of PTMA expression location in human bladder carcinoma.
Materials and Methods:
Ectopic nuclear or cytoplasmic expression of PTMA expression was created in several human bladder cancer cells carrying wild-type (WT), deleted nuclear localization signal (∆NLS) PTMA cDNA. The cDNA differential array of these 3 transfectants and PTMA immunoblot from BFTC905 bladder cancer cells was investigated with proteomics were utilized for exploring the interaction proteins. Paraffin-embedded tumors from 151 bladder cancer patients were investigated for prognostic value of PTMA immunostaining using univariate and multivariate Cox’s model analyses.
Results:
The in vivo tumorigenesis assay showed ∆NLSPTMA protein expression promotes J82 xenograft tumor growth in mice and shortens their survival. The cDNA differential array demonstrated the involved signaling pathways, include TGF-β1/smad, PIP3/Akt signaling, etc. Chromatin immunoprecipitation showed WTPTMA protein binds to the PTEN promoter and enhances both PTEN mRNA and protein expression. PTMA immunoblot proteomics revealed that tripartite motif-containing protein 21(TRIM21) was bound to PTMA. Both WTPTMA and ∆NLSPTMA protein can be downregulated by TRIM21, in which PTMA orchestrates with TRIM21 to regulate Nrf2 expression through p62/Keap1 signaling. From PTMA immunostaining studies, the absence of nuclear PTMA expression was significantly associated with lower tumor grade (p = 0.01) and tumor stage (p = 0.01), and was an unfavorable prognostic indicator for shorter disease-free survival (HR, 1.54; p = 0.009). Two tissue microarrays of 60 bladder tumors were immunostained for co-expression of PTMA and TRIM21 protein, revealing increased TRIM21 expression is associated with PTMA expression in human bladder cancer
Conclusion:
Our data support nuclear PTMA protein serves as a tumor suppressor in bladder cancer through upregulating PTEN and orchestrating TRIM21 for the regulation of Nrf2 signaling.
Presentation: Moderated Poster