Format

Send to

Choose Destination
Clin Cancer Res. 2017 Dec 15;23(24):7650-7663. doi: 10.1158/1078-0432.CCR-17-0002. Epub 2017 Sep 29.

Transmembrane and Coiled-Coil Domain 1 Impairs the AKT Signaling Pathway in Urinary Bladder Urothelial Carcinoma: A Characterization of a Tumor Suppressor.

Li CF1,2,3,4, Wu WR5, Chan TC1,5, Wang YH1,6, Chen LR4,7,8, Wu WJ9,10,11,12,13,14,15, Yeh BW9, Liang SS5,16, Shiue YL17,18,19.

Author information

1
Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan.
2
National Institute of Cancer Research, National Health Research Institute, Tainan, Taiwan.
3
Department of Pathology, Kaohsiung Medical University, Kaohsiung, Taiwan.
4
Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
5
Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
6
Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.
7
Division of Physiology, Livestock Research Institute, Council of Agriculture, Tainan, Taiwan.
8
Institute of Biotechnology, National Cheng Kung University, Tainan, Taiwan.
9
Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
10
Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
11
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
12
Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
13
Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
14
Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
15
Institute of Medical Science and Technology, Kaohsiung Medical University, Kaohsiung, Taiwan.
16
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
17
Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan. shirley@imst.nsysu.edu.tw.
18
Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
19
Doctoral degree program in Marine Biotechnology, National Sun Yat-sen University, Kaohsiung, Taiwan.

Abstract

Purpose: Urinary bladder urothelial carcinoma (UBUC) is a common malignant disease in developed countries. Cell-cycle dysregulation resulting in uncontrolled cell proliferation has been associated with UBUC development. This study aimed to explore the roles of TMCO1 in UBUCs.Experimental Design: Data mining, branched DNA assay, immunohistochemistry, xenograft, cell culture, quantitative RT-PCR, immunoblotting, stable and transient transfection, lentivirus production and stable knockdown, cell-cycle, cell viability and proliferation, soft-agar, wound-healing, transwell migration and invasion, coimmunoprecipitation, immunocytochemistry, and AKT serine/threonine kinase (AKT) activity assays and site-directed mutagenesis were used to study TMCO1 involvement in vivo and in vitroResults: Data mining identified that the TMCO1 transcript was downregulated during the progression of UBUCs. In distinct UBUC-derived cell lines, changes in TMCO1 levels altered the cell-cycle distribution, cell viability, cell proliferation, and colony formation and modulated the AKT pathway. TMCO1 recruited the PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) to dephosphorylate pAKT1(serine 473) (S473). Mutagenesis at S60 of the TMCO1 protein released TMCO1-induced cell-cycle arrest and restored the AKT pathway in BFTC905 cells. Stable TMCO1 (wild-type) overexpression suppressed, whereas T33A and S60A mutants recovered, tumor size in xenograft mice.Conclusions: Clinical associations, xenograft mice, and in vitro indications provide solid evidence that the TMCO1 gene is a novel tumor suppressor in UBUCs. TMCO1 dysregulates cell-cycle progression via suppression of the AKT pathway, and S60 of the TMCO1 protein is crucial for its tumor-suppressor roles. Clin Cancer Res; 23(24); 7650-63. ©2017 AACR.

PMID:
28972042
DOI:
10.1158/1078-0432.CCR-17-0002
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center