Overexpression of the transmembrane protein BST-2 induces Akt and Erk phosphorylation in bladder cancer

Shigematsu,Yoshinori; Oue,Naohide; Nishioka,Yuri; Sakamoto,Naoya; Sentani,Kazuhiro; Sekino,Yohei; Mukai,Shoichiro; Teishima,Jun; Matsubara,Akio; Yasui,Wataru

doi:10.3892/ol.2017.6230

Overexpression of the transmembrane protein BST-2 induces Akt and Erk phosphorylation in bladder cancer

Authors:
- Yoshinori Shigematsu
- Naohide Oue
- Yuri Nishioka
- Naoya Sakamoto
- Kazuhiro Sentani
- Yohei Sekino
- Shoichiro Mukai
- Jun Teishima
- Akio Matsubara
- Wataru Yasui
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Affiliations: Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734‑8551, Japan, Department of Urology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima 734‑8551, Japan
Published online on: May 23, 2017 https://doi.org/10.3892/ol.2017.6230
Pages: 999-1004

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Abstract

Bladder cancer, the majority of which is urothelial carcinoma (UC), is a common malignancy worldwide. Genes encoding transmembrane/secretory proteins expressed specifically in certain cancers may be ideal biomarkers for cancer diagnosis and may represent therapeutic targets. In the present study, the expression and function of the bone marrow stromal cell antigen 2 (BST2) gene was analyzed in UC. Reverse transcription‑quantitative polymerase chain reaction demonstrated that expression of BST2 in normal tissue samples was the highest in liver tissue. However, expression of BST2 in UC tissue samples was higher than in normal liver. Immunohistochemical analysis revealed weak or no staining of BST‑2 in non‑neoplastic mucosa, whereas UC tissue exhibited stronger and more extensive staining compared with non‑neoplastic mucosa. BST‑2 staining was observed mainly on UC cell membranes. In total, 28 (41%) of 69 UC cases were positive for BST‑2. UC cases positive for BST‑2 were more frequently T2/3/4 cases [so‑called muscle‑invasive bladder cancer (MIBC)] than Ta/is/1 cases (P=0.0001). However, Kaplan‑Meier analysis demonstrated no association between BST‑2 expression and survival. BST2 small interfering RNA (siRNA)‑transfected T24 cells exhibited significantly reduced cell growth relative to negative control siRNA‑transfected T24 cells. The levels of phosphorylated Akt and extracellular signal‑regulated kinase were lower in BST2 siRNA‑transfected T24 cells than in control cells. These results suggest the involvement of BST‑2 in the pathogenesis of UC. Since BST‑2 is expressed on the cell membrane, BST‑2 may be a good therapeutic target for MIBC.

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1	Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW and Kurth K: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: A combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 49:466–477. 2006. View Article : Google Scholar : PubMed/NCBI
2	Knollman H, Godwin JL, Jain R, Wong YN, Plimack ER and Geynisman DM: Muscle-invasive urothelial bladder cancer: An update on systemic therapy. Ther Adv Urol. 7:312–330. 2015. View Article : Google Scholar : PubMed/NCBI
3	Ferguson DA, Muenster MR, Zang Q, Spencer JA, Schageman JJ, Lian Y, Garner HR, Gaynor RB, Huff JW, Pertsemlidis A, et al: Selective identification of secreted and transmembrane breast cancer markers using Escherichia coli ampicillin secretion trap. Cancer Res. 65:8209–8217. 2005. View Article : Google Scholar : PubMed/NCBI
4	Mukai S, Oue N, Oshima T, Mukai R, Tatsumoto Y, Sakamoto N, Sentani K, Tanabe K, Egi H, Hinoi T, et al: Overexpression of Transmembrane Protein BST2 is Associated with Poor Survival of Patients with Esophageal, Gastric, or Colorectal Cancer. Ann Surg Oncol. 24:594–602. 2017. View Article : Google Scholar : PubMed/NCBI
5	Kupzig S, Korolchuk V, Rollason R, Sugden A, Wilde A and Banting G: Bst-2/HM1.24 is a raft-associated apical membrane protein with an unusual topology. Traffic. 4:694–709. 2003. View Article : Google Scholar : PubMed/NCBI
6	Goto T, Kennel SJ, Abe M, Takishita M, Kosaka M, Solomon A and Saito S: A novel membrane antigen selectively expressed on terminally differentiated human B cells. Blood. 84:1922–1930. 1994.PubMed/NCBI
7	Ozaki S, Kosaka M, Wakatsuki S, Abe M, Koishihara Y and Matsumoto T: Immunotherapy of multiple myeloma with a monoclonal antibody directed against a plasma cell-specific antigen, HM1.24. Blood. 90:3179–3186. 1997.PubMed/NCBI
8	Walter-Yohrling J, Cao X, Callahan M, Weber W, Morgenbesser S, Madden SL, Wang C and Teicher BA: Identification of genes expressed in malignant cells that promote invasion. Cancer Res. 63:8939–8947. 2003.PubMed/NCBI
9	Cai D, Cao J, Li Z, Zheng X, Yao Y, Li W and Yuan Z: Up-regulation of bone marrow stromal protein 2 (BST2) in breast cancer with bone metastasis. BMC Cancer. 9:1022009. View Article : Google Scholar : PubMed/NCBI
10	Yokoyama T, Enomoto T, Serada S, Morimoto A, Matsuzaki S, Ueda Y, Yoshino K, Fujita M, Kyo S, Iwahori K, et al: Plasma membrane proteomics identifies bone marrow stromal antigen 2 as a potential therapeutic target in endometrial cancer. Int J Cancer. 132:472–484. 2013. View Article : Google Scholar : PubMed/NCBI
11	Wang W, Nishioka Y, Ozaki S, Jalili A, Abe S, Kakiuchi S, Kishuku M, Minakuchi K, Matsumoto T and Sone S: HM1.24 (CD317) is a novel target against lung cancer for immunotherapy using anti-HM1.24 antibody. Cancer Immunol Immunother. 58:967–976. 2009. View Article : Google Scholar : PubMed/NCBI
12	Sobin LH, Gospodarowicz MK and Wittekind CH: TNM classification of malignant tumours. 7th. New York: Wiley-Liss; pp. 262–265. 2009
13	Kondo T, Oue N, Yoshida K, Mitani Y, Naka K, Nakayama H and Yasui W: Expression of POT1 is associated with tumor stage and telomere length in gastric carcinoma. Cancer Res. 64:523–529. 2004. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	Oue N, Naito Y, Hayashi T, Takigahira M, Kawano-Nagatsuma A, Sentani K, Sakamoto N, Oo H Zarni, Uraoka N, Yanagihara K, et al: Signal peptidase complex 18, encoded by SEC11A, contributes to progression via TGF-α secretion in gastric cancer. Oncogene. 33:3918–3926. 2014. View Article : Google Scholar : PubMed/NCBI
16	Sakamoto N, Oue N, Sentani K, Anami K, Uraoka N, Naito Y, Oo HZ, Hinoi T, Ohdan H, Yanagihara K, et al: Liver-intestine cadherin induction by epidermal growth factor receptor is associated with intestinal differentiation of gastric cancer. Cancer Sci. 103:1744–1750. 2012. View Article : Google Scholar : PubMed/NCBI
17	Yasui W, Ayhan A, Kitadai Y, Nishimura K, Yokozaki H, Ito H and Tahara E: Increased expression of p34cdc2 and its kinase activity in human gastric and colonic carcinomas. Int J Cancer. 53:36–41. 1993. View Article : Google Scholar : PubMed/NCBI
18	Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P and Ferguson KM: Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell. 7:301–311. 2005. View Article : Google Scholar : PubMed/NCBI
19	von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A and Arning M: Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 23:4602–4608. 2005. View Article : Google Scholar : PubMed/NCBI
20	Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet. 387:1909–1920. 2016. View Article : Google Scholar : PubMed/NCBI
21	Takeuchi K and Ito F: EGF receptor in relation to tumor development: Molecular basis of responsiveness of cancer cells to EGFR-targeting tyrosine kinase inhibitors. FEBS J. 277:316–326. 2010. View Article : Google Scholar : PubMed/NCBI
22	Choudhury NJ, Campanile A, Antic T, Yap KL, Fitzpatrick CA, Wade JL III, Karrison T, Stadler WM, Nakamura Y and O'Donnell PH: Afatinib activity in platinum-refractory metastatic urothelial carcinoma in patients With ERBB alterations. J Clin Oncol. 34:2165–2171. 2016. View Article : Google Scholar : PubMed/NCBI
23	Harada T and Ozaki S: Targeted therapy for HM1.24 (CD317) on multiple myeloma cells. Biomed Res Int. 2014:9653842014. View Article : Google Scholar : PubMed/NCBI