內皮型一氧化氮合成酶基因多型性對膀胱泌尿道上皮細胞癌發展的影響

Impact of endothelial nitric oxide synthase polymorphisms on bladder urothelial cell carcinoma development

蔡明道(Ming-Dow Tsay)

指導教授 ： 楊順發

中山醫學大學/醫學院/醫學研究所/博士(2020年)

https://doi.org/10.6834/CSMU202000015

摘要

泌尿道上皮細胞癌 (urothelial cell carcinoma, UCC) 是泌尿生殖系統中最主要的惡性腫瘤之一，可透由致癌病理因子所引起。內皮型一氧化氮合成酶 (endothelial nitric oxide synthase, eNOS) 是一氧化氮合成酶的主要亞型之一，且參與在許多病理與生理過程之中。本實驗我們利用了即時聚合酶連鎖反應 (real-time polymerase chain reaction; real-time PCR) 分析了431例泌尿道上皮細胞癌患者和862例健康對照組eNOS其兩個單核苷酸多型性(single nucleotide polymorphism; SNP)的相關性。結果顯示，272例患有泌尿道上皮細胞癌且帶有eNOS 894 G > T (rs1799983) G/T+T/T基因型的男性患者，其具有發展成大型腫瘤的高度風險 (T1-T4，p = 0.038)。此外在美國癌症基因體圖譜 (The Cancer Genome Atlas; TCGA) 資料庫中，膀胱泌尿道上皮細胞癌患者之eNOS的表現，與其腫瘤侵蝕、轉移以及較低的存活率之間有相關性。在本篇研究中，我們的研究成果顯示帶有eNOS 894 G > T (rs1799983) G/T+T/T基因型的男性泌尿道上皮細胞癌患者，其發展成大型腫瘤的風險很高，因此eNOS的基因多型性也許可作為泌尿道上皮細胞癌治療上之標記或治療標靶。

關鍵字

泌尿道上皮細胞癌 ； 內皮型一氧化氮合成酶基因多型性

並列摘要

Urothelial cell carcinoma (UCC), a major malignancy of the genitourinary tract, is induced through carcinogenic etiological factors. Endothelial nitric oxide synthase (eNOS) is one of the major isoforms of nitric oxide synthase and involved in various pathophysiologic and physiologic processes. Two SNPs of eNOS in 431 patients with UCC and 862 controls without cancer were analyzed using real-time polymerase chain reaction. The results showed that 272 men with UCC having eNOS 894 G > T (rs1799983) “G/T + T/T” variants had a high risk of developing a large tumor (T1–T4, p = 0.038). Furthermore, a correlation was observed between the expressions of eNOS and invasive tumor, metastasis and poor survival in urothelial cell carcinoma in TCGA (The Cancer Genome Atlas) data set. In this study, our results indicated that male patients with bladder UCC carrying eNOS 894 G > T (rs1799983) “G/T + T/T” genetic variants have a high risk of developing a large tumor, and eNOS gene polymorphisms may serve as a marker or therapeutic target in UCC treatment.

並列關鍵字

urothelial cell carcinoma ； endothelial nitric oxide synthase ； gene polymorphism

參考文獻

Adams, T., E. Wan, Y. Wei, R. Wahab, F. Castagna, G. Wang, M. Emin, C. Russo, S. Homma, T.H. Le Jemtel, and S. Jelic. 2015. Secondhand Smoking Is Associated With Vascular Inflammation. Chest. 148:112-119.

Antoni, S., J. Ferlay, I. Soerjomataram, A. Znaor, A. Jemal, and F. Bray. 2017. Bladder Cancer Incidence and Mortality: A Global Overview and Recent Trends. European urology. 71:96-108.

Brait, M., E. Munari, C. LeBron, M.G. Noordhuis, S. Begum, C. Michailidi, N. Gonzalez-Roibon, L. Maldonado, T. Sen, R. Guerrero-Preston, L. Cope, P. Parrella, V.M. Fazio, P.K. Ha, G.J. Netto, D. Sidransky, and M.O. Hoque. 2013. Genome-wide methylation profiling and the PI3K-AKT pathway analysis associated with smoking in urothelial cell carcinoma. Cell cycle (Georgetown, Tex.). 12:1058-1070.

Burger, M., J.W. Catto, G. Dalbagni, H.B. Grossman, H. Herr, P. Karakiewicz, W. Kassouf, L.A. Kiemeney, C. La Vecchia, S. Shariat, and Y. Lotan. 2013. Epidemiology and risk factors of urothelial bladder cancer. European urology. 63:234-241.

Calmels, S., P. Hainaut, and H. Ohshima. 1997. Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein. Cancer research. 57:3365-3369.