TRAF6 expression is associated with poorer prognosis and high recurrence in urothelial bladder cancer

Wu,Hanli; Hao,Aixia; Cui,Honghong; Wu,Wenbin; Yang,Huanrong; Hu,Baohong; Li,Peng

doi:10.3892/ol.2017.6427

TRAF6 expression is associated with poorer prognosis and high recurrence in urothelial bladder cancer

Authors:
- Hanli Wu
- Aixia Hao
- Honghong Cui
- Wenbin Wu
- Huanrong Yang
- Baohong Hu
- Peng Li
View Affiliations

Affiliations: Department of Nephrology, Yidu Central Hospital of Weifang, Weifang, Shandong 262500, P.R. China, East District of Shandong Provincial Hospital of Shandong Univeristy, Jinan, Shandong 250014, P.R. China, Department of Medical Oncology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. China
Published online on: June 20, 2017 https://doi.org/10.3892/ol.2017.6427
Pages: 2432-2438

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to investigate the clinical significance of TNF receptor-associated factor 6 (TRAF6) expression in urothelial bladder cancer. TRAF6 expression was detected by immunohistochemistry in 126 samples of patients with urothelial bladder cancer. The association between clinicopathological factors and TRAF6 expression was analyzed by χ2 test. The association between TRAF6 expression, overall survival rate and the recurrence‑free survival rate was evaluated in univariate analysis with Kaplan‑Meier test and in multivariate analysis with Cox‑regression model. In the cohort tested, the rate of high TRAF6 expression was 61.9% (78/126). TRAF6 expression was demonstrated to be significantly associated with positive metastasis (P=0.001) with χ2 test. Furthermore, TRAF6 expression was demonstrated to be associated with overall survival rate (P=0.016) and recurrence‑free survival rate (P=0.016). With Cox‑regression model, it was indicate that TRAF6 high expression was an independent predictive factor of poor prognosis (P=0.037) and high recurrence (P=0.011). High TRAF6 expression may predict unfavorable prognosis and high recurrence in urothelial bladder cancer, indicating that TRAF6 may be a potential and promising therapeutic target in urothelial bladder cancer.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Dy GW, Gore JL, Forouzanfar MH, Naghavi M and Fitzmaurice C: Global burden of urologic cancers, 1990–2013. Eur Urol. 71:437–446. 2017. View Article : Google Scholar : PubMed/NCBI
3	La Vecchia C, Bosetti C, Lucchini F, Bertuccio P, Negri E, Boyle P and Levi F: Cancer mortality in Europe, 2000–2004, and an overview of trends since 1975. Ann Oncol. 21:1323–1360. 2010. View Article : Google Scholar : PubMed/NCBI
4	Jiang X, Du L, Wang L, Li J, Liu Y, Zheng G, Qu A, Zhang X, Pan H, Yang Y and Wang C: Serum microRNA expression signatures identified from genome-wide microRNA profiling serve as novel noninvasive biomarkers for diagnosis and recurrence of bladder cancer. Int J Cancer. 136:854–862. 2015. View Article : Google Scholar : PubMed/NCBI
5	Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Böhle A, Palou-Redorta J and Rouprêt M; European Association of Urology (EAU), : EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol. 59:997–1008. 2011. View Article : Google Scholar : PubMed/NCBI
6	Wu XR: Urothelial tumorigenesis: A tale of divergent pathways. Nat Rev Cancer. 5:713–725. 2005. View Article : Google Scholar : PubMed/NCBI
7	Black PC, Brown GA and Dinney CP: Molecular markers of urothelial cancer and their use in the monitoring of superficial urothelial cancer. J Clin Oncol. 24:5528–5535. 2006. View Article : Google Scholar : PubMed/NCBI
8	Cheng L, Zhang S, MacLennan GT, Williamson SR, Lopez-Beltran A and Montironi R: Bladder cancer: Translating molecular genetic insights into clinical practice. Hum Pathol. 42:455–481. 2011. View Article : Google Scholar : PubMed/NCBI
9	Chiu HW, Lin SW, Lin LC, Hsu YH, Lin YF, Ho SY, Wu YH and Wang YJ: Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6. Cancer Lett. 365:229–239. 2015. View Article : Google Scholar : PubMed/NCBI
10	Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C and Chen ZJ: Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 103:351–361. 2000. View Article : Google Scholar : PubMed/NCBI
11	Chen H, Li M, Campbell RA, Burkhardt K, Zhu D, Li SG, Lee HJ, Wang C, Zeng Z, Gordon MS, et al: Interference with nuclear factor kappa B and c-Jun NH2-terminal kinase signaling by TRAF6C small interfering RNA inhibits myeloma cell proliferation and enhances apoptosis. Oncogene. 25:6520–6527. 2006. View Article : Google Scholar : PubMed/NCBI
12	Wang KZ, Galson DL and Auron PE: TRAF6 is autoinhibited by an intramolecular interaction which is counteracted by trans-ubiquitination. J Cell Biochem. 110:763–771. 2010. View Article : Google Scholar : PubMed/NCBI
13	Lamothe B, Besse A, Campos AD, Webster WK, Wu H and Darnay BG: Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation. J Biol Chem. 282:4102–4112. 2007. View Article : Google Scholar : PubMed/NCBI
14	Choi YB and Harhaj EW: HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation. PLoS Pathog. 10:e10044582014. View Article : Google Scholar : PubMed/NCBI
15	Chaudhry SI, Hooper S, Nye E, Williamson P, Harrington K and Sahai E: Autocrine IL-1β-TRAF6 signalling promotes squamous cell carcinoma invasion through paracrine TNFα signalling to carcinoma-associated fibroblasts. Oncogene. 32:747–758. 2013. View Article : Google Scholar : PubMed/NCBI
16	Liu J, Xu J, Li H, Sun C, Yu L, Li Y, Shi C, Zhou X, Bian X, Ping Y, et al: miR-146b-5p functions as a tumor suppressor by targeting TRAF6 and predicts the prognosis of human gliomas. Oncotarget. 6:29129–29142. 2015.PubMed/NCBI
17	Rong Y, Wang D, Wu W, Jin D, Kuang T, Ni X, Zhang L and Lou W: TRAF6 is over-expressed in pancreatic cancer and promotes the tumorigenicity of pancreatic cancer cells. Med Oncol. 31:2602014. View Article : Google Scholar : PubMed/NCBI
18	Liu H, Zhang T, Ye J, Li H, Huang J, Li X, Wu B, Huang X and Hou J: TNF receptor-associated factor 6 in advanced non-small cell lung cancer: Clinical and prognostic implications. J Cancer Res Clin Oncol. 138:1853–1863. 2012. View Article : Google Scholar : PubMed/NCBI
19	Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME and Lotan Y: Bladder cancer. Nat Rev Dis Primers. 3:170222017. View Article : Google Scholar : PubMed/NCBI
20	Liu H, Xu Y, Zhang Q, Yang H, Shi W, Liu Z, Li K, Gong Z, Ning S, Li S and Chen Y: Prognostic significance of TBL1XR1 in predicting liver metastasis for early stage colorectal cancer. Surg Oncol. 26:13–20. 2017. View Article : Google Scholar : PubMed/NCBI
21	Xu YF, Yang XQ, Lu XF, Guo S, Liu Y, Iqbal M, Ning SL, Yang H, Suo N and Chen YX: Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma. Biochem Biophys Res Commun. 446:54–60. 2014. View Article : Google Scholar : PubMed/NCBI
22	Xu Y, Yang X, Li Z, Li S, Guo S, Ismail S, Liu H, Huang Z, Zhang Z, Chen Y and Sun Q: Sprouty2 correlates with favorable prognosis of gastric adenocarcinoma via suppressing FGFR2-induced ERK phosphorylation and cancer progression. Oncotarget. 8:4888–4900. 2017.PubMed/NCBI
23	Hemdan T, Lindén M, Lind SB, Namuduri AV, Sjöstedt E, de Ståhl TD, Asplund A, Malmström PU and Segersten U: The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer. Br J Cancer. 111:1180–1187. 2014. View Article : Google Scholar : PubMed/NCBI
24	Yang XQ, Xu YF, Guo S, Liu Y, Ning SL, Lu XF, Yang H and Chen YX: Clinical significance of nerve growth factor and tropomyosin-receptor-kinase signaling pathway in intrahepatic cholangiocarcinoma. World J Gastroenterol. 20:4076–4084. 2014. View Article : Google Scholar : PubMed/NCBI
25	Liu H, Xu Y, Zhang Q, Li K, Wang D, Li S, Ning S, Yang H, Shi W, Liu Z and Chen Y: Correlations between TBL1XR1 and recurrence of colorectal cancer. Sci Rep. 7:442752017. View Article : Google Scholar : PubMed/NCBI
26	Solomon JP and Hansel DE: Prognostic factors in urothelial carcinoma of the bladder: Histologic and molecular correlates. Adv Anat Pathol. 22:102–112. 2015. View Article : Google Scholar : PubMed/NCBI
27	Gogalic S, Sauer U, Doppler S and Preininger C: Bladder cancer biomarker array to detect aberrant levels of proteins in urine. Analyst. 140:724–735. 2015. View Article : Google Scholar : PubMed/NCBI
28	Chan EC, Pasikanti KK, Hong Y, Ho PC, Mahendran R, Nee Mani L Raman, Chiong E and Esuvaranathan K: Metabonomic profiling of bladder cancer. J Proteome Res. 14:587–602. 2015. View Article : Google Scholar : PubMed/NCBI
29	Mitra AP, Bartsch CC and Cote RJ: Strategies for molecular expression profiling in bladder cancer. Cancer Metastasis Rev. 28:317–326. 2009. View Article : Google Scholar : PubMed/NCBI
30	Wang M, Chu H, Li P, Yuan L, Fu G, Ma L, Shi D, Zhong D, Tong N, Qin C, et al: Genetic variants in miRNAs predict bladder cancer risk and recurrence. Cancer Res. 72:6173–6182. 2012. View Article : Google Scholar : PubMed/NCBI
31	Shaid S, Brandts CH, Serve H and Dikic I: Ubiquitination and selective autophagy. Cell Death Differ. 20:21–30. 2013. View Article : Google Scholar : PubMed/NCBI
32	Pickart CM: Ubiquitin enters the new millennium. Mol Cell. 8:499–504. 2001. View Article : Google Scholar : PubMed/NCBI
33	Yang WL, Wang J, Chan CH, Lee SW, Campos AD, Lamothe B, Hur L, Grabiner BC, Lin X, Darnay BG and Lin HK: The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science. 325:1134–1138. 2009. View Article : Google Scholar : PubMed/NCBI
34	Lin Y, Qiu Y, Xu C, Liu Q, Peng B, Kaufmann GF, Chen X, Lan B, Wei C, Lu D, et al: Functional role of asparaginyl endopeptidase ubiquitination by TRAF6 in tumor invasion and metastasis. J Natl Cancer Inst. 106:dju0122014. View Article : Google Scholar : PubMed/NCBI