Characterization and prognostic significance of mortalin, Bcl‑2 and Bax in intrahepatic cholangiocarcinoma

Kang,Qiang; Zou,Hao; Yang,Xuan; Cai,Jia‑Bin; Liu,Li‑Xin; Xie,Nan; Wang,Lian‑Min; Li,Yue‑Hua; Zhang,Xiao‑Wen

doi:10.3892/ol.2017.7570

Characterization and prognostic significance of mortalin, Bcl‑2 and Bax in intrahepatic cholangiocarcinoma

Authors:
- Qiang Kang
- Hao Zou
- Xuan Yang
- Jia‑Bin Cai
- Li‑Xin Liu
- Nan Xie
- Lian‑Min Wang
- Yue‑Hua Li
- Xiao‑Wen Zhang
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Affiliations: Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Kunming Medical University, Kunming, Yunnan 650105, P.R. China, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
Published online on: December 8, 2017 https://doi.org/10.3892/ol.2017.7570
Pages: 2161-2168
Copyright: © Kang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Intrahepatic cholangiocarcinoma (ICC) is an aggressive type of cancer, and its incidence and mortality rates are increasing worldwide. Mortalin is a highly conserved chaperone protein involved in multiple pathological and physiological processes, including anti‑apoptosis, carcinogenesis and metastasis. The Bcl‑2 family of proteins can be divided into pro‑survival and pro‑apoptotic members, including B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑like protein 4 (Bax). The aim of the present study was to investigate the association between mortalin, Bcl‑2 and Bax, as well as the prognostic significance of the combined expression of mortalin, Bcl‑2 and Bax in ICC. Immunohistochemistry was used to determine the expression of mortalin, Bcl‑2 and Bax in 116 ICC samples and to assess the association between expression of 3 markers and clinicopathological features of ICC patients. This revealed that ICC tumor tissues overexpressed mortalin and Bcl‑2 and exhibited low expression of Bax in ICC tumor tissues compared with that in corresponding peritumoral samples. According to Pearson's correlation coefficient analysis, high expression of mortalin in ICC was positively correlated with Bcl‑2 expression and negatively correlated with Bax expression. Furthermore, multiple linear regression analysis demonstrated that mortalin was positively associated with Bcl‑2, but not with Bax, in patients with ICC. Patients with ICC exhibiting high expression of mortalin/Bcl‑2 or low expression of Bax were closely associated with a malignant ICC phenotype, a relatively low overall survival rate and a high recurrence rate. Multivariate analysis indicated that mortalin and Bcl‑2 were independent prognostic indicators for ICC patients. Meanwhile, the concomitant overexpression of mortalin and Bcl‑2 and the low expression of Bax were independent markers for predicting a relatively poor prognosis of ICC. The overexpression of mortalin and Bcl‑2 and/or the low expression of Bax are implicated in the anti‑apoptotic effect and tumor progression of ICC. Mortalin or Bcl‑2, or a combination of mortalin, Bcl‑2 and Bax may be used to predict the prognosis of ICC, as well as potential therapeutic targets.

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1	Rahnemai-Azar AA, Weisbrod AB, Dillhoff M, Schmidt C and Pawlik TM: Intrahepatic cholangiocarcinoma: Current management and emerging therapies. Expert Rev Gastroenterol Hepatol. 11:439–449. 2017. View Article : Google Scholar : PubMed/NCBI
2	Lubezky N, Facciuto M, Harimoto N, Schwartz ME and Florman SS: Surgical treatment of intrahepatic cholangiocarcinoma in the USA. J Hepatobiliary Pancreat Sci. 22:124–130. 2015. View Article : Google Scholar : PubMed/NCBI
3	Yamashita S, Koay EJ, Passot G, Shroff R, Raghav KP, Conrad C, Chun YS, Aloia TA, Tao R, Kaseb A, et al: Local therapy reduces the risk of liver failure and improves survival in patients with intrahepatic cholangiocarcinoma: A comprehensive analysis of 362 consecutive patients. Cancer. 123:1354–1362. 2017. View Article : Google Scholar : PubMed/NCBI
4	Buettner S, van Vugt JL, IJzermans JN and Koerkamp B Groot: Intrahepatic cholangiocarcinoma: Current perspectives. Onco Targets Ther. 10:1131–1142. 2017. View Article : Google Scholar : PubMed/NCBI
5	Zhang H, Yang T, Wu M and Shen F: Intrahepatic cholangiocarcinoma: Epidemiology, risk factors, diagnosis and surgical management. Cancer Lett. 379:198–205. 2016. View Article : Google Scholar : PubMed/NCBI
6	Oliveira DV, Zhang S, Chen X, Calvisi DF and Andersen JB: Molecular profiling of intrahepatic cholangiocarcinoma: The search for new therapeutic targets. Expert Rev Gastroenterol Hepatol. 11:349–356. 2017. View Article : Google Scholar : PubMed/NCBI
7	Si A, Li J, Xing X, Lei Z, Xia Y, Yan Z, Wang K, Shi L and Shen F: Effectiveness of repeat hepatic resection for patients with recurrent intrahepatic cholangiocarcinoma: Factors associated with long-term outcomes. Surgery. 161:897–908. 2017. View Article : Google Scholar : PubMed/NCBI
8	Reed JC: Bcl-2 and the regulation of programmed cell death. J Cell Biol. 124:1–6. 1994. View Article : Google Scholar : PubMed/NCBI
9	Hatok J and Racay P: Bcl-2 family proteins: Master regulators of cell survival. Biomol Concepts. 7:259–270. 2016. View Article : Google Scholar : PubMed/NCBI
10	Thomas S, Quinn BA, Das SK, Dash R, Emdad L, Dasgupta S, Wang XY, Dent P, Reed JC, Pellecchia M, et al: Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets. 17:61–75. 2013. View Article : Google Scholar : PubMed/NCBI
11	Kelly PN and Strasser A: The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 18:1414–1424. 2011. View Article : Google Scholar : PubMed/NCBI
12	Ermiah E, Buhmeida A, Khaled BR, Abdalla F, Salem N, Pyrhönen S and Collan Y: Prognostic value of bcl-2 expression among women with breast cancer in Libya. Tumour Biol. 34:1569–1578. 2013. View Article : Google Scholar : PubMed/NCBI
13	Casneuf VF, Fonteyne P, Van Damme N, Demetter P, Pauwels P, de Hemptinne B, De Vos M, Van de Wiele C and Peeters M: Expression of SGLT1, Bcl-2 and p53 in primary pancreatic cancer related to survival. Cancer Invest. 26:852–859. 2008. View Article : Google Scholar : PubMed/NCBI
14	Brady HJ and Gil-Gόmez G: Bax. The pro-apoptotic Bcl-2 family member, Bax. Int J Biochem Cell Biol. 30:647–650. 1998. View Article : Google Scholar : PubMed/NCBI
15	Liu Z, Ding Y, Ye N, Wild C, Chen H and Zhou J: Direct activation of bax protein for cancer therapy. Med Res Rev. 36:313–341. 2016. View Article : Google Scholar : PubMed/NCBI
16	Gross A, Jockel J, Wei MC and Korsmeyer SJ: Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J. 17:3878–3885. 1998. View Article : Google Scholar : PubMed/NCBI
17	Wadhwa R, Kaul SC, Ikawa Y and Sugimoto Y: Identification of a novel member of mouse hsp70 family. Its association with cellular mortal phenotype. J Biol Chem. 268:6615–6621. 1993.PubMed/NCBI
18	Kaul SC, Deocaris CC and Wadhwa R: Three faces of mortalin: A housekeeper, guardian and killer. Exp Gerontol. 42:263–274. 2007. View Article : Google Scholar : PubMed/NCBI
19	Wadhwa R, Yaguchi T, Hasan MK, Mitsui Y, Reddel RR and Kaul SC: Hsp70 family member, mot-2/mthsp70/GRP75, binds to the cytoplasmic sequestration domain of the p53 protein. Exp Cell Res. 274:246–253. 2002. View Article : Google Scholar : PubMed/NCBI
20	Londono C, Osorio C, Gama V and Alzate O: Mortalin, apoptosis, and neurodegeneration. Biomolecules. 2:143–164. 2012. View Article : Google Scholar : PubMed/NCBI
21	Saxena N, Katiyar SP, Liu Y, Grover A, Gao R, Sundar D, Kaul SC and Wadhwa R: Molecular interactions of Bcl-2 and Bcl-xL with mortalin: Identification and functional characterization. Biosci Rep. 33:e000732013. View Article : Google Scholar : PubMed/NCBI
22	Na Y, Kaul SC, Ryu J, Lee JS, Ahn HM, Kaul Z, Kalra RS, Li L, Widodo N, Yun CO and Wadhwa R: Stress chaperone mortalin contributes to epithelial-mesenchymal transition and cancer metastasis. Cancer Res. Mar 9–2016.(Epub ahead of print). View Article : Google Scholar : PubMed/NCBI
23	Cui X, Li Z, Piao J, Li J, Li L, Jin A and Lin Z: Mortalin expression in pancreatic cancer and its clinical and prognostic significance. Hum Pathol. 64:171–178. 2017. View Article : Google Scholar : PubMed/NCBI
24	Sun J, Che SL, Piao JJ, Xu M, Chen LY and Lin ZH: Mortalin overexpression predicts poor prognosis in early stage of non-small cell lung cancer. Tumour Biol. 39:10104283176959182017. View Article : Google Scholar : PubMed/NCBI
25	Huang XY, Zhang C, Cai JB, Shi GM, Ke AW, Dong ZR, Zhang PF, Fan J, Peng BG and Zhou J: Comprehensive multiple molecular profile of epithelial mesenchymal transition in intrahepatic cholangiocarcinoma patients. PLoS One. 9:e968602014. View Article : Google Scholar : PubMed/NCBI
26	Talwalkar JA, Seaberg E, Kim WR and Wiesner RH: Predicting clinical and economic outcomes after liver transplantation using the Mayo primary sclerosing cholangitis model and Child-Pugh score. National institutes of diabetes and digestive and kidney diseases liver transplantation database group. Liver Transpl. 6:753–758. 2000. View Article : Google Scholar : PubMed/NCBI
27	Wittekind C: Pitfalls in the classification of liver tumors. Pathologe. 27:289–293. 2006.(In German). View Article : Google Scholar : PubMed/NCBI
28	Edge SB and Compton CC: The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI
29	Kang Q, Cai JB, Dong RZ, Liu LX, Zhang C, Zhang PF, Zou H, Xie N, Zhang L, Zhang XY, et al: Mortalin promotes cell proliferation and epithelial mesenchymal transition of intrahepatic cholangiocarcinoma cells in vitro. J Clin Pathol. 70:677–683. 2017. View Article : Google Scholar : PubMed/NCBI
30	Chen J, Liu WB, Jia WD, Xu GL, Ma JL, Huang M, Deng YR and Li JS: Overexpression of Mortalin in hepatocellular carcinoma and its relationship with angiogenesis and epithelial to mesenchymal transition. Int J Oncol. 44:247–255. 2014. View Article : Google Scholar : PubMed/NCBI
31	Ando K, Oki E, Zhao Y, Ikawa-Yoshida A, Kitao H, Saeki H, Kimura Y, Ida S, Morita M, Kusumoto T and Maehara Y: Mortalin is a prognostic factor of gastric cancer with normal p53 function. Gastric Cancer. 17:255–262. 2014. View Article : Google Scholar : PubMed/NCBI
32	Wadhwa R, Takano S, Robert M, Yoshida A, Nomura H, Reddel RR, Mitsui Y and Kaul SC: Inactivation of tumor suppressor p53 by mot-2, a hsp70 family member. J Biol Chem. 273:29586–29591. 1998. View Article : Google Scholar : PubMed/NCBI
33	Zhang J, Huang K, O'Neill KL, Pang X and Luo X: Bax/Bak activation in the absence of Bid, Bim, Puma, and p53. Cell Death Dis. 7:e22662016. View Article : Google Scholar : PubMed/NCBI
34	Galluzzi L, Morselli E, Kepp O, Tajeddine N and Kroemer G: Targeting p53 to mitochondria for cancer therapy. Cell Cycle. 7:1949–1955. 2008. View Article : Google Scholar : PubMed/NCBI
35	Grover A, Priyandoko D, Gao R, Shandilya A, Widodo N, Bisaria VS, Kaul SC, Wadhwa R and Sundar D: Withanone binds to mortalin and abrogates mortalin-p53 complex: Computational and experimental evidence. Int J Biochem Cell Biol. 44:496–504. 2012. View Article : Google Scholar : PubMed/NCBI