Abstract
Background
Hu-antigen R (HuR) is an RNA-binding protein that regulates the stability, translation, and nucleus-to-cytoplasm translocation of messenger RNAs (mRNAs).
Objective
The aim of this study was to investigate the prognostic significance of HuR in cholangiocarcinoma patients who received adjuvant gemcitabine-based chemotherapy (AGC) after surgical resection.
Methods
Nuclear and cytoplasmic HuR expression was investigated immunohistochemically in 131 patients with resected cholangiocarcinoma, including 91 patients administered AGC and 40 patients who did not receive adjuvant chemotherapy. The correlation between HuR expression and survival was evaluated by statistical analysis.
Results
High nuclear and cytoplasmic HuR expression was observed in 67 (51%) and 45 (34%) patients, respectively. Cytoplasmic HuR expression was significantly associated with lymph node metastasis (p < 0.01), while high cytoplasmic HuR expression was significantly associated with poor disease-free survival [DFS] (p = 0.03) and overall survival [OS] (p = 0.001) in the 91 patients who received AGC, but not in the 40 patients who did not receive AGC (DFS p = 0.17; OS p = 0.07). In the multivariate analysis of patients who received AGC, high cytoplasmic HuR expression was an independent predictor of poor DFS (hazard ratio [HR] 1.77; p = 0.04) and OS (HR 2.09; p = 0.02). Nuclear HuR expression did not affect the survival of enrolled patients.
Conclusions
High cytoplasmic HuR expression was closely associated with the efficacy of AGC in patients with cholangiocarcinoma. The current findings warrant further investigations to optimize adjuvant chemotherapy regimens for resectable cholangiocarcinoma.
Similar content being viewed by others
References
Fitzmaurice C, Dicker D, Pain A, et al. The global burden of cancer 2013. JAMA Oncol. 2015; 1(4):505–27.
Ustundag Y, Bayraktar Y. Cholangiocarcinoma: a compact review of the literature. World J Gastroenterol. 2008; 14(42):6458–66.
Nathan H, Pawlik TM, Wolfgang CL, et al. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg. 2007; 11(11):1488–96; discussion 1496-7.
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010; 362(14):1273–81.
Murakami Y, Uemura K, Sudo T, et al. Adjuvant gemcitabine plus S-1 chemotherapy improves survival after aggressive surgical resection for advanced biliary carcinoma. Ann Surg. 2009; 250(6):950–6.
Murakami Y, Uemura K, Sudo T, et al. Gemcitabine-based adjuvant chemotherapy improves survival after aggressive surgery for hilar cholangiocarcinoma. J Gastrointest Surg. 2009; 13(8):1470–9.
Wang J, Guo Y, Chu H, et al. Multiple functions of the RNA-binding protein HuR in cancer progression, treatment responses and prognosis. Int J Mol Sci. 2013; 14(5):10015–41.
Kotta-Loizou I, Giaginis C, Theocharis S. Clinical significance of HuR expression in human malignancy. Med Oncol. 2014; 31(9):161.
Tatarian T, Jiang W, Leiby BE, et al. Cytoplasmic HuR status predicts disease-free survival in resected pancreatic cancer: a post-hoc analysis from the international phase III ESPAC-3 clinical trial. Ann Surg. 2018;267(2):364–9.
Elebro J, Ben Dror L, Heby M, et al. Prognostic effect of hENT1, dCK and HuR expression by morphological type in periampullary adenocarcinoma, including pancreatic cancer. Acta Oncol. 2016; 55(3):286–96.
Murakami Y, Uemura K, Sudo T, et al. Adjuvant chemotherapy with gemcitabine and S-1 after surgical resection for advanced biliary carcinoma: outcomes and prognostic factors. J Hepatobiliary Pancreat Sci. 2012; 19(4):306–13.
Richards NG, Rittenhouse DW, Freydin B, et al. HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients. Ann Surg. 2010; 252(3):499–505; discussion 505–6.
McAllister F, Pineda DM, Jimbo M, et al. DCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: a dual-institutional follow-up with the RTOG 9704 trial. Cancer Biol Ther. 2014; 15(6):688–98.
Costantino CL, Witkiewicz AK, Kuwano Y, et al. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res. 2009; 69(11):4567–72.
Heinonen M, Bono P, Narko K, et al. Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res. 2005; 65(6):2157–61.
Yoo PS, Sullivan CA, Kiang S, et al. Tissue microarray analysis of 560 patients with colorectal adenocarcinoma: high expression of HuR predicts poor survival. Ann Surg Oncol. 2009; 16(1):200–7.
Erkinheimo TL, Lassus H, Sivula A, et al. Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase 2 expression in serous ovarian carcinoma. Cancer Res. 2003; 63(22):7591–4.
Zhang C, Xue G, Bi J, et al. Cytoplasmic expression of the ELAV-like protein HuR as a potential prognostic marker in esophageal squamous cell carcinoma. Tumour Biol. 2014; 35(1):73–80.
Sun DP, Lin CY, Tian YF, et al. Clinicopathological significance of HuR expression in gallbladder carcinoma: with special emphasis on the implications of its nuclear and cytoplasmic expression. Tumour Biol. 2013; 34(5):3059–69.
Hostetter C, Licata LA, Witkiewicz A, et al. Cytoplasmic accumulation of the RNA binding protein HuR is central to tamoxifen resistance in estrogen receptor positive breast cancer cells. Cancer Biol Ther. 2008; 7(9):1496–506.
Prislei S, Martinelli E, Mariani M, et al. MiR-200c and HuR in ovarian cancer. BMC Cancer. 2013; 13:72.
Raspaglio G, De Maria I, Filippetti F, et al. HuR regulates beta-tubulin isotype expression in ovarian cancer. Cancer Res. 2010; 70(14):5891–900.
Jakstaite A, Maziukiene A, Silkuniene G, et al. HuR mediated post-transcriptional regulation as a new potential adjuvant therapeutic target in chemotherapy for pancreatic cancer. World J Gastroenterol. 2015; 21(46):13004–19.
John NP, Richard F, Daniel HP, et al. Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study. J Clin Oncol. 2017; 35(15 Suppl):4006.
Disclosures
All authors declared that they have no commercial interests in the subject of this study or received any financial or material support for this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Toyota, K., Murakami, Y., Kondo, N. et al. Cytoplasmic Hu-Antigen R (HuR) Expression is Associated with Poor Survival in Patients with Surgically Resected Cholangiocarcinoma Treated with Adjuvant Gemcitabine-Based Chemotherapy. Ann Surg Oncol 25, 1202–1210 (2018). https://doi.org/10.1245/s10434-018-6392-y
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-018-6392-y