肝内胆管癌病理机制表观基因组学研究进展

中国临床药理学与治疗学 ›› 2014, Vol. 19 ›› Issue (11): 1294-1298.

肝内胆管癌病理机制表观基因组学研究进展

刘谋泽^{1, 2}, 李浩^{1, 2, 3}, 张伟^{1, 2}

¹ 中南大学湘雅医院临床药理研究所, 长沙 410008,湖南;
² 中南大学临床药理研究所, 遗传药理学湖南省重点实验室,长沙 410078,湖南;
³ 湖南省人民医院肝胆医院,长沙 410002,湖南

收稿日期:2014-05-07 修回日期:2014-09-05 出版日期:2014-11-26 发布日期:2014-12-09
通讯作者: 张伟,男,博士,教授,博士生导师,研究方向:遗传药理学,分子药理学。Tel: 0731-84805380-8317 E-mail: yjsd2003@163.com
作者简介:刘谋泽,男,硕士研究生,研究方向:疾病表观基因组学和表观药物基因组学研究。 Tel: 15717415461 E-mail: liumouze0123@126.com
基金资助:
中南大学中央高校基本科研业务费专项资金(2014zzts325); 国家自然科学基金(81273595); 国家863计划(2012AA02A518)

Epigenomic research progress on pathological mechanisms of intrahepatic cholangiocarcinoma

LIU Mou-ze^{1, 2}, LI Hao^{1, 2, 3}, ZHANG Wei^{1, 2}

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China;
² Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan,China;
³ Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, Changsha 410002, Hunan, China

Received:2014-05-07 Revised:2014-09-05 Online:2014-11-26 Published:2014-12-09

摘要/Abstract

摘要： 肝内胆管癌(ICC)是一类高侵袭性的恶性肿瘤,分子机制不明确。其治疗术后易复发且化疗不理想,目前尚无可供特异性早期诊断的生物标记物。近年来研究发现特异性的基因突变如KRAS、 EGFR、 IDH1 和 IDH2等,基因甲基化和miRNA等表观遗传学改变, IL-6/STAT,酪氨酸激酶受体相关的信号通路异常激活等参与ICC的发病和转移,其中许多关键基因成为分子靶向药物治疗靶点。我们就其病理机制表观基因组学研究进展作一综述,旨在为促进发现新的诊断和治疗ICC的生物标记物,实施联合分子靶向治疗的策略提供思路。

关键词: 肝内胆管癌, 表观基因组, 病理机制, 分子靶向治疗

Abstract: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with its molecular mechanism poor understood. It is prone to postoperative relapse and the response of chemotherapy on it is always disappointing. There is no available specific biomarkers for its early diagnosis. Recently, researchers have found that some genetic mutations, such as KRAS, EGFR, IDH1 and IDH2, gene methylation, miRNA and other epigenetic changes, abnormal activation of IL-6/STAT, tyrosine kinase receptors related signaling pathways are involved in ICC pathogenesis. Some of the key genes in it are becoming targets for molecular therapy. We are here to make a review on epigenomic research progress of ICC pathological mechanisms with the aim to promoting discovery of new biomarkers for its diagnosis and treatment, and to providing ideals for new strategy of medication in combination with molecular target drugs.

Key words: intrahepatic cholangiocarcinoma, epigeneomic, pathological mechanism, molecular target therapy

中图分类号:

R969.1

刘谋泽, 李浩, 张伟. 肝内胆管癌病理机制表观基因组学研究进展[J]. 中国临床药理学与治疗学, 2014, 19(11): 1294-1298.

LIU Mou-ze, LI Hao, ZHANG Wei. Epigenomic research progress on pathological mechanisms of intrahepatic cholangiocarcinoma[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(11): 1294-1298.

参考文献 32

[1]	Sia D, Tovar V, Moeini A, et al.Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies[J].Oncogene, 2013, 32(41): 4861-4870.
[2]	崔云甫,李惠声.肝内胆管癌的诊治进展[J].国际外科学杂志, 2012, 39(5): 292-295.
[3]	Witjes CD, Karim-Kos HE, Visser O,et al.Intrahepatic cholangiocarcinoma in a low endemic area: rising incidence and improved survival[J].HPB (Oxford), 2012, 14(11): 777-781.
[4]	黄志强, 肝胆管外科的发展方向[J].外科理论与实践, 2011,16(4): 329-331.
[5]	Mavros MN, Economopoulos KP, Alexiou VG, et al.Treatment and Prognosis for Patients With Intrahepatic Cholangiocarcinoma: Systematic Review and Meta-analysis[J].JAMA Surg, 2014.
[6]	Poultsides GA, Zhu AX, Choti MA, et al.Intrahepatic cholangiocarcinoma[J].Surg Clin North Am, 2010, 90(4): 817-837.
[7]	O'Dell MR, Huang JL, Whitney-Miller CL,et al.Kras(G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma[J].Cancer Res, 2012, 72(6): 1557-1567.
[8]	Hsu M, Sasaki M, Igarashi S,et al.KRAS and GNAS mutations and p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas[J].Cancer, 2013, 119(9): 1669-1674.
[9]	Voss JS, Holtegaard LM, Kerr SE,et al.Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions[J].Hum Pathol, 2013, 44(7): 1216-1222.
[10]	Stutes M, Tran S, DeMorrow S.Genetic and epigenetic changes associated with cholangiocarcinoma: from DNA methylation to microRNAs[J].World J Gastroenterol, 2007, 13(48): 6465-6469.
[11]	Yoshikawa D, Ojima H, Iwasaki M,et al.Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma[J].Br J Cancer, 2008, 98(2): 418-425.
[12]	Dawson MA, Kouzarides T.Cancer epigenetics: from mechanism to therapy[J].Cell, 2012, 150(1): 12-27.
[13]	刘谋泽,何发忠,张伟.抗肿瘤药物的表观遗传学研究进展[J].药学学报, 2013,161(11): 1629-1636.
[14]	马爱妞, 王永祥, 周向军.靶向诱导DNA甲基化与肿瘤治疗研究进展[J].中国临床药理学与治疗学, 2009,14(3): 241-244.
[15]	Isomoto H, Mott JL, Kobayashi S,et al.Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing[J].Gastroenterology, 2007, 132(1): 384-396.
[16]	Dachrut S, Banthaisong S, Sripa M,et al.DNA copy-number loss on 1p36.1 harboring RUNX3 with promoter hypermethylation and associated loss of RUNX3 expression in liver fluke-associated intrahepatic cholangiocarcinoma[J].Asian Pac J Cancer Prev, 2009, 10(4): 575-582.
[17]	Gao Y, Yang M, Jiang Z,et al.IMP3 expression is associated with poor outcome and epigenetic deregulation in intrahepatic cholangiocarcinoma[J].Hum Pathol, 2014,45(6):1184-1191.
[18]	Li B, Han Q, Zhu Y,et al.Down-regulation of miR-214 contributes to intrahepatic cholangiocarcinoma metastasis by targeting Twist[J].FEBS J, 2012, 279(13): 2393-2398.
[19]	Chen L, Yan HX, Yang W,et al.The role of microRNA expression pattern in human intrahepatic cholangiocarcinoma[J].J Hepatol, 2009, 50(2): 358-369.
[20]	Qiu YH, Wei YP, Shen NJ,et al.miR-204 inhibits epithelial to mesenchymal transition by targeting slug in intrahepatic cholangiocarcinoma cells[J].Cell Physiol Biochem, 2013, 32(5): 1331-1341.
[21]	Iwaki J, Kikuchi K, Mizuguchi Y,et al.MiR-376c down-regulation accelerates EGF-dependent migration by targeting GRB2 in the HuCCT1 human intrahepatic cholangiocarcinoma cell line[J].PLoS One, 2013, 8(7): e69496.
[22]	Liu MZ, McLeod HL, He FZ,et al.Epigenetic perspectives on cancer chemotherapy response[J].Pharmacogenomics, 2014, 15(5): 699-715.
[23]	Iwahashi S, Shimada M, Utsunomiya T,et al.Histone deacetylase inhibitor enhances the anti-tumor effect of gemcitabine: a special reference to gene-expression microarray analysis[J].Oncol Rep, 2011, 26(5): 1057-1062.
[24]	Valle J, Wasan H, Palmer DH,et al.Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer[J].N Engl J Med, 2010, 362(14): 1273-1281.
[25]	Woo SM, Lee WJ, Kim JH,et al.Gemcitabine plus cisplatin versus capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer: a retrospective cohort study[J].Chemotherapy, 2013, 59(3): 232-238.
[26]	Zhu AX, Meyerhardt JA, Blaszkowsky LS,et al.Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study[J].Lancet Oncol, 2010, 11(1): 48-54.
[27]	Gruenberger B, Schueller J, Heubrandtner U,et al.Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study[J].Lancet Oncol, 2010, 11(12): 1142-1148.
[28]	Yoshikawa D, Ojima H, Kokubu A,et al.Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma[J].Br J Cancer, 2009, 100(8): 1257-1266.
[29]	Nathanson DA, Gini B, Mottahedeh J,et al.Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA[J].Science, 2014, 343(6166): 72-76.
[30]	Nakadate Y, Kodera Y, Kitamura Y,et al.KRAS mutation confers resistance to antibody-dependent cellular cytotoxicity of cetuximab against human colorectal cancer cells[J].Int J Cancer, 2014, 134(9): 2146-2155.
[31]	Gridelli C, Peters S, Sgambato A,et al.ALK inhibitors in the treatment of advanced NSCLC[J].Cancer Treat Rev, 2014, 40(2): 300-306.
[32]	Chang YT, Chang MC, Huang KW,et al.Clinicopathological and prognostic significances of EGFR, KRAS and BRAF mutations in biliary tract carcinomas in Taiwan[J].J Gastroenterol Hepatol, 2014, 29(5): 1119-1125.