董夏;焦佩娟;芮冉;孟博博;潘艳芳;方艳;李宏;应小平;

• 1:陕西中医药大学
• 2:陕西中医药大学病理学教研室

摘要(Abstract)：

肝癌是消化系统常见的恶性肿瘤之一,具有病情隐匿、预后凶险等临床特征,在我国发生率较高。肝癌前病变是指使肝脏发生恶变可能的良性病变,若长期不愈则可能转变为原发性肝癌。近年来大量研究表明,肝癌的发生与多种细胞信号转导通路密切相关。文章总结了Hippo-YAP/TAZ、Wnt/β-catenin、Hedgehog、Notch、JAK-STAT等信号通路与肝癌前病变相关性的最新研究进展及其在肝癌前病变发展过程中所发挥的重要作用,希望能够为临床及基础研究提供理论参考。

关键词(KeyWords)： 肝癌前病变;信号通路;研究进展

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金青年项目(81703842);; 陕西省科技厅项目(2017SF-306);; 陕西省中管局科研计划项目(JCMS032)

作者(Author): 董夏;焦佩娟;芮冉;孟博博;潘艳芳;方艳;李宏;应小平;

Email:

DOI: 10.13463/j.cnki.jlzyy.2019.05.036

参考文献(References)：

• [1]WANG F S,FAN J G,ZHANG Z,et al.The global burden of liver disease:The major impact of China[J].Hepatology,2014,60(6):2099-2108.
• [2]戴朝六,赵阳.原发性肝癌的综合治疗[J].中国普外基础与临床杂志,2014,21(2):133-137.
• [3]MO J S,PARK H W,GUAN K L.The hippo signaling pathway in stem cell biology and cancer[J].EMBO Rep,2014,15(6):642-656.
• [4]HARVEY K F,ZHANG X,THOMAS D M.The hippo pathway and human cancer[J].Nat Rev Cancer,2013,13(4):246-257.
• [5]YIMLAMAI D,CHRISTODOULOU C,GALLI G G G,et al.Hippo pathway activity influences liver cell fate[J].Cell,2014,157(6):1324-1338.
• [6]ZHAO B,WEI X,LI W,et al.Inactivation of YAP oncoprotein by the hippo pathway is involved in cell contact inhibition and tissue growth control[J].Genes&Development,2007,21(21):2747-2761
• [7]TANAKA I,OSADA H,FUJII M,et al.LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via hippo signaling cascade[J].Oncogene,2015,34(1):73-83
• [8]ZHAO H L,HAO F B,FU Z L,et al.Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors[J].Cancer Cell,2013,24(5):645-659.
• [9]JOHNSON R,HALDER G.The two faces of Hippo:targeting the Hippo pathway for regenerative medicine and cancer treatment[J].Nature Reviews Drug Discovery,2014,13(1):63-79.
• [10]PARK Y Y,SOHN B H,JOHNSON R L,et al.YES-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway of regulating amino acid transporters in hepatocellular carcinoma[J].Hepatology,2016,63(1):159-172.
• [11]王凯,李建远.Wnt/β-catenin信号通路与发育和疾病研究进展[J].中国医学创新,2012,9(11):160-161.
• [12]WHITTAKER S,MARAIS R,ZHU A X.The role of signaling pathways in the development and treatment of hepatocellular carcinoma[J].Oncogene,2010,29(36):4989-5005.
• [13]ZHOU D D,XIAO W,YANG W,et al.MicroRNA-145inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/β-catenin pathway[J].Molecular Immunology,2016,75(7):151-160.
• [14]LI W T,ZHU C L,LI Y,et al.ORiginal article:mest attenuates CCl4-induced liver fibrosis in rats by inhibiting the Wnt/B-Catenin signaling pathway[J].Gut&Liver,2014,8(3):282-291.
• [15]WENSONG G E,WANG Y,JIANXIN W U,et al.β-catenin is overexpressed in hepatic fibrosis and blockage of Wnt/β-catenin signaling inhibits hepatic stellate cell activation[J].Molecular Medicine Reports,2014,9(6):2145-2146.
• [16]金世龙,谢斌,刘宏鸣,等.siRNA对肝癌HepG2细胞β-catenin表达和细胞增殖的抑制作用[J].中华肝胆外科杂志,2009,15(12):921-923.
• [17]KATOH Y,KATOH M.Identification and characterization of rat Desert hedgehog and Indian hedgehog genes in silico[J].International Journal of Oncology,2005,26(2):545-546.
• [18]MICHELOTTI G A,XIE G,SWIDERSKA M,et al.Smoothened is a master regulator of adult liver repair[J].JClin Invest,2013,123(6):2380-2394.
• [19]CHUNG S I,MOON H,JU H L,et al.Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model[J].Journal of Hepatology,2016,64(3):618-619.
• [20]ZHANG F,HAO M,JIN H,et al.Canonical hedgehog signalling regulates hepatic stellate cell-mediated angiogenesis in liver fibrosis[J].British Journal of Pharmacology,2017,174(5):409-410.
• [21]樊雪强,陈新华,齐晓艳.靶向结缔组织生长因子的siRNA对于肝星状细胞介导肝纤维化的研究进展[J].中国医药导报,2012,35(9):58-60.
• [22]GEISLER F,STRAZZABOSCO M.Emerging roles of Notch signaling in liver disease[J].Hepatology,2015,61(1):382-392.
• [23]SUN L,LIU M,SUN G C,et al.Notch signaling activation in cervical cancer cells induces cell growth arrest with the involvement of the nuclear receptor NR4A2[J].Journal of Cancer,2016,7(11):1388-1395.
• [24]GEISLER F,STRAZZABOSCO M.Emerging roles of Notch signaling in liver disease[J].Hepatology,2015,61(1):382-392.
• [25]CHEN Y,ZHENG S,QI D,et al.Inhibition of notch signaling by aγ-secretase inhibitor attenuates hepatic fibrosis in rats[J].PLoS One,2012,7(10):e46512.
• [26]KAYLAN K B,ERMILOVA V,YADA R C,et al.Combinatorial microenvironmental regulation of liver progenitor differentiation by Notch ligands,TGF-β,and extracellular matrix[J].Scientific Reports,2016(6):23490.
• [27]ZHANG K,HAN X,ZHANG Z,et al.The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGF-βand Notch pathways[J].Nature Communications,2017,8(1)144-145.
• [28]慕永平,张笑,徐莹,等.Notch信号通路参与大鼠胆汁性肝纤维化肝祖细胞向胆管上皮细胞分化以及肝纤维化进展[J].中华病理学杂志,2017,46(6):400-405.
• [29]ZHANG X,DU G,XU Y,et al.Inhibition of notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes[J].Laboratory Investigation,2016,96(3):350-351.
• [30]吕磊,张岚.JAK/STAT信号通路在动脉粥样硬化中的作用[J].上海交通大学学报(医学版),2013,33(4):506-509.
• [31]王卫真,孟明辉,孔丽,等.Jak/Stat信号通路在经典CCl4大鼠肝纤维化模型中的动态变化及扶正化瘀方对其影响[J].临床肝胆病杂志,2014,30(4):344-348.
• [32]LYU X,ZHANG Y,CUI Y,et al.Inhibition of microRNA155 relieves sepsis induced liver injury through inactivating the JAK/STAT pathway[J].Molecular Medicine Reports,2015,12(4):6013-6014.
• [33]XU M Y,HU J J,SHEN J,et al.Stat3 signaling activation crosslinking of TGF-β1 in hepatic stellate cell exacerbates liver injury and fibrosis[J].Biochimica Et Biophysica Acta,2014,1842(11):2237.
• [34]ZHANG H,CHEN F,XU F,et al.Quantitative proteomic analysis on activated hepatic stellate cells reversion reveal STAT1 as a key regulator between liver fibrosis and recovery[J].Scientific Reports,2017,3(7):44910.