修回日期: 2008-03-03
接受日期: 2008-03-08
在线出版日期: 2008-03-28
经典Wnt信号转导通路的暂时激活在肝脏发育、出生后肝脏正常生长、肝细胞再生、肝小叶分带、肝脏代谢和氧化应激反应过程中发挥着重要作用, 研究显示这条通路异常持续激活与多种慢性肝病的进展显著相关. 近年来针对经典的Wnt信号通路在肝脏病理生理过程中的作用作了大量的研究, 并取得一些进展, 本文对此作一综述.
引文著录: 张影, 张福奎, 王宝恩. 经典Wnt信号通路与肝脏关系的研究进展. 世界华人消化杂志 2008; 16(9): 975-981
Revised: March 3, 2008
Accepted: March 8, 2008
Published online: March 28, 2008
A number of studies have demonstrated the important roles of canonical Wnt pathway in the essential physiologic processes in liver, such as development, growth, regeneration, zonation, metabolism, and oxidative stress. Likewise, there have been advances have been made in understanding the role of β-catenin in the development of various liver diseases. Studies of pathological specimens and rodent models of liver diseases have demonstrated aberrations in the canonical Wnt pathway in conditions ranging from hepatitis to hepatocellular carcinoma (HCC). In this article, we review the above roles of canonical Wnt pathway in liver health and diseases.
- Citation: zhang Y, Zhang FK, Wang BE. Advances in the relationship between canonical Wnt pathway and liver. Shijie Huaren Xiaohua Zazhi 2008; 16(9): 975-981
- URL: https://www.wjgnet.com/1009-3079/full/v16/i9/975.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v16.i9.975
经典Wnt信号通路也称为Wnt/β-catenin信号通路, 这条通路激活后将募集细胞内β-catenin, 后者活化转移入细胞核, 与转录因子LEF/TCF等共同作用激活特异基因的转录. 经典的Wnt信号转导通路的暂时激活在肝脏发育、出生后肝脏正常生长、肝细胞再生、肝小叶分带、肝脏代谢和氧化应激反应过程中发挥着重要作用, 研究显示这条通路异常持续激活与多种慢性肝病的进展显著相关. 近年来针对经典的Wnt信号通路在肝脏病理生理过程中的作用, 作了大量的研究, 取得了一些进展, 现综述如下.
激活经典的Wnt信号通路在器官发育和胚胎轴分化过程中发挥着重要作用. Haegel et al[1]发现β-catenin基因敲除小鼠的胚胎中, 一些表达前后轴极化标志分子的前端内脏内胚层细胞错误地定位在远端内脏内胚层, 而不是重新定位在前端, 从而不能形成中胚层和外胚层, 导致胚胎在形成后的d 7死亡. 因此, β-catenin是小鼠胚胎发育的两个早期阶段, 即前后轴形成和中胚层诱导不可缺少的条件[2-6]. 人类肝脏的发生始于受孕后的wk 3-4, 小鼠肝脏的发生始于受孕后的d 9, 由前肠内胚层发育而来. 该内胚层细胞首先形成肝原基, 然后由来源于中胚层的间充质细胞诱导发育成为肝细胞, 之后, 成肝细胞经过增殖和功能分化而发育成胆管谱系和肝细胞谱系的细胞. 在肝脏发生的不同阶段, 特异性基因表达不同, 受来自中胚层信号调控. 实验证明成纤维细胞生长因子和骨形态形成蛋白对肝脏发生起重要作用, 而他们都是经典Wnt信号通路的下游靶基因[7]. 研究发现斑马鱼肝脏发育期间, 中胚层Wnt2b信号通路被激活, 说明了Wnt信号通路在正向调控斑马鱼肝脏诱导分化过程中发挥着重要作用[8]. Micsenyi et al[9]发现在胚胎10-14 d, 胚胎肝细胞高水平表达β-catenin并且伴有胞质和核内累积, 与细胞增殖显著相关. 将胚胎10 d的肝脏与反义β-catenin基因寡核苷酸片段培养发现, β-catenin表达、细胞增殖和生存率显著降低[10]. 相反, 发育肝脏内持续激活β-catenin过度表达, 导致肝脏大小增加3倍和肝细胞前体细胞群扩大[11]. Cyclin D1介导了肝脏发育过程中的细胞增殖, Cyclin D1是β-连环蛋白在细胞核内激活的下游靶基因, 当β-连环蛋白在胞质累积时, β-连环蛋白蛋白转位入细胞核内, 与T细胞转录子Tcf结合, 激活CyclinD1基因转录, 而Cyclin D1是细胞周期增殖信号的关键蛋白, 为细胞周期从G1期到S期转换所必需的, Cyclin D1过度表达可促进细胞增殖[12], 因此, β-catenin通过共同转录激活作用对发育早期的肝细胞增殖起了重要作用. 在胚胎15 d后, 总β-catenin显著降低, 表达主要位于肝细胞膜. β-catenin在肝细胞膜上与E-cadherin、Met连接形成功能复合体, 这是肝细胞成熟和极性获得的标志, 反义β-catenin基因敲除维持胚胎肝细胞未分化表型, 持续表达干细胞和成熟肝细胞标记物[13]. 基质胶诱导原代肝细胞分化过程中, β-catenin是稳定的, 核内累积的减少, 同时与Met形成复合物, 说明肝细胞成熟可能是β-catenin介导的细胞-细胞黏附作用与他的转录辅助因子共同作用的结果[14]. 两项研究显示肝脏发育期间, β-catenin促进胆系分化, 胆管结构形成. 反义β-catenin基因敲除小鼠胚胎10 d肝脏培养发现, CK-19阳性细胞增殖能力丧失, 细胞凋亡增加. 相反, 小鼠胚胎肝组织在含有Wnt3a无血清条件培养基中培养, CK-19阳性细胞的生存和增殖能力增加[8,15]. 这些研究表明, 经典的Wnt信号通路在肝脏早期发育过程中起重要作用.
出生后的mo 1, 肝脏生长迅速. Apte et al[16]通过对CD-1小鼠出生后0, 30 d和3 mo肝脏发育的研究发现, 从出生后d 5-20, 发育肝脏内总β-catenin和激活的β-catenin蛋白水平显著增加, β-catenin-Tcf复合物也增加, 并伴有胞质和核内β-catenin累积, 肝细胞增殖率显著增加, 这是因为GSK3β失活, 酪氨酸蛋白激酶1α抑制及β-catenin基因表达暂时增加激活β-catenin所致. 对肝脏特异性β-catenin基因敲除的研究发现, 出生后30 d肝脏明显变小, 肝细胞增殖能力下降, 说明激活β-catenin对出生后肝脏的生长和发育是至关重要的. 过度表达稳定突变或全长β-catenin基因的小鼠的肝脏大小增加了3-4倍或15%, 这与肝细胞增殖能力显著增加有关. 条件性β-catenin基因敲除小鼠显示出生后mo 1肝脏大小明显减小, Cyclin D1表达显著减少, 肝细胞的增殖能力明显降低, 这些研究说明经典的Wnt信号通路在出生后早期正常肝脏生长中的重要作用[17-18].
Monga et al[19]为了研究大鼠肝再生期间经典Wnt信号通路的变化, 建立70%肝切除大鼠肝再生模型, 通过Western-blot分析、免疫沉淀检测和免疫荧光染色发现, Wnt-1和β-catenin蛋白表达主要位于肝细胞, 肝切除后5 min内伴随着核转录, β-catenin开始增加, 这与β-catenin降解减少相关; 同时还发现由APC、丝氨酸磷酸化的AXIN蛋白组成的β-catenin降解复合物在肝切除5 min后激活, 导致β-catenin降解增加, β-catenin开始减少, 研究同时发现在β-catenin开始增加时, E-cadherin下降, 而当β-catenin下降时, E-cadherin开始增加, 说明肝再生早期经典的Wnt信号通路通过严格调控胞质内β-catenin表达水平, 诱导肝细胞增殖和下游靶基因的表达. Sodhi et al[20]通过对反义β-catenin基因敲除大鼠2/3肝切除后24 h和7 d的研究发现, 肝切除24 h, 总β-catenin减少, 肝细胞增殖能力下降, 24 h和d 7肝脏质量/体质量显著下降, 下游靶及基因c-myc和uPAR的表达显著减少, 而cyclinD1的表达保持不变, 说明β-catenin在肝再生早期起着质量要作用, c-myc和uPAR是下游重要的靶基因. HGF信号通路也在早期肝再生过程中发挥着重要作用, Pediaditakis et al[21]研究发现肝再生早期, HGF水平和活性均增加, 导致β-catenin/Met复合体分离, 肝细胞再生, HGF/Met和经典Wnt信号通路均参与了早期肝再生, 二者可能存在crosstalk. Apte et al[22]为了研究这两个信号通路是否存在相互对话(crosstalk), 将人HGF基因导入正常大鼠体内, 使其过表达, 1 wk和4 wk的研究发现, 肝脏体积增大, 1 wk时Western-blot检测激活的β-catenin显著增加, 总GSK3β轻度增加, Ser45/Thr41磷酸化β-catenin(非激活状态)显著减少, 1 wk时免疫沉淀分析发现90% β-catenin/Met复合体解聚, 而β-catenin/E-cadherin复合体保持不变, 说明短期内HGF诱导β-catenin激活的机制是β-catenin/Met复合体解聚, 激活β-catenin. 4 wk时Western-blot检测ser37磷酸化β-catenin减少, 激活的β-catenin增加, 免疫沉淀分析β-catenin/E-cadherin复合体显著增加, 而β-catenin/Met复合体保持不变, 说明HGF诱导β-catenin长期激活是通过经典方式激活, 肝脏特异β-catenin基因敲除的部分肝脏切除的大鼠, 肝脏体积明显减小, 而将人HGF基因转入后仍不能诱导肝细胞再生, 这个研究说明β-catenin是HGF信号通路下游重要的效应基因, 这两条信号通路存在crosstalk, HGF通过激活β-catenin诱导了肝细胞再生. Tan et al[23]对条件性β-catenin基因敲除小鼠2/3肝切除模型的研究发现, 切除后肝再生高峰发生延迟了24 h, 肝细胞增殖在72 h后开始增加, 研究说明β-catenin参与早期肝再生, 能够触发一个成功肝再生所必须的级联反应.
肝小叶内的肝细胞由于所在位置、接受门静脉和肝动脉血的先后不同, 其功能特点、细胞形态和细胞化学方面有所差异. 自肝小叶周边至中央可将其大致划分为3带: 即周围带、中间带和中央带. 这3个功能带表达不同的特异性蛋白并且参与不同代谢活动, 但参与维持肝小叶分带的信号通路目前仍不清楚. Benhamouche et al[24]报道β-catenin和APC的相互作用对肝小叶分带起重要作用, 门脉周围肝细胞主要表达APC基因, 激活的β-catenin表达较少; 相反在中央静脉周围肝细胞APC基因表达缺乏, 激活的β-catenin表达相对较高, 并伴有下游靶基因的表达. APC基因敲除后, 门脉周围肝细胞的基因表达特 征与中央静脉周围相似, 这说明APC是肝小叶分带的重要调控基因. 通过对转基因和基因敲除的小鼠研究发现, 参与谷氨酰胺代谢编码谷氨酰胺合成酶、鸟氨酸氨基转移酶和谷氨酸转运体GLT-1的三个基因均是经典Wnt信号通路的下游靶基因, 中央静脉周围肝细胞在谷氨酰胺合成过程中发挥重要作用, 因为这个功能带肝细胞内β-catenin高度激活, 而在门脉周围的肝细胞则对尿素的形成起重要作用[25-26].
Funato et al[27]最近报道了氧应激与经典的Wnt信号通路之间存在重要联系. Essers et al[28]对C.elegans的研究已经明确了作为氧应激的保护反应, β-catenin直接与FOXO转录因子结合, 增强FOXO的转录活性, 调控细胞周期, 激活FOXO垂直同源基因DAF-16下游靶基因sod3表达, 从而减轻氧应激对肝脏的损害, β-catenin基因敲除抑制FOXO转录因子活性, 说明β-catenin调控FOXO转录因子活性, 从而减轻氧应激对肝脏的损害. 研究已经证实β-catenin调控许多肝脏内调控氧应激反应的基因, 包括CYP2e1、CYP1a2和S-谷胱甘肽转移酶. 氧应激参与了多种肝脏疾病的形成, 例如, 酒精性和非酒精性脂肪性肝炎, 明确氧应激在这些肝脏疾病中的作用, 将有助于更好的理解经典的Wnt信号通路对这个过程的影响[29-34].
肝纤维化是指肝脏内弥漫性的、过量的细胞外基质沉积, 他不是一个独立的疾病, 而是许多慢性肝病的共同病理过程. 肝脏星状细胞(hepatic stellate cell, HSC)激活是肝纤维化发生的中心环节. 近年来一些研究开始关注经典的Wnt信号通路在HSC激活过程中的作用, 不同研究结果争议较大. Higashi et al[35]为了研究HSC细胞间连接, 体外培养人和大鼠的HSC, Western blot检测到作为细胞间连接主要组成部分的β-catenin的表达, 免疫荧光染色也检测到β-catenin, 双重染色确定β-catenin主要表达在细胞间连接, 说明β-catenin参与HSC细胞间连接的形成, Sodhi et al建立大鼠2/3肝切除正常肝再生模型, 取切除后48 h的肝组织经免疫荧光染色确定HSC胞质及核内有β-catenin表达, 说明正常肝再生过程中, β-catenin可能参与了HSC的活化和增殖[20]. Myung et al[36]将LX-2细胞培养至5×104个加入Wnt3a条件培养基中继续培养24 h, collagen α1和α-SMA的表达显著增加, 而加入Wnt3a的抑制蛋白sFRP后, Collagen α1和α-SMA显著降低, 这项研究说明经典的Wnt信号通路通过激活HSC参与了肝纤维化的形成. 与上述结果不同, Jiang et al[37]提取静止和激活的大鼠HSC的RNA进行DNA点阵分析发现, 非经典Wnt信号通路的Wnt受体Frizzed2、配体Wnt4和Wnt5基因上调, 为了验证在体内的表达, 通过4 wk CCl4 ip建立大鼠肝纤维化模型, RT-PCR检测Wnt受体Frizzed2、配体Wnt4和Wnt5基因显著增加, 而Western blot未检测到激活的β-catenin, 这些结果表明非经典的Wnt信号通路诱导静止的HSC的基因和表型发生改变, 激活成为肌成纤维样细胞, 因此认为激活非经典的Wnt信号通路在肝纤维化形成过程中起重要作用. Zeng et al[38]研究发现无论是静止的还是激活的HSC或Kupffer细胞, Wnt和Frizzed基因的表达无显著性差异; 但sFRP-1只出现在激活的HSC或Kupffer细胞内, 说明sFRP-1调控HSC或Kupffer细胞激活过程中Wnt信号通路. 这些研究尽管结果不同, 但仍不难看出Wnt信号通路与肝纤维化形成具有一定的相关性, 这有待将来进一步研究阐明以便为肝纤维化的治疗提供新的治疗靶点.
异常激活的经典Wnt信号通路参与多个组织肿瘤的形成, 包括脑、乳腺、结肠、皮肤和肝[39-49]. 在肝脏, β-catenin与肝母细胞瘤、肝细胞癌和胆管细胞癌的发生密切相关[50-59]. (1)肝母细胞瘤: 肝母细胞瘤是儿童中最常见的肝脏恶性肿瘤, FAP患者发病率最高. 肝母细胞瘤患者当中, 无论家族性的还是散发的, 核和胞质β-catenin累积的发生率为90%-100%, 这主要是因为APC、β-catenin、Axin1和Axin2基因突变所致, 明确了经典Wnt信号通路在肝母细胞瘤发生中的作用[60]. 然而, 出生后肝脏生长期间激活经典Wnt信号通路是正常的, 因此应进一步研究在肝母细胞瘤患者当中, 是激活β-catenin导致肝母细胞瘤的发生, 还是仅仅就是巧合. (2)肝腺瘤: 经典的Wnt信号通路参与了一些少见的肝脏良性肿瘤恶变的发生, 肝腺瘤患者当中β-catenin胞质和核内累积占30%, 12%肝腺瘤患者伴有β-catenin基因突变, 这些患者当中, 46%会进展为肝细胞癌(hepatocellular carcinoma, HCC), 这说明了异常激活的经典的Wnt信号通路是发生HCC的一个重要步骤[61-62]. (3)HCC: 20%-90% HCC患者显示经典的Wnt信号通路持续激活, 这是由于β-catenin、AXIN-1、AXIN-2基因突变以及Frizzed7受体基因上调和GSK3β失活所致[63-64]. 肝脏特异性APC基因敲除的小鼠可以诱导β-catenin核转录, 激活经典Wnt信号通路, 从而增加HCC的发生[65]. 过度表达c-myc和TGF-β的转基因肝癌小鼠模型显示β-catenin基因突变和发生核转录. 通过对过度表达c-myc和TGF-β的转基因肝癌小鼠的研究发现, β-catenin激活可以促进肿瘤的生长和转移[66]. β-catenin和H-ras基因突变的小鼠HCC发生率为100%[67]. 这些研究说明β-catenin激活可能是HCC发生的触发或促进因素. 在HBV阳性的HCC患者当中, HBx蛋白与E-cadherin表达减少和β-catenin胞质或核累积密切相关, 同时这项研究还发现HBV编码的X抗原效应子URG11上调导致β-catenin的激活, 这说明HBV通过多种方式调控β-catenin[68]. 在HCV阳性的HCC患者当中β-catenin基因突变频率是其他原因引起HCC的2倍. 而Kutomi et al通过将HCV核心蛋白构建质粒转染Huh-7细胞系使其过度表达HCV核心蛋白后发现, Huh-7细胞增殖、DNA合成和细胞周期进展显著增加, 相反, 通过RNA干扰阻断Wnt1后, Huh-7细胞增殖、DNA合成和细胞周期进展显著下降, 说明HCV核心蛋白通过激活经典Wnt信号通路诱导了肿瘤细胞的增殖[69]. 一项研究发现进行抗病毒治疗的HCV患者HCC的发生率显著下降, 尽管这可能是归因于抗病毒治疗减少了病毒载量, 但这些抗病毒药物也非常可能调控经典的Wnt信号转导效应, 从而减少了HCC的发生, 这需要进一步研究[70]. (4) 胆管癌: 一些研究已经证实异常激活的经典的Wnt信号通路与胆管癌的一个亚型发生密切相关, 细胞膜上β-catenin/E-cadherin复合体减少, 同时出现β-catenin核转录, 这与组织学上低分化相关. 尽管与β-catenin基因突变仅仅出现在一小部分胆管癌患者当中, 但仍应进一步研究是否是酪氨酸磷酸化依赖的β-catenin激活或Wnt/frizzed功能失调所致以阐明β-catenin在胆管癌形成过程中的真正作用[71].
总之, 关于对经典Wnt信号通路在肝脏中作用的研究, 尚有许多基础机制需要阐明, 有许多问题需要探讨. 越来越多的研究证实了经典的Wnt信号通路在肝脏生理和病理中的重要地位和作用. 随着对经典Wnt信号通路进一步深入研究, 相信以经典Wnt信号通路为靶点的治疗将改善慢性肝病患者的预后.
经典Wnt信号转导通路在肝脏病理生理过程中发挥着重要作用. 越来越多的研究证实经典Wnt信号通路在肝脏生理和病理中的重要地位和作用. 随着对经典Wnt信号通路进一步深入研究, 相信以经典Wnt信号通路为靶点的治疗将改善慢性肝病患者的预后.
张吉翔, 教授, 南昌大学第二附属医院消化内科.
关于对经典Wnt信号通路在肝脏中作用的研究, 尚有许多基础机制需要阐明, 有许多问题需要探讨.
随着对经典Wnt信号通路进一步深入研究, 以经典Wnt信号通路为靶点的治疗将改善慢性肝病患者的预后.
经典Wnt信号转导通路: 也称为Wnt/β-catenin信号通路, 这条通路激活后将募集细胞内β-catenin, 后者活化转移入细胞核, 与转录因子LEF/TCF等共同作用激活特异基因的转录.
本文对经典Wnt转导通路在胎儿肝脏发育、出生后肝脏的生长和某些肝疾病中的作用进行系统综述, 参考文献较新, 是一篇质量较高的文章. 本文对经典Wnt转导通路在胎儿肝脏发育、出生后肝脏的生长和某些肝疾病中的作用进行系统综述, 参考文献较新, 是一篇质量较高的文章.
编辑:李军亮 电编:吴鹏朕
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