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        肝細(xì)胞核因子4α與肝細(xì)胞癌關(guān)系的研究進(jìn)展

        2018-03-07 21:29:58紀(jì)龍珊孫學(xué)華周振華
        關(guān)鍵詞:肝細(xì)胞癌基因工程調(diào)節(jié)

        紀(jì)龍珊+孫學(xué)華+周振華

        [摘要] 肝細(xì)胞核因子4α(HNF4α)是調(diào)節(jié)肝臟內(nèi)特異性基因表達(dá)的轉(zhuǎn)錄因子,在肝細(xì)胞發(fā)育分化,肝臟脂質(zhì)、膽固醇代謝及肝臟藥物代謝中起重要作用,并且抑制肝臟腫瘤的發(fā)生。HNF4α主要通過(guò)抑制腫瘤細(xì)胞增殖,促進(jìn)腫瘤細(xì)胞分化、凋亡,逆轉(zhuǎn)肝細(xì)胞上皮-間質(zhì)轉(zhuǎn)化等過(guò)程,影響肝細(xì)胞癌(HCC)的發(fā)生發(fā)展。本文對(duì)HNF4α的來(lái)源分布、結(jié)構(gòu)特點(diǎn)、生物學(xué)功能及其在HCC發(fā)生發(fā)展中的作用進(jìn)行了系統(tǒng)綜述,旨在探索HNF4α干預(yù)HCC的新思路。

        [關(guān)鍵詞] 肝細(xì)胞核因子4α;肝細(xì)胞癌;調(diào)節(jié);基因工程

        [中圖分類(lèi)號(hào)] R575 [文獻(xiàn)標(biāo)識(shí)碼] A [文章編號(hào)] 1673-7210(2018)01(b)-0032-04

        [Abstract] Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that regulates the expression of specific genes in the liver, plays an important role in hepatocyte developmental and differentiation, liver lipid and cholesterol metabolism, liver drug metabolism and inhibits the formation of liver tumor. HNF4α mainly affects the formation and development of hepatocellular carcinoma (HCC) by inhibiting the proliferation of tumor cells, promoting the differentiation and apoptosis of tumor cells, reversing the processes of hepatocyte epithelial-mesenchymal transition. In this paper, the origin, distribution, structural characteristics, biological function of HNF4α and the role of HNF4α in the formation and development of HCC were reviewed in order to explore a new approach to HNF4α intervening in HCC.

        [Key words] Hepatocyte nuclear factor 4α; Hepatocellular carcinoma; Regulation; Genetic engineering

        肝細(xì)胞核因子4(hepatocyte nuclear factor 4,HNF4)是1990年Sladek等[1]從大鼠肝臟中發(fā)現(xiàn)的,屬類(lèi)固醇激素受體超家族成員。其DNA結(jié)合活性與α1-抗胰蛋白酶、載脂蛋白A1和丙酮酸激酶基因轉(zhuǎn)錄調(diào)控有關(guān)。HNF4包括HNF4α、HNF4β、HNF4γ和變異剪切體,與肝臟疾病相關(guān)的HNF4分子主要是HNF4α。本文就HNF4α的來(lái)源分布、結(jié)構(gòu)特點(diǎn)、生物學(xué)功能,及其與肝細(xì)胞癌(hepatocellular carcinoma,HCC)關(guān)系的研究進(jìn)展進(jìn)行綜述。

        1 HNF4α來(lái)源及分布

        HNF4來(lái)源于胚泡的原始內(nèi)胚層,可持續(xù)表達(dá)于卵黃囊內(nèi)臟內(nèi)胚層。HNF4α在胚胎肝臟發(fā)育形成的第8天即可檢測(cè)到,其成體表達(dá)于肝臟、腎臟、胰腺、小腸、結(jié)腸以及睪丸中,在分化成熟的肝細(xì)胞高表達(dá),與肝特異基因的表達(dá)密切相關(guān)[2]。

        2 HNF4α的結(jié)構(gòu)特點(diǎn)

        人HNF4α編碼基因位于20號(hào)染色體長(zhǎng)臂(20q13.12)。HNF4α含“鋅指結(jié)構(gòu)”,其蛋白質(zhì)三級(jí)結(jié)構(gòu)由6個(gè)功能性結(jié)構(gòu)域(A-F)組成[3]:A/B區(qū)(N端),包含激活結(jié)構(gòu)域1(activation function domain1,AF1),其與啟動(dòng)子特殊序列密切相關(guān);C區(qū)含高度保守的“鋅指結(jié)構(gòu)”,與D區(qū)(鉸鏈區(qū))結(jié)合,形成可與靶基因特殊DNA序列激素反應(yīng)元件結(jié)合的DNA結(jié)合域;E區(qū)為多功能配體結(jié)合域,包括激活功能域AF2和配體結(jié)合域;F區(qū)(C端)是特異性配體結(jié)合區(qū),為HNF4α所獨(dú)有。

        HNF4α有?;o酶A和游離脂肪酸兩個(gè)配體結(jié)合位點(diǎn),分別以不同模式調(diào)節(jié)HNF4α的轉(zhuǎn)錄活性。HNF4α可由多種途徑調(diào)控激活,如磷酸化、乙?;痆4]或與細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)蛋白4[5]結(jié)合等,與啟動(dòng)子序列結(jié)合形成同源二聚體,調(diào)節(jié)染色體結(jié)構(gòu),激活靶基因的表達(dá)[6]。

        3 HNF4α的生物學(xué)功能

        Odom等[7]通過(guò)定位分析肝細(xì)胞中的HNFs基因組發(fā)現(xiàn):HNF4α與人基因啟動(dòng)子區(qū)域的基因結(jié)合的比例高達(dá)12%,其中,RNA聚合酶Ⅱ結(jié)合基因中有41%與HNF4α結(jié)合,說(shuō)明HNF4α調(diào)控著大部分肝細(xì)胞基因的轉(zhuǎn)錄,與肝臟關(guān)系密切。

        3.1 肝臟發(fā)育分化、表型維持及肝細(xì)胞極化

        Parviz等[8]研究發(fā)現(xiàn),HNF4α表達(dá)缺失的小鼠肝細(xì)胞縮小,胞漿含量少、染色深,細(xì)胞核畸形并充滿異染色質(zhì),與細(xì)胞連接有關(guān)的蛋白分子表達(dá)缺失,細(xì)胞失去連接結(jié)構(gòu),細(xì)胞間出現(xiàn)異??障?,無(wú)法形成肝竇狀隙等結(jié)構(gòu),表明HNF4α對(duì)肝上皮的發(fā)育和肝臟形態(tài)的發(fā)生是必不可少的。應(yīng)用轉(zhuǎn)基因技術(shù)將HNF4α轉(zhuǎn)入人骨髓間充質(zhì)干細(xì)胞[9],或?qū)⒈磉_(dá)HNF4α和HNF?4α shRNA的重組腺病毒轉(zhuǎn)染大鼠肝星狀細(xì)胞[10],均可誘導(dǎo)特定細(xì)胞為成熟的肝細(xì)胞樣細(xì)胞(hepatocyte-like cell,iHep cell),這些分化的iHep cell具有典型的上皮細(xì)胞形態(tài),表達(dá)肝細(xì)胞功能。在HNF4α表達(dá)缺失的小鼠中,組蛋白的甲基化和乙?;揎椄用黠@,這些修飾間接地影響肝臟表型相關(guān)因子的表達(dá),導(dǎo)致肝細(xì)胞表型的改變,表明HNF4α可能是肝臟表觀遺傳修飾的主要協(xié)調(diào)者[11]。在肝細(xì)胞極化方面,Chiba等[12]發(fā)現(xiàn)HNF4α可參與肝細(xì)胞頂端極的形成,加速肝細(xì)胞膽小管微絨毛的形成。以上表明,HNF4α是肝細(xì)胞發(fā)育和分化,肝細(xì)胞表型維持以及肝細(xì)胞極化結(jié)構(gòu)形成的重要轉(zhuǎn)錄因子。endprint

        3.2 肝臟脂質(zhì)和膽固醇代謝

        Yin等[13]發(fā)現(xiàn),HNF4α缺失致使脂質(zhì)代謝的多個(gè)基因失調(diào),HNF4α基因敲除的小鼠脂質(zhì)代謝嚴(yán)重障礙,表明HNF4α是維持正常的脂質(zhì)代謝必不可少的轉(zhuǎn)錄因子。HNF4α可能通過(guò)上調(diào)磷脂酶A2 GXIIB[14]或下調(diào)膽固醇?;D(zhuǎn)移酶2[15]和三磷酸腺苷-結(jié)合轉(zhuǎn)運(yùn)子A1[16]等的表達(dá)調(diào)節(jié)肝臟脂質(zhì)和膽固醇的正常代謝。

        3.3 肝臟藥物代謝

        CYP3A4是細(xì)胞色素P450的重要亞族,參與50%以上臨床用藥的Ⅰ相代謝,是肝臟中最多的藥物代謝酶。孕烷X受體(Progesterone X Receptor,PXR)與結(jié)構(gòu)性雄烷受體共同調(diào)節(jié)CYP3A4的表達(dá)。Kamiya等[17]研究證實(shí),HNF4α與PXR啟動(dòng)子結(jié)合可激活胚胎肝細(xì)胞中PXR。Tirona等[18]發(fā)現(xiàn)HNF4α通過(guò)與CYP3A4基因增強(qiáng)子上的順式作用元件結(jié)合,調(diào)節(jié)CYP3A4的活化。此外,HNF4α也可激活藥物代謝酶CYP2A8、CYP2B6、CYP2D6、CYP3A5、CYP8B1以及藥物代謝酶膽鹽磺基轉(zhuǎn)移酶2A1[19]。有研究發(fā)現(xiàn),在HNF4α表達(dá)缺失的大鼠肝內(nèi),藥物代謝和解毒相關(guān)基因如多藥耐藥基因B1、ABC?B11、三磷酸腺苷-結(jié)合轉(zhuǎn)運(yùn)子C2等的表達(dá)下降。由此可見(jiàn)HNF4α對(duì)肝臟藥物代謝的重要性。

        4 HNF4α與HCC的關(guān)系

        Lazarevich等[20]發(fā)現(xiàn),快速生長(zhǎng)的去分化變體HCC細(xì)胞(fast-growing dedifferentiated variant,fgHCC)中HNF4α表達(dá)增強(qiáng)后,fgHCC侵襲性降低,增殖速度減慢,成熟肝細(xì)胞的結(jié)構(gòu)和功能恢復(fù);該細(xì)胞移植在同源小鼠中不形成腫瘤,表明HNF4α發(fā)揮強(qiáng)有力的抗腫瘤作用。研究認(rèn)為HNF4α主要通過(guò)抑制腫瘤細(xì)胞增殖,促進(jìn)腫瘤細(xì)胞分化、凋亡,逆轉(zhuǎn)肝細(xì)胞上皮-間質(zhì)轉(zhuǎn)化(epithelial- to-mesenchymal transition,EMT)等過(guò)程,影響HCC的發(fā)生發(fā)展?,F(xiàn)將HNF4α調(diào)控HCC發(fā)生發(fā)展的機(jī)制研究總結(jié)如下。

        4.1 抑制腫瘤細(xì)胞增殖,促進(jìn)腫瘤細(xì)胞分化和凋亡

        研究發(fā)現(xiàn)YAP1-TEAD4可誘導(dǎo)HCC細(xì)胞增殖和分化,在HCC細(xì)胞中YAP1通過(guò)泛素-蛋白酶體途徑抑制HNF4α表達(dá),而HNF4α通過(guò)與YAP1競(jìng)爭(zhēng)性結(jié)合TEAD4,抑制YAP1-TEAD4的轉(zhuǎn)錄激活及其靶基因的表達(dá),YAP1-TEAD4與HNF4α通過(guò)雙向負(fù)反饋機(jī)制調(diào)控HCC細(xì)胞的增殖和分化[21]。細(xì)胞凋亡信號(hào)調(diào)節(jié)激酶1(apoptosis signal regulated kinase,ASK1)是參與細(xì)胞凋亡的死亡受體,是HCC的抑制基因,但在HCC中表達(dá)下降,HNF4α與ASK1啟動(dòng)子直接結(jié)合,激活并促進(jìn)ASK1表達(dá),抑制HCC發(fā)生發(fā)展并抑制HCC惡化[22]。鄧龍飛等[23]通過(guò)構(gòu)建質(zhì)粒pET28a-P-HNF4α,利用細(xì)胞穿膜肽PEP-1成功介導(dǎo)融合蛋白P-HNF4α進(jìn)入Huh7細(xì)胞并定位于細(xì)胞核;P-HNF4α蛋白可促進(jìn)Huh7細(xì)胞肝功能基因表達(dá),誘導(dǎo)HCC細(xì)胞向成熟肝細(xì)胞分化,并顯著抑制HCC細(xì)胞增殖、遷移和侵襲,降低HCC細(xì)胞的惡性程度。mir-548p是HBx相關(guān)的HCC抑癌基因,mir-548p通過(guò)與HBXIP mRNA3′端-非翻譯區(qū)結(jié)合,抑制HBXIP蛋白表達(dá);而HNF4α促進(jìn)mir-548p表達(dá)的同時(shí)被HBx抑制,由此形成HBx/HNF4α/mir-548p/HBXIP通路抑制HCC細(xì)胞增殖,促進(jìn)HCC細(xì)胞凋亡[24]。

        4.2 逆轉(zhuǎn)肝細(xì)胞EMT過(guò)程

        有研究發(fā)現(xiàn),HNF4α是肝臟microRNAs(如miR-192、miR-193a、miR-194和mir-802)表達(dá)必不可少的因子[25]。Mir-122是肝臟特異性的microRNA,受HN?F1α、HNF3α、HNF3β、HNF4α、HNF6、C/EBPα等轉(zhuǎn)錄因子調(diào)控,抑制HCC細(xì)胞侵襲、轉(zhuǎn)移,但在HCC中表達(dá)下調(diào);HNF4α可通過(guò)保守的DR-I元件結(jié)合至mir-122啟動(dòng)子區(qū),正向調(diào)控其表達(dá)[26-28]。HNF4α通過(guò)上調(diào)靶基因miR-122[29],或與β-catenin競(jìng)爭(zhēng)性結(jié)合T淋巴細(xì)胞因子[30],募集轉(zhuǎn)錄抑制因子與Wnt靶基因啟動(dòng)子結(jié)合,抑制Wnt-β-catenin信號(hào)通路激活,從而逆轉(zhuǎn)EMT過(guò)程。同時(shí),HNF4α可將β-catenin從細(xì)胞核內(nèi)移至細(xì)胞膜上,參與上皮細(xì)胞間的黏附連接,增強(qiáng)細(xì)胞的上皮表型,逆轉(zhuǎn)EMT過(guò)程,促進(jìn)肝細(xì)胞間質(zhì)-上皮轉(zhuǎn)變[31-32]。

        5 小結(jié)

        綜上所述,HNF4α是抑制肝臟腫瘤的重要轉(zhuǎn)錄因子,利用基因工程手段或轉(zhuǎn)染技術(shù)誘導(dǎo)相關(guān)細(xì)胞分化為iHep cell,有望成為治療HCC的有效手段。進(jìn)一步深入研究HNF4α的功能及其調(diào)控HCC的分子機(jī)制,全面揭示HNF4α與HCC的關(guān)系,是未來(lái)攻克HCC的新方向。

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        (收稿日期:2017-09-14 本文編輯:李岳澤)endprint

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