临床医学进展  >> Vol. 11 No. 2 (February 2021)

FOXF2基因在肿瘤中的研究进展
Research Progress on FOXF2 Gene in Tumors

DOI: 10.12677/ACM.2021.112109, PDF, HTML, XML, 下载: 40  浏览: 101 

作者: 陈 勍:复旦大学附属中山医院骨科,上海;曹炎焱:复旦大学附属中山医院核医学科,上海

关键词: FOXF2转录因子转移肿瘤FOXF2 Transcription Factor Metastasis Tumor

摘要: 叉头盒蛋白F2 (FOXF2)是叉头/有翼螺旋家族的转录因子,参与正常的胚胎发育并调节多器官的发育和功能。最近的研究揭示了FOXF2在肿瘤中的发展和转移中起着抑制肿瘤增殖、迁移和侵袭的作用,但对其确切的潜在作用机制知之甚少。本文对FOXF2在肿瘤发生和发展中的功能和调控机制进行综述。
Abstract: Forkhead box protein F2 (FOXF2), a transcription factor of the forkhead/winged-helix family, is required for mesenchymal lineage specification and organ development during normal embryogenesis. Recent studies have revealed that FOXF2 plays a novel role in the development and metastasis of tumors, but very little is known about its exact potential mechanisms. This review summarizes the function and regulatory mechanisms of FOXF2 in tumorigenesis and progression.

文章引用: 陈勍, 曹炎焱. FOXF2基因在肿瘤中的研究进展[J]. 临床医学进展, 2021, 11(2): 763-772. https://doi.org/10.12677/ACM.2021.112109

1. 引言

FOX基因最初是在果蝇中进行随机诱变筛选后克隆出的一类叉头基因(Forkhead),其功能对胚胎正常发育和组织分化中起至关重要的作用 [1]。人类FOX基因家族目前有19个亚族,由200个成员组成,命名从FOXA1至FOXS1。FOX基因家族主要编码蛋白为生物进化上的转录因子 [2],其功能涵盖通过与特定的DNA序列(启动子或增强子)结合来控制DNA向信使RNA的遗传信息的转录速率,充当下游基因精细调控的激活物和阻遏物,同时FOX蛋白负责胚胎发育各个阶段基因的表达的微调以及体内的监测保护,另外还作为多种网络的活性调节剂参与其他生物功能诸如细胞衰老、细胞周期进展、DNA损伤反应、免疫应答以及细胞代谢等 [3] [4]。最近越来越多的研究证实FOX基因家族的成员FOXF2与肿瘤的发生及转移具有相关性,并且在多水平、多层次上调控肿瘤的发生发展,包括DNA水平、RNA水平、蛋白表达水平和蛋白质的相互作用,同时参与多种信号通路。因此,FOXF2作为一种转录因子可能成为肿瘤治疗的有效标志物和治疗的有效靶点。

2. FOX基因家族与FOXF2结构

FOX家族是具有高保真DNA区域和组织特异性表达特点的基因家族,叉头框为含有约100个氨基酸的DNA结合域,具有高度的保守性,因其核心部分含有α螺旋排列和β链故被称为翼状螺旋蛋白。FOX蛋白通过其叉头结构域将基因组DNA作为单体结合,以转录调节其靶基因。FOX蛋白的生物学功能主要在胚胎的形成及发育和调控细胞的生长分化中有着重要的作用,如果其下游蛋白的异常表达可能会导致胚胎的发育不良,发育畸形以及肿瘤的发生。Pierrou [5] 在1994年最早发现FOXF2,如图该基因位于人类染色体6p25.3 [6] [7] [8],编码同族FOXF2转录因子,其结构具有1个DNA结合结构域和两种DNA激活结构域分别为:1个AD1激活结构域和2个AD2激活结构域。FOXF2在邻近上皮细胞的间充质细胞中表达,并且在胚胎发生和组织发育过程中具有组织特异性,基因表达模式中,调节细胞外基质合成和上皮–间充质相互作用已经被证实在肿瘤的发展、侵袭和转移过程中发挥重要作用。

3. FOXF2与肿瘤相关特征和功能

FOXF2作为一种重要的叉头转录因子,其编码蛋白通常在间质细胞中表达,通过增加纤维的运动来促进间质细胞的转移。FOXF2对于多个基因的表达及不同信号通路都有重要的调节作用。

3.1. FOXF2与Wnt信号通路

Wnt信号通路在调节细胞周期和监测正常以及恶性上皮细胞增殖等过程中扮演着关键的角色,Wnt通路主要包含三种模式,其中Wnt/β-catenin途径是Wnt信号通路的经典途径之一,在肿瘤的发生发展中起重要作用 [9] [10]。在Wnt信号通路激活后,Anxin-GSK-3β-β-catenin蛋白复合物被降解,释放出β-catenin,β-catenin是经典途径的关键细胞质和细胞核介质,可以促进细胞增殖和分化 [11]。LEF1是该信号通路中另外一个关键的转录因子 [12],LEF1/β-catenin转录因子复合物的形成是Wnt通路下游靶基因转录的前提 [13],其复合物形成与否主要取决于β-catenin水平的调节。在不改变β-catenin mRNA表达的情况下,FOXF2大大降低了β-catenin的水平,从而抑制了β-catenin诱导的Wnt信号通路 [14]。在Wnt信号通路未被激活的情况下,β-catenin通过与GSK-3β继续组成磷酸化复合物,最终被蛋白酶体泛素化并降解 [15]。以上研究表明FOXF2通过降低β-catenin水平抑制Wnt通路,同时FOXF2以GSK-3β非依赖性方式通过蛋白–蛋白酶体途径促进β-catenin降解。研究人员还发现一种新的FOXF2-IRF2BPL-β-catenin信号转导轴抑制胃癌中的Wnt信号传导活性。FOXF2转录结合并上调泛素E3连接酶IRF2BPL,其反过来与β-catenin相互作用对其进行泛素化和降解。FOXF2的这些作用有助于抑制Wnt信号传导活性以抑制肿瘤细胞生长。

Nik等人 [16] 研究发现FOXF2在成纤维细胞中的表达与Wnt信号传导的抑制相关,成纤维细胞可诱导激活原始低克隆形成肿瘤细胞中的Wnt通路的活性和干性,从而预防腺瘤的形成。因此,FOXF2正在成为抗癌药物潜在重要的新靶点。

3.2. FOXF2与EMT

在正常生理情况下,上皮间充质转化(EMT)是上皮细胞逐渐获得间充质细胞表型的过程,该过程受到多种信号通路和转录因子的调控并最终获得间充质的特征,病理情况下发生则会导致上皮细胞失去上皮属性如黏附性、紧密连接蛋白和失去极性,并获得间充质细胞的特征其中包括:运动性、侵袭性和细胞凋亡的抗性 [17] [18] [19]。在肿瘤的发生发展过程中,EMT导致上皮细胞间失去上皮属性,而获得了间质属性,表现为细胞间黏附作用的丧失、细胞骨架的异常重构,继而导致肿瘤细胞的增殖和转移 [20]。

FOXF2的上调刺激E-cadherin表达并抑制Vimentin和Snail表达。E-cadherin,Vimentin和Snail是三种与EMT相关的基因。E-cadherin是一种分布在上皮细胞侧交界处的跨膜糖蛋白,是介导细胞连接的分子基础 [21]。细胞膜表面E-cadherin的减少破坏了细胞间连接,从而导致肿瘤细胞的侵袭和转移能力增强 [22]。FOXF2介导E-cadherin的转录下调并因此破坏细胞–细胞粘附。TWIST1被认为是EMT的关键调节因子,其过表达能够触发EMT表型和肿瘤转移 [23],Wang等研究者 [24] 确定TWIST1是FOXF2的转录靶标,同时受到FOXF2的负调控,并介导FOXF2调节诱导细胞的上皮–间质转化。

3.3. FOXF2与microRNA182

微小RNA (miRNA)属于一类高度保守、内源表达的单链小非编码RNA (ncRNA)分子,其长度大约为22 nt [25] [26]。它们通过碱基配对方式与靶mRNA的3’非翻译区(3’UTR)内的特定互补位点结合而负调节基因表达,导致mRNA降解或翻译受到抑制。每个miRNA可以有效调节和协调多个细胞过程,包括细胞增殖、凋亡、分化、侵袭、转移和血管生成 [27]。miRNA主要通过调节靶基因起到癌基因或肿瘤抑制基因的作用参与肿瘤进程 [28] [29]。越来越多的证据突出miR-182在癌症进展和患者生存中的调节作用,目前已发现miR-182异常过表达会促进乳腺癌、卵巢癌、前列腺癌、黑色素瘤、胶质瘤和结直肠癌的肿瘤发生 [30] - [36]。

Zhang [36] 研究确定了miR-182和FOXF2之间存在调节关联,使用荧光素酶报告基因测定证实miR-182与FOXF2 mRNA的3’非翻译区(3’UTR)存在直接结合。另外在miR-182敲低细胞中观察到FOXF2表达升高,Yu [37] 为了进一步探究,在计算机软件上预测到位于485~491 (U1)和688~695 (U2)的FOXF2是miR-182的潜在靶区域,实验qRT-PCR和蛋白质印迹显示,与对照组相比miR-182模拟物转染的人乳腺癌细胞系MCF7细胞中FOXF2表达显着降低,因此FOXF2被鉴定为miR-182的直接靶标,因此可以推测miR-182可能通过靶向下调FOXF2促进肿瘤细胞增殖和侵袭。Wang等人 [38] 采用相同的方法验证了在卵巢癌(OC)中FOXF2是作为miR-182的直接靶标,在研究中发现miR-182-5p通过直接靶向卵巢癌细胞中FOXF2的3’UTR而负调节FOXF2表达,FOXF2表达显著降低,并与卵巢癌组织中miR-182-5p表达呈负相关。Zhang和Kundu [39] [40] 分别在乳腺癌(BC)最具侵袭性的三阴性乳腺癌(TNBC)亚型和肺癌中同样验证了以上的结果。

3.4. FOXF2与MAZ

MYC相关锌指蛋白(MAZ)是一个转录因子位于染色体16p11.2,编码2.7 kb的mRNA,翻译蛋白分子量约为60 kd。研究表明,MAZ在基因转录中起重要作用,如反式激活致癌基因c-MYC、HRAS、PDPN和血管内皮生长因子(VEGF)的表达 [41] [42] [43] [44] [45],并反式抑制某些癌基因p53、Sp4和内皮细胞一氧化氮合成酶(eNOS) [46] [47]。最近的研究表明,MAZ的失调表达与各种肿瘤的进展密切相关,MAZ在胰腺癌,肝癌,乳腺癌、前列腺癌和脂肪瘤中高度表达 [48] [49] [50] [51] [52]。

MAZ是具有C2H2型锌指蛋白的转录因子,MAZ与富含GC的顺式元件结合以调节靶基因的表达 [53],已知FOXF2启动子区域富含GC的顺式元件且含有多个候选MAZ结合元件,这些表明MAZ可能与FOXF2启动子在特定区域特异性结合,因此FOXF2被确定为MAZ的转录目标。由于MAZ和FOXF2均有抑制乳腺癌细胞的侵袭性,推测MAZ可能激活乳腺癌细胞中FOXF2的表达,Yu [54] 通过调节FOXF2确定了MAZ在乳腺癌增殖和进展中的功能,在BLBC细胞的EMT过程中通过检测细胞特异性类型的方式发现MAZ-FOXF2-TWIST1轴,验证了MAZ与FOXF2在肿瘤中的相关性。

进一步生存分析后发现MAZ mRNA水平与FOXF2mRNA水平的组合,可以作为检测乳腺癌患者的预后标志物。MAZ-FOXF2轴在调节癌症发生和进展中反映出多功能转录因子的多效性,有助于癌症的诊断和治疗。

4. FOXF2在不同肿瘤发生、发展中的作用

4.1. FOXF2与乳腺癌

乳腺肿瘤在多个方面表现出显著的异质性 [55] [56],多项研究已经将乳腺癌分为至少五种亚型,其中包括正常乳腺样型、管腔A型、管腔B型、HER2阳性型和基底样/三阴性型(BLBC/TNBC) [57] [58]。Lo [59] 近些年发现FOXF2可以对乳腺癌的不同分子亚型发挥不同的功能作用。在管腔型、HER2阳性型乳腺癌中采用表观遗传机制沉默FOXF2表达,在DNA甲基转移酶的介导下,使含有CpG岛的FOXF2启动子发生DNA甲基化是沉默FOXF2表达的关键机制,此外还有组蛋白去乙酰化和受多种miRNA靶向调控如miRNA-182、miRNA-200、miRNA-301等众多表观遗传机制 [37] [39] [60] [61] [62]。FOXF2的沉默会导致CDK2-Rb-E2F信号轴的阻断,触发G1期停滞,诱导细胞凋亡,抑制肿瘤形成。因此,FOXF2在这两种亚型乳腺癌中作为肿瘤抑制剂发挥作用,严格控制DNA复制调节并限制细胞生长防止肿瘤形成。相比之下,FOXF2在基底样乳腺癌中表现为过度表达,且FOXF2在调节DNA复制中的肿瘤抑制功能在基底样乳腺癌中丧失,同时通过研究证实了FOXF2是以组织环境依赖性方式驱动EMT和肿瘤转移进展的致癌激活剂。

Feng [63] 等人对305例原发性乳腺癌组织中的FOXF2 mRNA水平进行了RT-qPCR分析,发现原发性乳腺癌中FOXF2 mRNA水平与乳腺肿瘤进展呈负相关,包括肿瘤大小,转移淋巴结数量和临床分期。此外,FOXF2敲低促进BLBC/TNBC细胞在体外和体内的转移能力,进一步发现FOXF2缺乏激活EMT并同时抑制BLBC/TNBC细胞的增殖 [64]。因此,他们认为FOXF2作为EMT的抑制剂抑制两种EMT转录因子TWIST1和FOXC2的表达和BLBC/TNBC细胞中增殖的启动子起作用 [64] [65] [66]。基于这些发现,可以假设FOXF2是BLBC/TNBC中的EMT抑制转录因子,其敲除后通过激活TWIST1和FOXC2的转录促进BLBC/TNBC细胞的转移能力,从而增强EMT程序 [67] [68] [69]。我们可以发现在Lo和Feng的研究中存在着差异性的结果引起了FOXF2在乳腺癌中具体作用的争议,其中可能的原因是实验方法的不同所导致的 [70],可通过构建乳腺癌小鼠模型继续验证假说,此争议仍有待商榷和进一步的探讨。

4.2. FOXF2与肝癌

Shi X等人 [71] 研究证实从组织蛋白水平到mRNA水平上,肝癌组织中FOXF2的表达明显低于癌旁组织且存在显著差异,并且其表达水平与HCC患者的总体存活率和无复发存活率密切相关。进一步发现RNAi介导的MHCC-97H肝癌细胞系中FOXF2基因的沉默显著促进细胞增殖和抗凋亡能力。Dou等人 [72] 重点研究了FOXF2缺陷与早期肝癌转移之间相关性的潜在机制,发现HCC细胞中的FOXF2缺乏使E-cadherin得到增加而Vimentin却减少,并重新激活Wnt通路,从而促进肿瘤细胞增殖。FOXF2的下调不仅提升HCC细胞迁移和侵袭的能力,而且促进HCC细胞的增殖和裸鼠皮下肿瘤的生长,FOXF2缺陷诱导Huh7细胞的间充质–上皮细胞转化(EMT)进程,这可能与促进循环肿瘤细胞的定植和转移有关。总之,以上结果表明FOXF2可能在HCC进展中起重要作用。

4.3. FOXF2与宫颈癌

β-catenin是一种多功能蛋白,具有介导细胞粘附和信号转导的双重活性 [73] [74],细胞核中β-catenin的积累是肿瘤进展的重要标志 [75] [76]。如先前研究所示,c-Myc,CyclinD1,MMP9和Lgr5参与肿瘤的发展过程,其过表达对肿瘤的发展具有显着的促进作用 [77] [78]。Zhang等人 [79] [80] 通过研究发现FOXF2的过表达降低了细胞核中β-catenin的表达水平,同时FOXF2的上调显著抑制宫颈癌Hela细胞在体外的增殖,迁移和侵袭以及体内的生长。另外,过表达的FOXF2促进E-cadherin的表达,并抑制Vimentin和Snail的表达以及靶基因在细胞核中的Wnt信号通路(包括c-Myc,CyclinD1,MMP9和Lgr5)。基于这些发现,FOXF2可能通过调节Wnt信号通路抑制Hela细胞的增值、迁移和侵袭,从而抑制宫颈癌的发展,这可能是宫颈癌诊断和治疗的潜在靶点。

4.4. FOXF2与胃癌

异常的DNA甲基化已是公认的胃癌标志 [19],通过识别被DNA启动子甲基化抑制的抑癌基因会为研究胃癌的分子发病机制提供新的见解。Higashimori等人 [81] 通过研究发现,使用启动子甲基化序列对胃癌中高甲基化候选物的全基因组进行筛选,发现FOXF2基因的启动子在胃癌细胞系中优先甲基化,因为FOXF2主要在人的胃肠道中表达 [82],所以与正常胃组织相比,胃癌细胞系中的FOXF2启动子甲基化水平显著升高,同时使用去甲基化剂二甲苯(5-Aza)和组蛋白去乙酰化酶抑制剂(TSA)治疗可恢复所有胃癌细胞系中的FOXF2表达。

进一步探究在动物水平上FOXF2的过表达可抑制在肿瘤发生过程中体内外裸鼠的胃癌细胞生长,而FOXF2的敲低则促进其胃癌细胞生长。推测FOXF2抑制胃癌细胞生长是通过抑制G1-S细胞周期转变和诱导细胞凋亡来介导的进而达到FOXF2抑制胃癌的迁移和侵袭能力。另有研究发现 [83],通过测定FOXF2mRNA表达水平发现胃轻瘫患者平滑肌组织中FOXF2的表达降低。随后从小鼠胃平滑肌中敲除FOXF2基因,导致胃液排空延迟,在FOXF2敲除小鼠的胃肌层中检测到平滑肌收缩蛋白,核转录因子(SRF)和心肌素的表达降低。由此得知FOXF2的表达下降可能导致胃轻瘫患者胃排空受损,导致胃液潴留,进而引起胃黏膜表面发生一系列的病理变化促使胃癌的发生。因此,FOXF2是胃癌发生中的关键肿瘤抑制因子,是有助于诊断和治疗该疾病的潜在生物标志物。

4.5. FOXF2与前列腺癌

van der Heul [84] 最早通过定量逆转录聚合酶链反应分析12种不同的FOX基因,最初发现FOXF2在正常前列腺区域表现为高表达,而在前列腺癌中表达降低。进一步探究FOXF2的表达谱验证了FOXF2在前列腺区域中良性和恶性的差异表达同时表明其在上皮细胞向间充质细胞转变中起作用。他们还证实了FOXF2的失调引起的前列腺基质变化可导致多种肿瘤相关分泌因子的上调或下调,如金属硫蛋白家族基因(MTs),锌离子结合内肽酶(MMPs),TGF-β3和CXCL12,这将创造出有利于肿瘤生长的微环境 [85] [86] [87]。

另有部分研究发现 [88] [89],与正常前列腺组织和细胞系相比,前列腺癌组织和细胞系中miR-182-5p表达显著更高,miR-182-5p可能是前列腺癌中的致癌基因,因为microRNA主要通过调节其他靶基因的表达发挥其作用,FOXF2可以抑制前列腺癌细胞系中细胞的侵袭和迁移,并最终证实其潜在的靶基因是FOXF2。

综上所述,随着FOXF2研究的深入,越来越多的证据表明FOXF2在肿瘤中发挥着多种功能,同时FOXF2与不同肿瘤间存在着密切的相关性。因此从多维度探索FOXF2基因功能,寻找肿瘤的治疗靶点,对肿瘤的预防和防治具有重大的临床意义。首先在与肿瘤相关的特征和功能中,FOXF2能够通过降低β-catenin的水平,从而阻断β-catenin诱导的Wnt信号通路;FOXF2上调刺激E-cadherin表达并抑制Vimentin和Snail表达触发EMT过程;FOXF2被鉴定为miR-182的直接靶标,miR-182可能通过靶向下调FOXF2促进肿瘤细胞增殖和侵袭;MAZ可能与FOXF2启动子在特定区域特异性结合达到共同抑制肿瘤癌细胞的侵袭性。另外在肿瘤疾病的发生发展过程中,FOXF2也扮演着不同的角色,令人意外的是FOXF2在乳腺癌的不同分子亚型中分别表现为促癌或抑癌作用,而在肝癌、宫颈癌、胃癌、前列腺癌中表现为抑癌作用,这说明了FOXF2通过参与多条与肿瘤疾病相关的重要信号通路,调控肿瘤的增殖、分化和侵袭。目前国内外对于FOXF2基因在肿瘤中的作用机制研究相对较少,且在不同水平上的分子调控机制尚不明确,因此十分有必要深入研究FOXF2基因,为探讨人类肿瘤的病因、诊断、治疗及预后提供新的理论依据。

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