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通讯作者:

李玉民(1962-),男,甘肃武威人,博士生导师,主要从事肝胆胰外科、微创外科及消化系肿瘤外科方面的研究。E-mail:liym@lzu.edu.cn

中图分类号:R730

文献标识码:A

文章编号:2096-8965(2021)04-0041-08

DOI:10.12287/j.issn.2096-8965.20210406

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目录contents

    摘要

    Septin9是细胞骨架GTPase保守家族的一员,参与了多种生物过程。许多研究表明,Septin9与多种恶性肿瘤的发生发展有关。甲基化的Septin9基因可作为一些恶性肿瘤早期筛查、诊断和预后的标志物,并有可能成为抗癌治疗的新靶点。本文综述了Septin9基因及其甲基化在常见恶性肿瘤中的研究进展。

    Abstract

    Septin9 is a member of the cytoskeletal GTPase conserved family and is involved in a variety of biological processes. Many studies have shown that Septin9 is related to the occurrence and development of many malignant tumors. The methylated Septin9 gene can be used as a marker for early screening, diagnosis and progno‐ sis of some malignant tumors, and may become a new target for anticancer therapy. This article reviewed the re‐ search progress of Septin9 gene and its methylation in common malignant tumors.

    关键词

    Septin9甲基化恶性肿瘤

  • 恶性肿瘤一直是全球关注的医学焦点,“早发现、早诊断、早治疗”对于提高恶性肿瘤患者的生存率至关重要。随着科技的发展,恶性肿瘤筛查、诊断、预后的侵入性手段逐渐转变为寻找肿瘤分子标志物等非侵入性方法。近几年来,Septin9与恶性肿瘤的关系成为研究热点,它在许多恶性肿瘤中异常表达,存在多种不同的亚型。不同类型的恶性肿瘤中,Septin9的转录表达模式不同。例如,Septin9 的v2、v4、v4*和v5亚型在肿瘤上皮细胞中的表达均高于正常细胞[1]。同时,Septin9 作为早期筛查恶性肿瘤标志物的重要性,已经被结直肠癌患者血液中甲基化的 Septin9mSeptin9) 检测技术的发展所强调[2]。这些研究提示 Septin9基因及其甲基化可能在恶性肿瘤的发展中发挥重要作用,并可能成为个体化抗癌治疗的新靶点。本文就 Septin9 及其甲基化在常见恶性肿瘤的研究进行综述。

  • 1 Septin9基因的结构与功能

  • 在酵母中首次发现 Septin基因距今已有40多年。在此期间,人们对 Septin基因家族进行了大量深入的研究。Septin 系基因是一类具有三磷酸鸟苷活性的保守基因家族,在芽殖酵母 (Saccharomyces Cerevisiae) 的细胞周期过程中首次被发现[3],后续研究表明其广泛存在于真核生物中[4]。这些基因通过变异剪接产生不同的剪接体,导致极其复杂的基因家族成员和基因功能。Septin 由一个高度可变的N端结构域、一个中心GTP结合域和一个C端结构域组成[5, 6]。GTP结合域可以通过鸟嘌呤核苷酸结合位点或N端和C端延伸形成线性细丝[4]Septin还可组装成结构更加高级的杂聚物[7]。Septin家族是具有GTP结合蛋白活性的保守支架蛋白,与微管细胞骨架、肌动蛋白和磷脂膜相互作用[5, 8, 9],在细胞骨架形成、细胞极化、胞质分裂、细胞膜重塑和细胞分裂中,可作为蛋白质-蛋白质相互作用的支架或作为蛋白质区室化的扩散屏障[10-14]

  • Septin9是Septin家族的一员,是一种细胞周期相关蛋白[4],在细胞质分裂过程中协调肌动蛋白[15]Septin9基因广泛存在于人类细胞中,定位于染色体17q25.3,并形成18个转录产物[16]Septin基因间的高亲和力可形成含有数个多肽的三聚体、六聚体和八聚体复合物。哺乳动物的 Septin可以形成一个八聚体复合物,即 Septin9-Septin7-Septin6-Septin2-Septin2-Septin6-Septin7-Septin9 [17]。这一独特的结构可结合Septin依赖的Rho鸟嘌呤核苷酸交换因子 (SA-Rho-GEF) 和肌球蛋白,对于肌球蛋白的完全激活和细胞分裂至关重要[18, 19]Septin9 在此复合物的两端,维持亚基聚合和整个八聚体的稳定[20]

  • 2 Septin9基因与DNA甲基化

  • DNA甲基化参与表观遗传转录调控机制,许多癌症具有异常的DNA甲基化模式。DNA甲基化异常包括启动子区域的高甲基化和整个基因组的低甲基化,被认为通过不同的机制参与了癌症转移[21]。胞嘧啶鸟嘌呤二核苷酸 (Cytosine phosphate-Guano⁃ sine,CpG) 是DNA甲基化的主要位点,与肿瘤的发生发展密切相关[22]。研究表明,Septin9 在细胞分裂中起关键作用,是一种候选肿瘤抑制基因,其高甲基化与致癌作用有关[7, 23]。此甲基化过程可改变基因序列构象,同时甲基化的CpG位点招募结合甲基化的CpG结合蛋白并与其他蛋白作用形成异常染色质,从而抑制基因表达[24]。由此可见,Septin9 基因甲基化异常导致基因表达异常、基因转录活性降低和细胞生理功能异常,最终促使癌症的发展。

  • 3 Septin9与恶性肿瘤

  • 3.1 Septin9与消化系肿瘤

  • 3.1.1 Septin9与结直肠癌

  • 结直肠癌 (Colorectal Cancer,CRC) 是消化道常见的恶性肿瘤。根据2018年GLOBOCAN的数据,CRC有180万例病例,在全球所有恶性肿瘤中发病率排名第三。同时,CRC病例中约有88万人死亡,在全球所有恶性肿瘤的死亡率中排名第二[25]。近年来,粪便潜血试验 (Fecal Occult Blood Test,FOBT)、内镜等筛查方法已被用于CRC的早期诊断和检测。然而,患者对这些检查的低依从性等问题仍未得到解决,因此,需要开发如生物标志物检测等无创筛查策略。

  • 研究发现,在CRC患者的上皮细胞中 Septin9 的v2、v4、v4*和v5转录本过表达[23]。同时,CpG岛高甲基化等异常的表观遗传改变是CRC发生的起始事件,因此 Septin9 基因的高甲基化状态可能成为筛查CRC的有用的生物标志物[26, 27]

  • Septin9基因启动子区CpG岛的高甲基化可以抑制其表达,消除其肿瘤抑制功能,最终导致恶性肿瘤的形成[28]。除上述 Septin9具有稳定Septin八聚体的作用外,其在细胞过程中还有多种功能。Septin9蛋白是第四个细胞骨架的组成部分,在细胞分裂过程中可以聚集并形成纤维微丝和其他复合物,还可招募靶蛋白并稳定胞质分裂。 Septins-Cdc3、 Cdc10、Cdc11、Cdc12和Shs1形成芽颈环,并在细胞分裂过程中诱导母代细胞和子代细胞的分离。周期蛋白依赖激酶1磷酸化的Septin9通过与脯氨酸异构酶相互作用,在子代细胞的分离中发挥重要作用。它还影响细胞分裂后期的染色体聚集和分离。因此,磷酸化的Septin9可调节有丝分裂,促进细胞增殖和存活[29]Septin9错误定位或甲基化可介导胞质分裂失败,导致非整倍体、中心体扩增和多极有丝分裂,进而导致恶性肿瘤的发生[30]。目前的研究证明,SEPT9_v2 转录本的第三CpG岛 (CGI3) 的甲基化对CRC致癌具有特异性[24], CGI3包含 SEPT9_v2 的启动子区域和启动密码子,也是检测CRC患者 Septin9 甲基化的靶点。还有研究表明,细胞自噬可抑制CRC的发生[31]。Septin蛋白复合物可参与细胞自噬[32, 33]Septin9 基因的甲基化可抑制Septin9蛋白的表达,降低细胞自噬功能,从而促进CRC的发生发展。

  • Septin9基因的甲基化程度伴随着CRC的发展,出现在CRC的早期,没有明显的组织改变[34]Septin9基因的甲基化程度随着病理组织的发展而逐渐增加[35]。Fu等[36] 发现,组织学级别越高的CRC, Septin9 甲基化阳性率越高。Xie等[37] 的研究表明, mSeptin9 对远处转移患者具有更高的敏感性。Sun等[34] 发现,Septin9的甲基化对CRC的筛查、诊断和复发监测都是有用的,其与TNM类型、Dukes分期、肿瘤体积、错配修复缺陷状态有关。另一项研究还显示,高水平 Septin9 甲基化的患者总生存率有较低的趋势[38],这表明Septin9甲基化可能是有用的CRC预后生物标志物。

  • 3.1.2 Septin9及其甲基化在结直肠癌中的临床应用

  • 目前,外周血 Septin9 的甲基化检测因其高特异性、高敏感性、较低价格、非禁食、血液样本易获得、无侵袭性、患者依从性良好等特点[39],已在我国被应用于CRC的筛查、诊断、预后和复发监测。

  • 多项研究对血浆 mSeptin9 检测进行了评估。 Epigenomics AG (ECX:FRA) 于2008年在欧洲首次实施 Septin9 甲基化生物标志物检测[40]。两年后,商业化的Epi proColon qPCR试剂盒1.0版在欧洲推出,随后升级至2.0版[41]。中国食品药品监督管理总局和美国FDA分别于2015年和2016年批准了Epi proColon试剂盒。在前瞻性研究“PRESEPT” 中,甲基化 Septin9 检测对CRC的敏感性为48%(Ⅰ~Ⅳ期分别为35%、63%、46%和77%),特异性为92%,但只有11%的晚期腺瘤被确诊[42]。市售试剂盒提供两种不同算法,2/3算法测试真阴性率较高,1/3算法灵敏度较高[43]。2019年发表的一项包括22篇研究文章的荟萃分析研究发现,mSeptin9 检测对CRC具有高特异性 (92%) 和中等敏感性 (69%),因此对于粪便免疫化学实验 (Fecal Immu⁃ nochemical Test,FIT) 或其他筛查方式受限的人来说,它是一种潜在的替代筛查方法[44]。由于其相对较低的敏感性,美国预防服务工作组和ACS目前没有将Epi proColon检测纳入其CRC筛查指南[45]

  • 有研究比较了 mSeptin9 检测和FIT单独或联合在CRC筛查中的诊断效果。结果显示,独立应用时, mSeptin9 检测比FIT的敏感性低 (73.3%~81.5%和53.8%~88.9%),但特异性高 (81.5%~95.3%和54.1%~97.4%)。二者联合检测时的敏感性进一步升高 (88.7%~97.8%) [46]。还有研究显示,mSeptin9检测的敏感性和特异性均高于临床常用的血清CEA检测[34, 47, 48]。最近的研究提示,与血浆甲基化 Septin9 试验相比,粪便甲基化 Septin9 试验在检测晚期腺瘤和Ⅰ~Ⅱ期CRC方面分别提高了35.9%和7.9%[49],这说明粪便甲基化Septin9试验可能是更适合早期CRC筛查的工具。此外,结肠镜检查中可能出现禁忌症和并发症。所有这些限制都可能导致患者较差的依从性。因此,中国的临床专家推荐了早期CRC筛查过程的共识,以便对筛查人群的风险进行分层。mSeptin9等非侵入性检测可用于低风险人群,结肠镜检查可用于高危人群[50]。然而,mSeptin9 检测对癌前病变 (晚期腺瘤和息肉) 的诊断性能较差且成本相对较高[51],因此,仍需大量研究以改善这种情况。

  • 3.1.3 Septin9与其他消化系肿瘤

  • CRC以外的消化系统癌症和癌前病变的早期检测仍然是一项重大挑战。Song等[52] 调查了血液甲基化 Septin9 对消化系统肿瘤的检测性能,他们招募了2 030名受试者,包括764名癌症患者 (291例结直肠癌、239例胃癌、106例食管癌和128例肝细胞癌)、423名癌前病变患者以及843名正常受试者,研究发现,无论是单独使用血甲基化 Septin9 检测还是与血清蛋白标志物结合使用,对于消化道癌症的机会性筛查都是有效的。还有研究显示,在肝硬化患者中,Septin9甲基化检测是一种很有前景的循环表观遗传生物标志物,可用于患者个体水平的肝细胞癌诊断[3, 53]

  • 2020年4月,中国国家药品监督管理局批准上市了由第四军医大学樊代明院士、香港中文大学于君教授、博尔诚 (北京) 科技有限公司联合带头研发的血浆 RNF180/Septin9甲基化检测试剂盒 (灵敏度:61.76%;特异度:85.07%。NMPA索引号: XZXK-2020-1430)。该试剂盒开创了通过检测血浆 RNF180Septin9甲基化来筛查胃癌的先例,但仅限于有胃癌家族史者或年龄在40岁以上胃癌高风险人群的检测。Xu等[54] 在最近的研究中发现 mSeptin9mRNF180 和CA724组合对GC检测具有足够的敏感性 (三者联合检测胃癌的阳性率为68.6%),血mSeptin9或许可以预测胃癌预后。

  • 以上研究证明,甲基化的 Septin9 是消化系统癌症患者早筛和长期生存有价值的预测因子。

  • 3.2 Septin9与乳腺癌

  • 多项研究表明 Septin9 基因参与到了乳腺癌的发生发展中[55-64]。Montagna等[55] 通过实时荧光定量PCR分析发现,在多种乳腺癌小鼠模型和6株人类肿瘤细胞系中 Septin9 基因的表达水平持续升高。同时,Thsp1和bax介导的细胞凋亡在人乳腺癌和高 Septin9 表达的乳腺癌细胞系中降低,这种效应可以通过转染小干扰RNA抑制 Septin9 的表达来逆转。这提示升高的 Septin9 水平可能有助于乳腺癌细胞进行快速的有丝分裂,从而促进其发生发展。 Marcus等[56] 还发现Septin9促进了黏着斑附近金属蛋白酶的上调、运输和分泌,从而增强了乳腺癌细胞的迁移和侵袭。近十年的研究热点聚焦在 Septin9 不同亚型与乳腺癌的关系上。Gonzalez等[57] 描述了 Septin9在乳腺癌细胞系和原发性乳腺癌中的表达改变,并表明Septin9_v1可通过增强细胞增殖、侵袭、细胞运动、集落形成和非整倍体型来影响促癌表型。此外,Septin9_v1 的高表达促进了乳腺细胞的上皮间充质转化,这是上皮癌的一个标志性特征。他们在之后的研究中还发现,乳腺上皮细胞中 Septin9_v1 的高表达可激活JNK信号通路,使内源性周期蛋白D1上调,从而加速乳腺上皮细胞的增殖[58]。Zeng等[59] 证明,Septin9_i1 可通过靶向Rho/ROCK和FAK信号通路,在体外促进乳腺癌细胞迁移和细胞骨架重排,并在体内增加乳腺癌的转移潜能。过表达 Septin9-i1 亚型还可增强细胞对紫杉醇的抗性,微管聚谷氨酰胺化进一步增强了这种抗性[60]。然而,与 Septin9_i1 相反,Septin9_i2 不支持癌细胞迁移,并诱导亚核肌动蛋白丝的丢失,这取决于 Septin9_i2 特定的N端序列。与正常乳腺组织相比,Septin9_i2 在乳腺肿瘤中被强烈下调[61]。因此,Septin9_i2 是乳腺肿瘤发生的负调节因子, Septin9致瘤特性或许取决于 Septin9_i1 Septin9_i2 表达水平之间的平衡。还有研究发现,Septin9_v2 也与乳腺癌相关,在67%的乳腺癌细胞系和53%的乳腺癌组织中发现了 Septin9_v2 启动子的高甲基化,而在正常乳腺组织中却没有[62]。Connolly等[1] 发现 Septin9_v3 亚型的表达是通过备选启动子上的DNA甲基化来调控的,这可能会在乳腺癌的起始和进展过程中驱动 Septin9 基因亚型表达的变化。他们还发现乳腺上皮细胞中 Septin9_v1Septin9_v3Septin9_v6Septin9_v7 亚型的表达水平最高,其次是 Septin9_v2Septin9_v5,而 Septin9_v4 几乎检测不到[63]。Devlin等[64] 在最近的研究中对MCF-7乳腺癌细胞进行了蛋白质组学筛选,识别了 Septin9亚型i1、i4和i5的相互作用,它们的N端延伸存在显著差异。虽然这三种亚型都与 Septin2Septin7 相互作用,但截断的 Septin9_i4Septin9_i5Septin6 组的相互作用比 Septin9_i1 更为复杂,而 Septin9_i1 主要与 Septin8 结合,这种现象来自于 Septin9不同亚型N端延伸的差异。以上研究提示了 Septin9在乳腺癌发病机制中的潜在作用。

  • Matsui等[62] 在67%(8/12) 的乳腺癌细胞系和53%(10/19) 的乳腺肿瘤组织中发现了 SEPT9_v2 启动子的甲基化,但在正常乳腺组织 (0/19) 中没有发现。同时,在乳腺癌细胞系和乳腺癌组织中, SEPT9_v2 mRNA的表达与甲基化指数之间存在明显的负相关。这说明 SEPT9_v2 启动子的高甲基化沉默了其mRNA的表达,并且甲基化的 SEPT9_v2 或许是乳腺癌潜在的肿瘤标志物[62]。但是,目前尚未将 Septin9 或其甲基化状态作为乳腺癌筛查、诊断及评估预后的标志物应用于临床。

  • 3.3 Septin9与血液肿瘤

  • 白血病作为血液系统肿瘤的代表,研究者发现与之相关的基因融合现象。混合谱系白血病 (Mixed Lineage Leukemia,MLL) 基因重排在白血病中较为常见[65]Septin9作为MLL基因融合的靶标之一,可与其N端融碱基序列融合后,产生新的嵌合蛋白[66]。目前在急性淋巴母细胞白血病、急性髓系白血病[67] 和骨髓增生异常综合征[68] 中都发现了这一现象,但具体机制还需进一步研究。在Kurosu等[69] 的研究中,一例成人新生急性单核细胞白血病出现了t (11;17)(q23;q25),同时存在变异型 MLL/Septin9 融合转录本。在另一项研究中,发现 MLL基因重排与Septin9基因相关[70]。近期的研究均报道了 Septin9 参与到了部分白血病的t (11;17) 中。另一项研究显示,急性巨核母细胞白血病和t (11; 17)(q23; 25) 患者有 KMT2A-Septin9 融合[71]。Altahan等[72] 也发现了一例急性髓系白血病病例中发生不同位点的t (11;17),并分别融合有 KMT2ASeptin9 基因。还有研究报道了伴有 KM2TA易位的单核细胞急性髓系白血病病例[73],其临床表现可能模拟急性早幼粒细胞白血病,Septin9 同样参与其中。因此,上述研究均提示 Septin9 可能通过与MLL基因融合在白血病的发生发展中发挥重要作用。在其他血液系统肿瘤如T细胞淋巴瘤中,发现小鼠逆转录病毒SL3-3可以整合到Septin9 基因位点[74]

  • 然而,目前尚无 Septin9 甲基化与血液肿瘤关系的确切研究。同时,尽管国内外有一些关于 Septin9参与到血液肿瘤中的病案报道,但能否将其作为早期筛查、诊断和评估预后的标志物而应用于临床仍需大量研究。

  • 3.4 Septin9与头颈部鳞状细胞癌

  • 头颈部鳞状细胞癌 (Head and Neck Squamous Cell Carcinoma,HNSCC) 是一种侵袭性很强的癌症。到了晚期,患者接受有效治疗的机会很小,存活率很低。为了便于及时诊断和改善治疗,确定早期检测标志物至关重要。早在2008年,有研究发现了一组在HNSCC中最常被甲基化的基因 (EBF3 IRX1SLC5A8FUSSEL18Septin9[75],这表明 Septin9基因与HNSCC有关。之后,该小组对上述发现进行了深入研究,证实了这些基因的甲基化可能会破坏其在转化生长因子-β (Transforming Growth Factor-β,TGF-β) 信号通路中的作用,进而导致HNSCC进展过程中不受控制的增殖和凋亡抵抗[76]。该小组的另一项研究还发现,烟草及酒精暴露和放疗与 Septin9 等基因的甲基化具有相关性 (P=0.021) [77],由此提示,这些基因的甲基化极有可能与HNSCC患者的不良预后相关。最近的一项研究通过检测284例HNSCC患者和122例正常人血浆 Septin9SHOX2 甲基化水平发现,59%的HN⁃ SCC患者甲基化阳性,特异性为96%[78]Septin9SHOX2甲基化水平的增加与HNSCC患者死亡风险的增加有关 (Septin9HR=5.27, P=0.001; SHOX2HR=2.32,P=0.024)。这表明血浆中游离循环DNA中的SHOX2Septin9甲基化与HNSCC预后相关。因此,尽管需要进一步验证,Septin9甲基化作为临床中HNSCC评估预后及药物靶向治疗的生物标志物仍具有极大潜力。

  • 3.5 Septin9与其他恶性肿瘤

  • 卵巢癌是致命的妇科恶性肿瘤。Lyu等[79] 使用荧光定量PCR检测了 Septin9 在卵巢良性、交界性和恶性浆液、黏液性肿瘤中的表达。结果显示,在卵巢交界性肿瘤中 Septin9 的v1和v4亚型表达显著升高,而在卵巢良性肿瘤和卵巢癌中无明显升高。同时,这两种 Septin9 亚型的高表达程度相一致,且它们之间的比例与边缘性肿瘤和恶性肿瘤的表型相关。这说明 Septin9 可能具有判断卵巢癌恶性程度的潜在作用。目前尚无卵巢癌与 Septin9 基因甲基化相关性的报道,临床中也并未应用 Septin9 来检测卵巢癌。

  • Powrózek等[80] 在癌症患者中观察到不同基因启动子区域甲基化的表观遗传变化,从而影响了抑癌基因的表达,如 Septin9。他们在一项有70名肺癌患者和100名健康人的研究中探讨了肺癌与Septin9 之间的关系。结果显示,在31名 (44.3%) 肺癌患者中检测到 Septin9 启动子甲基化,而在对照组中这一比例只占到4%。这提示,分析 Septin9启动子区域甲基化可能有助于肺癌的早期诊断。

  • 4 小结与展望

  • 研究证明,Septin9 基因参与到以CRC为代表的消化系肿瘤、乳腺癌、血液肿瘤、头颈鳞癌、肺癌、卵巢癌等多种恶性肿瘤的发生发展过程中。 Septin9 基因的遗传和表观遗传变化与肿瘤细胞增殖、自噬、血管生成、侵袭、染色体不稳定、对抗癌药物的耐药性等过程有关。DNA甲基化是调控 Septin9转录本差异表达的重要机制,与恶性肿瘤的发生、发展、预后和化疗反应密切相关。PCR检测外周血中mSeptin9水平可用于评估一些恶性肿瘤起始和复发的风险,在我国已被应用于CRC的筛查、诊断、预后和复发监测。

  • Septin9及其甲基化在恶性肿瘤中的研究仍有不足之处。首先,目前关于 Septin9 的大部分研究都集中在CRC上,在其它类型的恶性肿瘤中研究较少,且仍处于基础研究阶段。在除CRC和胃癌外的恶性肿瘤中,血 mSeptin9 检测也并未应用于临床。其次,即使是目前临床唯一能成熟应用 mSeptin9检测的CRC,也存在较高的人工成本、并不令人满意的灵敏度等缺点。最近的研究显示,与每年的FIT筛查相比,mSeptin9所需结肠镜检查的数量高出63%,总费用高出26%[81]。因此,在未来,需要在更多类型的恶性肿瘤中深入研究Septin9 调控并影响肿瘤发生发展的具体机制。同时,需要在临床工作中进一步探索 mSeptin9检测的新技术、新方法,如与传统的肿瘤检测手段联用等,从而达到提高筛查效率的目的。相信随着研究的不断深入,Septin9及其甲基化能在多种癌症的早期筛查、诊断、靶向治疗、预后和复发监测中发挥新的作用。

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