MUC16(CA125):抗癌潜力靶点,更多癌症预测新标志

浏览次数:459      日期:2021-01-23 11:40:27

2020年11月9日,韩国OncoQuest Pharmaceuticals子公司OncoQuest Pharma USA宣布,在研MUC16单抗药物Oregovomab已在美国临床试验中心完成针对原发性卵巢癌患者的首例患者用药。这也意味着靶向MUC16药物,将为卵巢癌患者的治疗带来新的希望。同样值得关注的是,近年来,MUC16在其它肿瘤中所扮演角色也被进一步发掘,如2020年12月25日,发表在Molecular Therapy(影响因子:8.986)杂志上的一篇文章揭示了MUC16在胰腺癌方面的新型调控机制 [1]。那么MUC16是什么?它主要的功能是什么?靶向MUC16在肿瘤靶向治疗方面的前景如何?看完这篇文章,相信你会有所收获。

1、MUC16的结构

MUC16又称CA125,是粘蛋白家族(MUC)家族的成员之一,属于I型跨膜粘蛋白。MUC16作为MUC家族中最大的糖蛋白,其基因位于人染色体19p13.2,由179 kb基因组DNA编码,共编码了22152个氨基酸 [2]。该蛋白由以下几个结构域组成:N端结构域,含有约12070个氨基酸,富含丝氨酸和苏氨酸;串联重复结构域,含有60多个由156个氨基酸随机重复组成的串联结构域以及16个重复的SEA结构域;C端结构域,也就是跨膜结构域,含284个氨基酸,可细分为胞外段、跨膜段和胞质尾端(cytoplasmic tail,CT)。其中,CT是由32个氨基酸所组成,这些氨基酸为磷酸化提供了潜在位点,这可能与MUCl6将参与某些信号通路有关 [3, 4] 图1)。

MUC16结构示意图

图1. MUC16结构示意图

*本图来源于MUC16结构示意图 出版物[4]

与其他跨膜型粘蛋白不同的是,MUC16没有EGF(表皮生长因子)样结构域,且携带有16个SEA结构域,相对于MUC家族中一些其他只含有1个或几个SEA结构域的MUC而言 [3],MUC16这种特殊的结构可能激活某些肿瘤信号通路 [5]

2、MUC16的表达与功能

MUC16常表达于眼表(包括角膜和结膜)、呼吸道和女性生殖道黏膜上皮等多个组织器官 [6]。MUC16在正常的子宫内膜组织中,特别是在腺体和上皮细胞中,以及宫颈粘液中也有表达 [7]

MUC16是一类高分子量、高度糖基化蛋白,在正常组织中,为表皮细胞提供了足够的亲水性和润滑功能,并为表皮层构筑起一道保护屏障抵御外来颗粒和感染因子 [9]。在眼表上皮中的研究表明,正常表达的MUC16在提供眼部润滑,帮助眨眼等运动中起重要作用[10]

然而,异常表达的MUC16往往是多种疾病的诱因。比如,高表达的MUC16是诱发干眼症的关键因素 [11]。此外,研究发现MUC16在许多相对良性的病症中表达水平居高,如子宫内膜异位症 [12]、子宫腺肌症 [13]、卵巢囊肿 [14]、肝硬化 [15]、糖尿病 [16]、胸膜炎 [17]和腹膜炎 [18]等。更为重要的是,越来越多的研究发现异常表达的MUC16与多种癌症进展相关 [1, 2, 3, 5],尤其是在卵巢癌中 [19]

3、MUC16与肿瘤信号通路的关系

前面提到,MUC16是最大的糖蛋白,由于其巨大的分子量,使得研究其信号通路及其在肿瘤中的作用机理变得极为困难。已有研究发现,在卵巢癌中,MUC16的过表达可稳定β-catenin蛋白并促其进入细胞核从而激活Wnt信号通路 [20]。另外有报道指出,在乳腺癌中,MUC16与酪氨酸激酶JAK2的相互作用诱导乳腺癌细胞增殖 [21]

事实上,MUC16在正常细胞中的表达受到复杂的调控影响,其表达通常被上皮细胞极性限制。然而,在癌变过程中,细胞极性丧失后,MUC16表达于全部的上皮细胞表面,并与多种生长因子相互作用,调节其下游信号通路,诱导癌症的发展 [3]

图2所示,MUC16和肿瘤信号通路的联系主要有以下几种,(a)MUC16-siglec-9:MUC16与NK细胞表面的抑制性受体siglec-9结合,从而发挥免疫抑制作用,为肿瘤细胞提供免疫保护机制;(b)MUC16-galectin-1/3:MUC16被认为是Galectin的反受体,如Gal-1Gal-3,但其在肿瘤发生中的作用尚待解读;(c)MUC16-Mesothelin:MUC16与间皮素相互作用介导肿瘤细胞转移到腹膜;(d)MUC16-选择素:MUC16能结合内皮细胞表面的E-选择素和淋巴细胞表面的L-选择素,促进肿瘤细胞转移;(e)MUC16-JAK2:MUC16与酪氨酸激酶(JAK2)的相互作用,一方面,导致cyclin-D1上调,促进肿瘤细胞增殖(见图2中实心箭头),另一方面,导致MO2和NANOG等基因上调,使得肿瘤干细胞表型和转移能力增强(见图2中虚线箭头) [22]

MUC16和肿瘤信号通路的关系

图2. MUC16和肿瘤信号通路的关系

*本图来源于Cancer research 出版物[22]

4、靶向MUC16在肿瘤治疗中的应用和前景

众所周知,MUC16是卵巢癌中过度表达的一种肿瘤特异性抗原,目前是临床上应用最为广泛的,诊断卵巢癌的重要血清生物标志物。近期,MUC16单抗药物Oregovomab已用于原发性卵巢癌患者的用药。其次,另一项抗MUC16抗体药物(JCAR-020)正处于临床一期,同样是用于卵巢癌靶向治疗。不难看出,对于靶向MUC16抗体药物的研发正是发展阶段,也就是说,目前市场上还没有FDA批准的MUC16靶向药物。《2020年卵巢癌药物全球市场报告》提出,到2022年全球卵巢癌药物市场价值19.9亿美元,预计到2035年卵巢癌患者人数将上升55%。数据表明了MUC16靶向药巨大的市场潜力,相信很快会有更多药企或研究者投入对靶向MUC16药物的研发,以抢占在未来市场中的地位。

不仅如此,越来越多的研究发现MUC16在其它肿瘤中过度表达,包括子宫内膜癌 [23]、输卵管癌 [24]、胰腺癌 [25]、结肠癌 [26]、腹膜癌 [27]、鼻咽癌 [28]、肺癌 [29]、乳腺癌 [30]和胃癌 [31]等,这些研究结果表明MUC16可能是一个非常诱人的抗肿瘤抗体药物靶点。由于MUC16发现的历史较短,靶向MUC16在众多肿瘤治疗中的作用有待探索。相信随着对MUC16研究的不断深入,其在肿瘤治疗中也将发挥越来越重要的生物学价值。因此,MUC16有望作为更多肿瘤的预测新标志,为抗癌治疗提供新策略。

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