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Protein Cell :姜海/张雷合作发现新型原癌基因以及Hippo通路新调控因子SHANK2

2020-07-29 兮、迦溆 BioArt

癌细胞中原癌基因的一个重要激活方式是通过所在染色体区段的局域扩增,获得基因拷贝数的增加。经典原癌基因如c-Myc、HER2、SKP2等都是主要通过这种方式激活。

癌细胞中原癌基因的一个重要激活方式是通过所在染色体区段的局域扩增,获得基因拷贝数的增加。经典原癌基因如c-Myc、HER2、SKP2等都是主要通过这种方式激活。然而,染色体的区段扩增并不是一个精准的过程,绝大多数肿瘤中都会出现原癌基因附近的几个甚至上百个基因被附带扩增的现象(co-amplification)。因此,对于肿瘤中的一些染色体扩增区段,哪些是驱动肿瘤的原癌基因,哪些是被附带扩增的基因,目前结论仍不明确。

针对这一问题,一个较为直观的推断是,由于原癌基因扩增是肿瘤的内在促发因素,因此它的扩增应该出现在所有带有该染色体区段扩增的肿瘤样本中。因此,系统性地分析肿瘤中某一促癌染色体区段上各个基因的扩增频率,其中扩增最为频繁的基因可能是促进肿瘤的原癌基因。然而,此前癌症基因扩增的研究数据少且分散,难以提供足够多的样本量以保证上述分析的分辨率。

近期肿瘤基因组数据的积累为解析这一问题提供了新的机遇。2020年7月13日,中科院分子细胞科学卓越创新中心(生化与细胞所)姜海课题组与细胞分子科学卓越创新中心的张雷课题组合作在Protein &Cell杂志上发表文章“SHANK2 is a frequently amplified oncogene with evolutionarily conserved roles in regulating Hippo signaling”,首次发现自闭症相关基因SHANK2是一个此前未知的原癌基因并参与Hippo信号通路调控。

姜海课题组从COSMIC肿瘤基因组数据库中,汇总了所有蛋白编码基因在一万四千多个肿瘤基因组中的扩增情况,并与各个基因所在的染色体区段进行比对,生成了高分辨度的肿瘤基因扩增——染色体编码位置的对照数据组。在此基础上,对各个染色体扩增区段中的原癌基因进行了预测。这些分析发现,11q13是人类肿瘤中扩增第二频繁的染色体区段,然而其中扩增频率最高的不是传统上所认为的细胞周期调控因子Cyclin D1(CCND1),而是此前并未被发现有促癌作用的SHANK2基因,扩增后者的肿瘤样本的数目是前者的近两倍。这提示SHANK2可能是一个新的潜在原癌基因。

巧合的是,张雷课题组在果蝇中筛选HIPPO信号通路的新调控因子时,发现SHANK2的同源基因在果蝇中过表达后,引发了极为显着的HIPPO通路失活、细胞过度增殖的表型。这提示SHANK2可能通过干扰HIPPO通路,从而促进细胞增殖和癌症发生。结合这一发现,姜海课题组在哺乳动物细胞中深入分析了SHANK2的促细胞增殖效应,利用多个小鼠肿瘤模型证实了SHANK2的促肿瘤效应,验证了SHANK2调控HIPPO通路的能力,并阐述其分子机理。研究表明,SHANK2通过其PDZ结构域竞争性地结合ARHGEF7,使其不能与LATS1结合,导致后者对YAP磷酸化程度的降低。删除PDZ结构域后,SHANK2不再能够抑制HIPPO通路活性,并且失去了促肿瘤能力。

此外,在SHANK2过表达的肿瘤细胞系中,敲减SHANK2可以恢复HIPPO通路活性,并且完全抑制细胞增殖以及裸鼠内的成瘤能力。这提示SHANK2可能是一个新的潜在治疗靶点。由于在成年人中SHANK2仅在神经系统中表达,不参与外周组织正常细胞的增殖,因此作为一个潜在的治疗靶点,可能可以利用血脑屏障,实现低毒性的癌症治疗。

SHANK2作为自闭症相关基因,此前的研究主要聚焦于其在神经系统中的作用。该项研究首次发现SHANK2是一个此前未知的原癌基因。该项研究还表明,SHANK2是一个进化上保守的HIPPO通路调控因子,并指出了肿瘤细胞逃逸HIPPO抑癌效应的新途径。

据悉,姜海课题组的博士生徐亮是第一作者,张雷课题组的李培学、丰雪和卢仪完成了果蝇中的研究工作,姜海和张雷是该项研究的共同通讯作者。

值得注意的是,尽管一直以来CyclinD1被认为是11q13上的主要驱动因素,11q13扩增的肿瘤在临床上对CyclinD-CDK4/6抑制剂并不敏感。近期发表的一项肿瘤样本的蛋白染色研究也发现,近80%的扩增11q13的食管癌样本中过表达SHANK2,而同样的11q13扩增样本中仅25%过表达Cyclin D1,这些研究提示11q13区段可能存在额外的、独立于CyclinD1的驱动因素。该项研究通过系统性地分析上万个肿瘤样本中的基因扩增情况,并结合基因的染色体定位,发现SHANK2可以填补这一可能性。除了SHANK2以外,肿瘤其余染色体扩增区段还存在有一些潜在的新型原癌基因。类似方法也可用于肿瘤染色体删除区的抑癌基因等相关问题的研究。

原始出处:

Liang Xu, Peixue Li, Xue Hao, et al.SHANK2 is a frequently amplified oncogene with evolutionarily conserved roles in regulating Hippo signaling.Protein Cell. 2020 Jul 13. doi: 10.1007/s13238-020-00742-6.

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    2020-12-09 维他命
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    2020-07-31 sunylz
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