Tumor Suppression of Ras GTPase-Activating Protein RASA5 through Antagonizing Ras Signaling Perturbation in Carcinomas
Tumor Suppression of Ras GTPase-Activating Protein RASA5 through Antagonizing Ras Signaling Perturbation in Carcinomas
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Ras GTP 酶激活蛋白 RASA5 通过拮抗癌症中的 Ras 信号传导扰动来抑制肿瘤
DOI：
10.1016/j.isci.2019.10.007
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发表时间：
2019-11-22
期刊：
影响因子：
5.8
通讯作者：
Tao, Qian
中科院分区：
文献类型：
--
作者：
Li, Lili;Fan, Yichao;Tao, Qian
RAS信号的异常激活在RAS突变很少的癌症中很常见，这表明除了基因突变外，还有其他的调节失调。我们发现了一个RAS GTP酶激活基因RASA5/SYNGAP1，位于常见的6p21.3缺失，在多种肿瘤中甲基化/下调，不同于其他RASA家族成员(RASA1-RASA4)，表明它在肿瘤发生中具有特殊的功能。与其他RASA成员不同，RASA5突变很少见，而其启动子CpG甲基化在多种癌细胞系和原发癌中频繁出现，并与患者的低生存率有关。在小鼠模型中，RASA5的表达抑制了肿瘤细胞的迁移、侵袭和生长，发挥了肿瘤抑制作用。RASA5通过激活RAS GTP酶激活蛋白的活性抑制RAS信号转导，该作用可被致癌基因HRAS Q61L突变所抵消。RASA5基因敲除增强了RAS信号，促进了肿瘤细胞的生长。RASA5还通过调节肌动蛋白重组抑制上皮间充质转化(EMT)。因此，RASA5的表观遗传失活有助于RAS信号的过度活跃，参与了RAS驱动的人类肿瘤的发生。
Aberrant RAS signaling activation is common in cancers with even few Ras mutations, indicating alternative dysregulation other than genetic mutations. We identified a Ras GTPase-activating gene RASA5/SYNGAP1, at the common 6p21.3 deletion, methylated/downregulated in multiple carcinomas and different from other RASA family members (RASA1-RASA4), indicating its special functions in tumorigenesis. RASA5 mutations are rare, unlike other RASA members, whereas its promoter CpG methylation is frequent in multiple cancer cell lines and primary carcinomas and associated with patient's poor survival. RASA5 expression inhibited tumor cell migration/invasion and growth in mouse model, functioning as a tumor suppressor. RASA5 suppressed RAS signaling, depending on its Ras GTPase-activating protein catalytic activity, which could be counteracted by oncogenic HRas Q61L mutant. RASA5 knockdown enhanced Ras signaling to promote tumor cell growth. RASA5 also inhibited epithelial-mesenchymal transition (EMT) through regulating actin reorganization. Thus, epigenetic inactivation of RASA5 contributing to hyperactive RAS signaling is involved in Ras-driven human oncogenesis.