The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42
The novel GINS4 axis promotes gastric cancer growth and progression by activating Rac1 and CDC42
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新型 GINS4 轴通过激活 Rac1 和 CDC42 促进胃癌生长和进展
DOI：
10.7150/thno.36256
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Huang, Chen
中科院分区：
文献类型：
--
作者：
Zhu, Zhonglin;Yu, Zhilong;Huang, Chen
理由：GINS4作为GINS复合物的一个组成部分，在真核生物中启动DNA复制和细胞周期G1/S期延长是必不可少的，在正常生理过程中起着至关重要的作用。然而，GINS4在人类肿瘤中的确切功能和调控机制尚不清楚。方法：采用qRT-PCR和western blotting分析GINS4在胃癌组织中的表达，并应用TMA分析其临床意义。在体外和体内检测GINS4的生物学功能。通过cDNA阵列、co-IP、GST下拉和GTPase激活实验研究GINS4的下游调控机制。通过circRNA测序、生物信息学分析、荧光素酶报告基因测定和拯救实验，探索并论证了GINS4的上游调控机制。结果：胃癌组织中GINS4的高表达与分化差、肿瘤分期晚期、浸润深度及淋巴结转移相关。GINS4在体外和体内均能促进细胞生长和转移，抑制细胞凋亡。机制上，GINS4通过直接结合Rac1/CDC42激活Rac1/CDC42，从而激活它们的下游通路。此外，circMLLT10作为miR-509-3-5p海绵，减弱其对靶GINS4的抑制作用。此外，circMLLT10促进细胞生长和转移，抑制细胞凋亡，而miR-509-3-5p抑制细胞生长和转移，促进细胞凋亡。结论：本研究首次提示新型GINS4轴通过激活Rac1和CDC42促进胃癌细胞生长和进展。GINS4可能是一种有前景的生物标志物和胃癌的诊断和治疗靶点。
Rationale: As a component of GINS complex, GINS4 is essential for initiating DNA replication and elongation of the cell cycle G1/S phase in eukaryotes and plays a vital role in normal physiological processes. However, the precise functions and regulation mechanisms of GINS4 in human tumors remain elusive.Methods: GINS4 expression was analyzed in gastric cancer tissues by qRT-PCR and western blotting, and its clinical relevance was studied using TMA. The biological functions of GINS4 were detected in vitro and in vivo. cDNA array, co-IP, GST pull-down and GTPase activation assays were performed to investigate the downstream regulation mechanism of GINS4. Upstream regulation mechanism of GINS4 was explored and demonstrated by circRNA sequencing, bioinformatics analysis, luciferase reporter assay and rescue experiments.Results: Strikingly high GINS4 expression was detected in gastric cancer tissues and correlated with poor differentiation, advanced tumor stage, invasion depth and lymph node metastasis. GINS4 promoted cell growth and metastasis in vitro and in vivo, and suppressed cell apoptosis in vitro. Mechanistically, GINS4 activated Rac1/CDC42 through directly binding to Rac1/CDC42, thereby activating their downstream pathways. Furthermore, circMLLT10 acts as a miR-509-3-5p sponge to attenuate its repressive effect on target GINS4. In addition, circMLLT10 promoted cell growth and metastasis and suppressed cell apoptosis, whereas miR-509-3-5p inhibited cell growth and metastasis and promoted cell apoptosis.Conclusion: The findings indicate for the first time that the novel GINS4 axis promotes gastric cancer cell growth and progression by activating Rac1 and CDC42. GINS4 may be a promising biomarker and target for diagnosis and treatment of gastric cancer.