EFNA4 promotes cell proliferation and tumor metastasis in hepatocellular carcinoma through a PIK3R2/GSK3β/β-catenin positive feedback loop.
EFNA4 promotes cell proliferation and tumor metastasis in hepatocellular carcinoma through a PIK3R2/GSK3β/β-catenin positive feedback loop.
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EFNA4通过PIK3R2/GSK3β/β-连环蛋白正反馈环促进肝细胞癌的细胞增殖和肿瘤转移
DOI：
10.1016/j.omtn.2021.06.002
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发表时间：
2021-09-03
期刊：
影响因子：
--
通讯作者：
Chen F
中科院分区：
文献类型：
--
作者：
Lin J;Zeng C;Zhang J;Song Z;Qi N;Liu X;Zhang Z;Li A;Chen F
快速的肿瘤进展、转移和疾病晚期的诊断是导致肝细胞癌患者生存时间短、死亡率高的主要原因。促肾上腺皮质激素释放激素(EPH)家族的配体--肾上腺素A4(EFNA4)通过调节细胞迁移和排斥反应参与血管和上皮的发育。在我们的研究中，基于生物信息学分析，我们发现EFNA4在肝癌患者中高表达，并导致预后不良。我们证明了EFNA4的过表达在体内和体外都显著促进了肝癌细胞的增殖和迁移。此外，EFNA4基因敲除抑制了肝癌细胞的增殖和迁移。此外，还发现EFNA4直接与EphA2相互作用，促进其在Ser897位的磷酸化，然后募集磷脂酰肌醇-3-激酶调节亚基2(PIK3R2)，激活糖原合成酶-3β(GSK3β)/β-连环蛋白)信号通路。此外，β-连环蛋白的过表达进一步促进了PIK3R2的表达，形成了一个正反馈环。结果表明，EFNA4的异常表达是PIK3R2/GSK3β/β-连环蛋白环路的主要开关，影响肝癌细胞的增殖和迁移，提示EFNA4可能是肝癌患者潜在的预后指标和治疗靶点。EFNA4是一种癌基因，与肝癌患者的临床预后呈负相关。EFNA4的异常表达可能通过激活GSK3β-β-连环蛋白-PIK3R2正反馈环而促进肝癌的增殖和迁移。因此，阐明EFNA4的作用机制将有助于为肝癌患者提供新的治疗靶点。
Rapid tumor progression, metastasis, and diagnosis in advanced stages of disease are the main reasons for the short survival time and high mortality rate of patients with hepatocellular carcinoma (HCC). Ephrin A4 (EFNA4), the ligand of the EPH family, participates in the development of blood vessels and epithelium by regulating cell migration and rejection. In our study, based on bioinformatics analyses, we found that EFNA4 was highly expressed and led to poor prognosis in patients with HCC. We demonstrated that overexpression of EFNA4 significantly promoted HCC cell proliferation and migration in vivo or in vitro. In addition, knockdown of EFNA4 inhibited the proliferation and migration of HCC cells. Furthermore, EFNA4 was found to directly interact with EPHA2 and promote its phosphorylation at Ser897, followed by recruitment of phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) and activation of the glycogen synthase kinase-3beta (GSK3β)/β-catenin signaling pathway. Moreover, overexpression of β-catenin further promoted the expression of PIK3R2, which formed a positive feedback loop. The results revealed that abnormal expression of EFNA4 is the main switch of the PIK3R2/GSK3β/β-catenin loop that influenced the proliferation and migration of HCC cells and suggest that EFNA4 is a potential prognostic marker and a prospective therapeutic target in patients with HCC. EFNA4 is an oncogene that negatively relates to the clinical prognosis in HCC patients. Abnormal expression of EFNA4 would contribute to HCC proliferation and migration by activating a GSK3β-β-catenin-PIK3R2 positive feedback loop. Thus, clarification of the mechanism of EFNA4 would be helpful for providing a new therapeutic target for HCC patients.
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