The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China.
The Hormel Institute, University of Minnesota, Austin, MN, USA.
Carcinogenesis. 2020 May 14;41(3):377-389. doi: 10.1093/carcin/bgz113.
The phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway is important in the regulation of cell proliferation through its production of phosphatidylinositol 3,4,5-triphosphate (PIP3). Activation of this pathway is frequently observed in human cancers, including non-small cell lung carcinoma. The PI3-K/Akt pathway is negatively regulated by the dual-specificity phosphatase and tensin homolog (PTEN) protein. PTEN acts as a direct antagonist of PI3-K by dephosphorylating PIP3. Studies have shown that PTEN phosphatase activity is inhibited by PREX2, a guanine nucleotide exchanger factor (GEF). Multiple studies revealed that CELF2, an RNA binding protein, cooperates synergistically with PTEN as a tumor suppressor in multiple cancers. However, the underlying mechanism as to how CELF2 enhances PTEN activity remains unclear. Here, we report that CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN. Consistent with this observation, PTEN phosphatase activity is upregulated with CELF2 overexpression. In addition, overexpression of CELF2 represses both Akt phosphorylation and cell proliferation only in the presence of PTEN. In an ex vivo study, CELF2 gene delivery could significantly inhibit patient-derived xenografts (PDX) tumor growth. To further investigate the clinical relevance of this finding, we analyzed 87 paired clinical lung adenocarcinoma samples and the results showed that CELF2 protein expression is downregulated in tumor tissues and associated with poor prognosis. The CELF2 gene is located on the chromosome 10p arm, a region frequently lost in human cancers, including breast invasive carcinoma, low-grade glioma and glioblastoma. Analysis of TCGA datasets showed that CELF2 expression is also associated with shorter patient survival time in all these cancers. Overall, our work suggests that CELF2 plays a novel role in PI3-K signaling by antagonizing the oncogenic effect of PREX2.
磷酸肌醇 3-激酶（PI3-K）/Akt 信号通路通过其产生的磷脂酰肌醇 3,4,5-三磷酸（PIP3）在细胞增殖的调节中起重要作用。该通路的激活在包括非小细胞肺癌在内的人类癌症中经常观察到。PI3-K/Akt 通路受双特异性磷酸酶和张力蛋白同系物（PTEN）蛋白的负调控。PTEN 通过去磷酸化 PIP3 作为 PI3-K 的直接拮抗剂起作用。研究表明，PREX2，一种鸟嘌呤核苷酸交换因子（GEF），抑制 PTEN 磷酸酶活性。多项研究表明，CELF2，一种 RNA 结合蛋白，与 PTEN 协同作用作为多种癌症的肿瘤抑制因子。然而，CELF2 如何增强 PTEN 活性的潜在机制尚不清楚。在这里，我们报告 CELF2 与 PREX2 相互作用并减少 PREX2 与 PTEN 的结合。与这一观察结果一致，CELF2 过表达可上调 PTEN 磷酸酶活性。此外，仅在存在 PTEN 的情况下，CELF2 的过表达可抑制 Akt 磷酸化和细胞增殖。在体外研究中，CELF2 基因递送可显著抑制患者来源的异种移植（PDX）肿瘤生长。为了进一步研究这一发现的临床相关性，我们分析了 87 对配对的临床肺腺癌样本，结果表明 CELF2 蛋白表达在肿瘤组织中下调，并与预后不良相关。CELF2 基因位于 10p 臂染色体上，该区域在人类癌症中经常丢失，包括乳腺癌浸润性癌、低级别胶质瘤和胶质母细胞瘤。对 TCGA 数据集的分析表明，CELF2 表达也与所有这些癌症中患者生存时间缩短相关。总体而言，我们的工作表明，CELF2 通过拮抗 PREX2 的致癌作用在 PI3-K 信号中发挥新的作用。
