Downregulation of CPA4 inhibits non small-cell lung cancer growth by suppressing the AKT/c-MYC pathway
Downregulation of CPA4 inhibits non small-cell lung cancer growth by suppressing the AKT/c-MYC pathway
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DOI：
10.1002/mc.23095
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发表时间：
2019-08-09
影响因子：
4.6
通讯作者：
Huang, Xiaoying
中科院分区：
文献类型：
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作者：
Fu, Yangyang;Su, Lihuang;Huang, Xiaoying
羧肽酶A4（CPA4）是金属羧肽酶家族的成员。先前的一项研究表明，CPA4可能参与肽类激素活性的调节以及激素调控的组织生长和分化。然而，CPA4在肺肿瘤发生中的作用仍不清楚。我们的研究显示，CPA4在肺癌细胞和肿瘤组织中的表达均较高。我们进行了3 -（4,5 - 二甲基噻唑 - 2 - 基）- 2,5 - 二苯基四氮唑溴盐测定、集落形成测定以及Cellomics ArrayScan Infinity分析，以证明CPA4的敲低抑制了非小细胞肺癌（NSCLC）细胞的增殖。相反，CPA4的异位表达增强了肺癌细胞的增殖。与这些观察结果一致，我们构建了异种移植肿瘤模型，证实CPA4的下调抑制了NSCLC细胞的生长。从机制上讲，我们发现CPA4的下调可能通过抑制蛋白激酶B/c - MYC通路诱导细胞凋亡和G1 - S期阻滞。这些结果表明，CPA4对肺癌生长具有致癌作用。综上所述，我们在肺癌中鉴定出一个新的基因，这可能为新的治疗靶点提供依据。
Carboxypeptidase A4 (CPA4) is a member of the metallocarboxypeptidase family. A previous study indicated that CPA4 may participate in the modulation of peptide hormone activity and hormone-regulated tissue growth and differentiation. However, the role of CPA4 in lung tumorigenesis remains unclear. Our study revealed that CPA4 expression was higher in both lung cancer cells and tumor tissues. We performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays, colony-formation assays, and Cellomics ArrayScan Infinity analysis to demonstrate that CPA4 knockdown inhibited non small-cell lung cancer (NSCLC) cell proliferation. Conversely, ectopic expression of CPA4 enhanced lung cancer cell proliferation. Consistent with these observations, we generated xenograft tumor models to confirm that CPA4 downregulation suppressed NSCLC cell growth. Mechanistically, we revealed that CPA4 downregulation may induce apoptosis and G1-S arrest by suppressing the protein kinase B/c-MYC pathway. These results suggest that CPA4 has an oncogenic effect on lung cancer growth. Taken together, we identified a novel gene in lung cancer that might provide a basis for new therapeutic targets.