PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma.
PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma.
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PRKAR1A 是一种功能性肿瘤抑制因子，抑制肺腺癌中的 ERK/Snail/E-cadherin 通路
DOI：
10.1038/srep39630
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发表时间：
2016-12-20
影响因子：
4.6
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Wang S;Cheng Y;Zheng Y;He Z;Chen W;Zhou W;Duan C;Zhang C
蛋白激酶cAMP依赖性调节I型α（PRKAR 1A）是一种组织特异性熄灭剂，通过不同靶蛋白的磷酸化转导信号。PRKAR 1A的缺失在内分泌瘤和间质细胞瘤中经常观察到。然而，在上皮性肿瘤中观察到少数病例。此前，我们首次发现PRKAR 1A在肺腺癌患者中下调。因此，本研究旨在阐明其作为肺腺癌肿瘤抑制因子的临床意义和生物学功能。PRKAR 1A转录物的低水平与肿瘤进展和总生存率差相关。PRKAR 1A在H1299细胞中的重新表达抑制了肿瘤细胞的增殖和迁移;在A549细胞中稳定敲低（KD）PRKAR 1A在体外和体内均增强了这种功能。此外，A549细胞中PRKAR 1A的KD促进了循环肿瘤细胞在裸鼠中向肺的统计学定殖。PRKAR 1A的这些作用归因于抑制E-钙粘蛋白表达。升高的E-钙粘蛋白显著抑制PRKAR 1A-KD诱导的细胞增殖和迁移。最值得注意的是，PRKAR 1A的缺失通过激活ERK/Snail信号传导抑制E-钙粘蛋白。结论：PRKAR 1A是一种有效的抑制剂，通过抑制PRKAR 1A-ERK-Snail-E-cadherin轴可以作为潜在的治疗靶点。
Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue-specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma. The low levels of PRKAR1A transcript were correlated with tumor progression and poor overall survival. The re-expression of PRKAR1A in H1299 cells suppressed the tumor cell proliferation and migration; stable knockdown (KD) of PRKAR1A in A549 cells enhanced this function both in vitro and in vivo. Moreover, KD of PRKAR1A in A549 cells promoted the statistical colonization of circulating tumor cells to the lungs in nude mice. These effects by PRKAR1A were attributed to inhibiting E-cadherin expression. Elevated E-cadherin significantly suppressed the PRKAR1A-KD induced cell proliferation and migration. Most notably, deletion of PRKAR1A inhibited E-cadherin by activating ERK/Snail signaling. In conclusion, PRKAR1A was a potent suppressor, and through the inhibition of PRKAR1A-ERK-Snail-E-cadherin axis could serve as a potential therapeutic target.