GPRC5A deficiency leads to dysregulated MDM2 via activated EGFR signaling for lung tumor development.
GPRC5A deficiency leads to dysregulated MDM2 via activated EGFR signaling for lung tumor development.
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GPRC5A 缺陷通过激活 EGFR 信号通路导致 MDM2 失调，从而促进肺肿瘤的发展。
DOI：
10.1002/ijc.31726
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发表时间：
2018
影响因子：
6.4
通讯作者：
Deng Jiong
中科院分区：
文献类型：
--
作者：
Song Hongyong;Sun Beibei;Liao Yueling;Xu Dongliang;Guo Wenzheng;Wang Tong;Jing Bo;Hu Min;Li Kaimi;Yao Feng;Deng Jiong
GPRC5A是维甲酸诱导基因，在肺组织中优先表达。Gprc5a基因缺失导致自发性肺肿瘤发展。然而，Gprc5a介导的肺肿瘤抑制机制尚不完全清楚。本研究表明，与野生型相比，Gprc5a敲除（ko）小鼠气管上皮细胞（ko - MTEC）中p53负调节因子MDM2出现了失调。通过MDM2抑制剂Nutlin‐3a或sh‐RNA （small hairpin RNA）靶向1601-a Gprc5a‐ko小鼠源性肺癌细胞系和a549人肺癌细胞中的MDM2，恢复p53信号通路，降低癌症干细胞标志物，抑制致瘤性。这表明失调的MDM2通路对这些细胞的致癌活性至关重要。研究发现，MDM2主要通过激活EGFR信号来稳定，厄洛替尼或sh - RNA以转录独立的方式抑制MDM2靶向EGFR。重要的是，MDM2的过表达和GPRC5A蛋白和mRNA水平的表达降低在临床人肺癌组织中经常被发现。综上所述，GPRC5A缺乏通过激活EGFR信号导致MDM2失调，从而促进肺肿瘤的发展。
GPRC5A, a retinoic acid induced gene, is preferentially expressed in lung tissue. Gprc5a gene deletion leads to spontaneous lung tumor development. However, the mechanism of Gprc5a‐mediated lung tumor suppression is not fully understood. Here we showed that MDM2, a p53‐negative regulator, was dysregulated in Gprc5a‐knockout (ko) mouse tracheal epithelial cells (KO‐MTEC) compared to wild type ones. Targeting MDM2 in 1601—a Gprc5a‐ko mouse derived lung tumor cell line—and A549—human lung cancer cells, by MDM2 inhibitor Nutlin‐3a or small hairpin RNA (sh‐RNA)—restored p53 signaling pathway, reduced cancer stem cell markers, and inhibited tumorigenicity. This suggests that dysregulated MDM2 pathway is essential for the oncogenic activities of these cells. MDM2 was found to be stabilized mainly by activated EGFR signaling as targeting EGFR by Erlotinib or sh‐RNA repressed MDM2 in a transcription‐independent manner. Importantly, overexpression of MDM2 and reduced GPRC5A expression at both protein and mRNA levels were frequently found in clinical human lung cancer tissues. Taken together, GPRC5A deficiency contributes to dysregulated MDM2 via activated EGFR signaling, which promotes lung tumor development.