TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice.
TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice.
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DOI：
10.1038/onc.2012.253
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发表时间：
2013-05-02
期刊：
影响因子：
8
通讯作者：
Xiao, H.
中科院分区：
文献类型：
--
作者：
Li, A.;Zhang, C.;Gao, S.;Chen, F.;Yang, C.;Luo, R.;Xiao, H.
肺腺癌是人类最常见的非小细胞肺癌(NSCLC)，常过度表达EGFR。然而，EGFR过度表达的机制尚不完全清楚。最近的研究发现，TIP30的低表达与人非小细胞肺癌的转移有关，但TIP30缺乏与非小细胞肺癌发生发展之间的关系尚不清楚。我们在这里表明，Tip30缺失会导致小鼠肺腺瘤和腺癌的自发发展。在Tip30−/−小鼠肺肿瘤发生之前，肺泡干/祖细胞和肺泡II型细胞的异常扩张，以及EGFR及其下游信号因子在肺中的表达增加。此外，TIP30基因敲除人肺腺癌细胞可导致早期内吞体内EGFR活性延长，EGFR降解延迟，EGFR核定位增加，进而上调PACK和pERK1/2的表达。重要的是，在人类肺腺癌中，TIP30的低表达与患者总体和进展后生存时间的延长相关。综上所述，这些结果表明，TIP30作为一种肿瘤抑制因子，可以抑制EGFR胞浆和核信号，抑制肺腺癌的发生，并突出了针对TIP30低表达的肺腺癌患者旨在抑制EGFR信号转导的治疗策略的潜力。
Lung adenocarcinoma, the most common type of human non-small cell lung cancer (NSCLC), frequently overexpresses EGFR. However, the mechanisms underlying EGFR overexpression are not completely understood. Recent studies have identified that decreased expression of TIP30 is associated with the metastasis of human NSCLCs, but a causative relationship between TIP30 deficiency and NSCLC development remains unclear. We show here that Tip30 deletion leads to spontaneous development of lung adenomas and adenocarcinomas in mice. Lung tumor development was preceded by aberrant expansion of bronchioalveolar stem/progenitor and alveolar type II cells, as well as increased expression of EGFR and its downstream signaling factors in the lung of Tip30−/− mice. Moreover, TIP30 knockdown in human lung adenocarcinoma cells resulted in prolonged EGFR activity in early endosomes, delayed EGFR degradation, increased EGFR nuclear localization, leading to up-regulated pAKT and pERK1/2 expression. Importantly, in human lung adenocarcinomas, low TIP30 expression correlates with prolonged patient overall and post-progression survival times. Together, these results suggest that TIP30 functions as a tumor suppressor to inhibit EGFR cytoplasmic and nuclear signaling and suppress adenocarcinogenesis in the lung and highlight the potential of therapeutic strategies aiming at inhibiting EGFR signaling for patients with low TIP30 expression lung adenocarcinoma.
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