Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma

Erh Hsuan Lin, Yu Rung Kao, Chih An Lin, Ting Yu Kuo, Sheng Ping Yang, Chiung Fang Hsu, Teh Ying Chou, Chao Chi Ho, Cheng-Wen Wu Lee*

*此作品的通信作者

研究成果: Article同行評審

30 引文 斯高帕斯(Scopus)

摘要

Hedgehog (HH) pathway plays an important role in embryonic development, but is largely inactive in adult except for tissue repair. Aberrant activation of HH pathway has been found in a variety of cancer types. In non-small cell lung cancer, however, the role and importance of HH pathway remain controversial. In the current study, we found that HH pathway was maintained in low activity in lung adenocarcinoma (LAC) cells under normal culture condition, but was highly induced in response to stress conditions. Activation of HH pathway promoted cell survival, growth, and invasion partially through HGF and MET signaling. Hedgehog-Interacting Protein (HHIP), a cell-surface negative regulator of HH pathway, was epigenetically silenced in LAC. Overexpression of HHIP blocked the activation of HH and HGF/MET pathways, and made cells significantly more susceptible to stress conditions. In LAC cells with acquired resistance to Epidermal Growth Factor Receptor Tyrosin Kinase Inhibitor (EGFR-TKI), we found that a part of tumor cells were much more sensitive to HH or HGF/MET inhibitors, suggesting an oncogenic addiction shift from EGFR to HH and HGF/MET pathways. In conclusion, this study showed that HH pathway is a survival signaling that drives LAC cell growth under stress conditions, and HHIP is a key regulator to block the induction of HH pathway. Targeting the HH pathway through inhibitors or HHIP thus holds promise to address EGFR-TKI resistance in LAC in clinic.

原文English
頁(從 - 到)24179-24193
頁數15
期刊Oncotarget
7
發行號17
DOIs
出版狀態Published - 26 四月 2016

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