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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)24179-24193
Number of pages15
JournalOncotarget
Volume7
Issue number17
DOIs
StatePublished - 26 Apr 2016

Keywords

  • Drug-resistance
  • HGF/MET
  • HHIP
  • Hedgehog pathway
  • Lung adenocarcinoma

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