Research Papers:

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 and Cheng-Wen Wu _

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Oncotarget. 2016; 7:24179-24193. https://doi.org/10.18632/oncotarget.8253

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Erh-Hsuan Lin1,2,3,4, Yu-Rung Kao1, Chih-An Lin5, Ting-Yu Kuo4, Sheng-Ping Yang2, Chiung-Fang Hsu1, Teh-Ying Chou3,6, Chao-Chi Ho7, Cheng-Wen Wu1,2,3,4

1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

2Institute of Microbiology and Immunology, National Yang Ming University, Taipei, Taiwan

3Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

4Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei, Taiwan

5Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei, Taiwan

6Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

7Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan

Correspondence to:

Cheng-Wen Wu, e-mail: cwwu@ym.edu.tw

Keywords: lung adenocarcinoma, Hedgehog pathway, HHIP, drug resistance, HGF/MET

Received: July 30, 2015     Accepted: March 02, 2016     Published: March 22, 2016


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.

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