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Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma
- Source :
- Oncotarget
- Publication Year :
- 2016
- Publisher :
- Impact Journals, LLC, 2016.
-
Abstract
- // Erh-Hsuan Lin 1, 2, 3, 4 , Yu-Rung Kao 1 , Chih-An Lin 5 , Ting-Yu Kuo 4 , Sheng-Ping Yang 2 , Chiung-Fang Hsu 1 , Teh-Ying Chou 3, 6 , Chao-Chi Ho 7 , Cheng-Wen Wu 1, 2, 3, 4 1 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 2 Institute of Microbiology and Immunology, National Yang Ming University, Taipei, Taiwan 3 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 4 Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei, Taiwan 5 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei, Taiwan 6 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 7 Department 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 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.
- Subjects :
- HGF/MET
0301 basic medicine
Lung Neoplasms
HHIP
Mice, Nude
Apoptosis
Drug resistance
Adenocarcinoma
Hedgehog pathway
Mice
03 medical and health sciences
0302 clinical medicine
Stress, Physiological
Carcinoma, Non-Small-Cell Lung
Biomarkers, Tumor
Tumor Cells, Cultured
medicine
Animals
Humans
Hedgehog Proteins
Epidermal growth factor receptor
Protein Kinase Inhibitors
Hedgehog
Cell Proliferation
Mice, Inbred BALB C
drug resistance
Membrane Glycoproteins
biology
Kinase
Cell growth
Cancer
lung adenocarcinoma
medicine.disease
Xenograft Model Antitumor Assays
Hedgehog signaling pathway
030104 developmental biology
Oncology
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Immunology
Cancer research
biology.protein
Carrier Proteins
Research Paper
Signal Transduction
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....2144e7a17ae5a2de56a0a8460c586452
- Full Text :
- https://doi.org/10.18632/oncotarget.8253