title: Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma.
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.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Institute of Microbiology and Immunology, National Yang Ming University, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei, Taiwan.
authors.forename: Erh-Hsuan
authors.initials: EH
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Rung
authors.initials: YR
authors.lastname: Kao
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei, Taiwan.
authors.forename: Chih-An
authors.initials: CA
authors.lastname: Lin
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei, Taiwan.
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Kuo
authors.affiliation: Institute of Microbiology and Immunology, National Yang Ming University, Taipei, Taiwan.
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Yang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chiung-Fang
authors.initials: CF
authors.lastname: Hsu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Teh-Ying
authors.initials: TY
authors.lastname: Chou
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan.
authors.forename: Chao-Chi
authors.initials: CC
authors.lastname: Ho
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Institute of Microbiology and Immunology, National Yang Ming University, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei, Taiwan.
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Wu
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C117596:HHIP protein, human; D053823:Hedgehog Proteins; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors
keywords: HGF/MET; HHIP; Hedgehog pathway; drug resistance; lung adenocarcinoma