https://scholars.lib.ntu.edu.tw/handle/123456789/511547
標題: | Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma | 作者: | Lin E.-H. Kao Y.-R. Lin C.-A. Kuo T.-Y. Yang S.-P. Hsu C.-F. Chou T.-Y. CHAO-CHI HO Wu C.-W. |
公開日期: | 2016 | 出版社: | Impact Journals LLC | 卷: | 7 | 期: | 17 | 起(迄)頁: | 24179-24193 | 來源出版物: | Oncotarget | 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. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84966570027&doi=10.18632%2foncotarget.8253&partnerID=40&md5=c3bdf4b08514c0163682c6a8f4a53737 https://scholars.lib.ntu.edu.tw/handle/123456789/511547 |
ISSN: | 1949-2553 | DOI: | 10.18632/oncotarget.8253 | SDG/關鍵字: | crizotinib; cyclopamine; gefitinib; scatter factor; scatter factor receptor; sonic hedgehog protein; carrier protein; HHIP protein, human; membrane protein; protein kinase inhibitor; sonic hedgehog protein; tumor marker; animal experiment; animal model; animal tissue; Article; cancer resistance; cell growth; cell invasion; cell proliferation; cell stress; cell survival; chemosensitivity; clonogenesis; controlled study; down regulation; epigenetics; gene expression regulation; gene overexpression; gene silencing; HGF gene; HHIP gene; human; human cell; human tissue; in vivo study; lung adenocarcinoma; lung cancer cell line; major clinical study; MET gene; mouse; nonhuman; oncogene; pharmacological blocking; promoter region; protein phosphorylation; sensitivity analysis; signal transduction; tumor spheroid; adenocarcinoma; animal; apoptosis; Bagg albino mouse; drug effects; drug resistance; drug screening; lung tumor; metabolism; non small cell lung cancer; nude mouse; pathology; physiological stress; signal transduction; tumor cell culture; Adenocarcinoma; Animals; Apoptosis; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carrier Proteins; Cell Proliferation; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Lung Neoplasms; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Kinase Inhibitors; Signal Transduction; Stress, Physiological; Tumor Cells, Cultured; Xenograft Model Antitumor Assays |
顯示於: | 醫學系 |
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