title: A targetable HB-EGF-CITED4 axis controls oncogenesis in lung cancer.
abstract: Aberrant epidermal growth factor (EGF) receptor (EGFR) signaling contributes to neoplastic initiation and progression in lung. Mutated EGFR has become as an important therapeutic target in lung cancer, whereas targeted treatment is not available for wild-type EGFR or its ligands. In this study, we found that heparin-binding (HB)-EGF, a member of the EGF family, was highly expressed in a subset of lung cancer, proliferation of which was dependent on HB-EGF signaling. Silencing of HB-EGF with RNA interference inhibited cell cycle progression in lung cancer cells. We observed that, upon HB-EGF induction, CITED4 was induced through a signal transducer and activator of transcription 3 (STAT3)-dependent pathway, regulating cell proliferation. CITED4 interacted with MYC and potentiated MYC-mediated transactivation of the CCND1 promoter, leading to cell cycle progression. Correlation analysis revealed that HB-EGF and CITED4 were significantly positively associated in primary lung tumors, and expression of HB-EGF predicted a poor survival outcome in patients. In vitro and in vivo experiments revealed that pharmacological inhibition of HB-EGF with CRM197 significantly attenuated tumor cell growth. Thus, CITED4 functions as a molecular switch in HB-EGF-induced growth control, and HB-EGF provides a novel therapeutic target for lung cancer intervention.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: C-H
authors.initials: CH
authors.lastname: Hsieh
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan, ROC.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Chou
authors.affiliation: Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan, ROC.
authors.forename: M-H
authors.initials: MH
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
authors.forename: H-P
authors.initials: HP
authors.lastname: Tsai
authors.affiliation: Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, ROC.|Department of Biomedical Engineering, Ming Chuan University, Taoyuan, Taiwan, ROC.
authors.forename: J-L
authors.initials: JL
authors.lastname: Chang
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, ROC.|Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan, ROC.
authors.forename: C-W
authors.initials: CW
authors.lastname: Wu
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C451405:CITED4 protein, human; D066257:Heparin-binding EGF-like Growth Factor; D014157:Transcription Factors