title: Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer.
abstract: Colon cancer is the third leading cause of death from cancer worldwide with less than 10% survival rate at the late stage. Although mutations of certain genes have been implicated in familial colon cancer development, the etiology of the majority of colon cancer remains unknown. Herein, we identified TYRO3 as a potential oncogene. Immunohistochemical staining results demonstrated that levels of TYRO3 were markedly elevated in polyps and colon cancer cells and were negatively correlated with prognosis. Overexpression of TYRO3 enhanced cell motility, invasion, anchorage-independent growth and metastatic ability, while knockdown of TYRO3 impaired all these processes. Results from meta-analysis showed that TYRO3 was associated with epithelial-mesenchymal transition (EMT) signatures. Gain-of-function and loss-of-function experiments demonstrated that expression of SNAI1, the master regulator of EMT, was regulated by TYRO3 and played a major role in mediating TYRO3-induced EMT processes. The murine model also demonstrated that Tyro3 and Snai1 were upregulated in the early stage of colon cancer development. To provide a proof-of-concept that TYRO3 is a druggable target in colon cancer therapy, we raised anti-TYRO3 human antibodies and showed that treatment with the human antibody abolished TYRO3-induced EMT process. More importantly, administration of this anti-TYRO3 antibody increased drug sensitivity in primary cultured colon cancer cells and xenografted mouse tumors. These findings demonstrate that TYRO3 is a novel oncogene and a druggable target in colon cancer.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: C-W
authors.initials: CW
authors.lastname: Chien
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: P-C
authors.initials: PC
authors.lastname: Hou
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Nankang, Taipei, Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Wu
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Nankang, Taipei, Taiwan.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: S-C
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: S-C
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: B-W
authors.initials: BW
authors.lastname: Lin
authors.affiliation: Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: J-C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: H S
authors.initials: HS
authors.lastname: Sun
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Tsai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D003111:Colonic Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human