title: Overexpression of Tyro3 and its implications on hepatocellular carcinoma progression.
abstract: While various tyrosine kinases have been associated with the pathogenesis of hepatocellular carcinoma (HCC), the identification of a dominant therapeutic target among them remains a challenge. Here, we investigated the role of Tyro3, a relatively uncharacterized member of the TAM (Tyro3, Axl and Mer) receptor family. The present study aimed to profile and identify potential association between Tyro3 expression in HCC and cancer phenotypes. RNAs obtained from 55 HCC patients were quantified for Tyro3 expression in both cancerous tissue and the adjacent normal tissue. Expression profile was correlated with clinical data. These observations were further substantiated with in vitro HCC cell culture investigations.Tyro3 was strongly upregulated (>2-fold elevation) in the tumor tissue of ~42% of the patients. It was shown that higher expression level of Tyro3 was associated with the key tumor marker AFP, and the tumor diameter and liver injury marker ALT. Subsequent cell culture models indicated high expression in various HCC cell lines, in particular Hep3B. Gene silencing of Tyro3 in Hep3B effectively reduced cell proliferation, ERK phosphorylation and cyclin D1 expression, indicating a key in maintaining the proliferative state of these cells. Notably, silencing also suppressed the transcriptional and translational expression of HCC tumor marker AFP. Overall, these data suggest that Tyro3 contributes significantly to tumor growth, aggressiveness and liver dysfunction. Inhibition of Tyro3 and its aberrant signaling in tumors with high expression could present new opportunities for HCC treatment.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Republic of Singapore.
authors.forename: Yan
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Republic of Singapore.
authors.forename: Winnie
authors.initials: W
authors.lastname: Wong
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Republic of Singapore.
authors.forename: Sonja Courtney
authors.initials: SC
authors.lastname: Chua
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Republic of Singapore.
authors.forename: Hwee Lin
authors.initials: HL
authors.lastname: Wee
authors.affiliation: Department of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Republic of Singapore.
authors.forename: Seng Gee
authors.initials: SG
authors.lastname: Lim
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore 138673, Republic of Singapore.
authors.forename: Boon Tin
authors.initials: BT
authors.lastname: Chua
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Republic of Singapore.
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
mesh_terms: D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human