title: Protein S drives oral squamous cell carcinoma tumorigenicity through regulation of AXL.
abstract: The TAM family of proto-oncogenic receptor protein tyrosine kinases, comprising of TYRO3, AXL, and MERTK, is implicated in many human cancers. Their activation leads to cancer cell proliferation, enhanced migration, invasion, and drug resistance; however how TAMs are activated in cancers is less understood. We previously showed that Protein S (PROS1) is a ligand of the TAM receptors. Here we identify PROS1 as a mediator of Oral Squamous Cell Carcinoma (OSCC) in proliferation, cell survival and migration. We demonstrate that excess PROS1 induces OSCC proliferation and migration. Conversely, blocking endogenous PROS1 expression using shRNA significantly inhibits cell proliferation and migration in culture. This inhibition was rescued by the addition of purified PROS1. Moreover, PROS1 knockdown reduced anchorage-independent growth in-vitro, reduced tumor xenograft growth in nude mice and altered their differentiation profile. Mechanistically, we identify the downregulation of AXL transcripts and protein following PROS1 knockdown. Re-introducing PROS1 rescues AXL expression both at the protein and transcriptional levels. The anti-proliferative effect of the AXL inhibitor R428 was significantly reduced following PROS1 inhibition, indicating the functional significance of PROS1-mediated regulation of AXL in OSCC. Taken together, we identify PROS1 as a driver of OSCC tumor growth and a modulator of AXL expression. Our results point to PROS1 as a potential novel anti-cancer therapeutic target.
authors.affiliation: Institute for Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Ghada
authors.initials: G
authors.lastname: Abboud-Jarrous
authors.affiliation: Institute for Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Shivam
authors.initials: S
authors.lastname: Priya
authors.affiliation: Institute for Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Maimon
authors.affiliation: Institute for Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Stuart
authors.initials: S
authors.lastname: Fischman
authors.affiliation: Institute for Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Mayan
authors.initials: M
authors.lastname: Cohen-Elisha
authors.affiliation: Department of Oral Medicine, The Hebrew University - Hadassah School of Dental Medicine, Jerusalem, Israel.
authors.forename: Rakefet
authors.initials: R
authors.lastname: Czerninski
authors.affiliation: Institute for Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Burstyn-Cohen
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000473:pathology*; D017293:Protein S; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D001798:Blood Proteins; C523390:PROS1 protein, human; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase
keywords: AXL; OSCC; PROS1; protein S; squamous cell carcinoma