Protein S drives oral squamous cell carcinoma tumorigenicity through regulation of AXL

Oncotarget. 2017 Feb 21;8(8):13986-14002. doi: 10.18632/oncotarget.14753.

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.

Keywords: AXL; OSCC; PROS1; protein S; squamous cell carcinoma.

MeSH terms

  • Animals
  • Blood Proteins / metabolism*
  • Blotting, Western
  • Carcinoma, Squamous Cell / pathology*
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Cell Proliferation / physiology
  • Gene Expression Regulation, Neoplastic / physiology*
  • Gene Knockdown Techniques
  • Head and Neck Neoplasms / pathology*
  • Heterografts
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Mouth Neoplasms / pathology*
  • Proto-Oncogene Proteins / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Squamous Cell Carcinoma of Head and Neck

Substances

  • Blood Proteins
  • PROS1 protein, human
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase