Osteoglycin (OGN) reverses epithelial to mesenchymal transition and invasiveness in colorectal cancer via EGFR/Akt pathway

J Exp Clin Cancer Res. 2018 Mar 2;37(1):41. doi: 10.1186/s13046-018-0718-2.

Abstract

Background: Many types of cancers are devoid of the small leucine-rich proteoglycans: osteoglycin (OGN), but its role in tumorigenesis is poorly studied especially in colorectal cancers (CRC). Here we aim to evaluate the relationship between OGN expression patterns and the clinical course of CRC, and the role of OGN in cancer progression.

Methods: The tissue microarray staining was performed and the relevance between OGN expression and oncologic outcomes was performed using Cox regression analysis. The effect of OGN on cell proliferation and tumorigenesis was examined in vitro and in vivo. Immunoprecipitation assay, immunofluorescence analysis and internalization assay were used for mechanistic study.

Results: Patients with high expression of OGN were associated with a profound longer survival in CRC and the high serum OGN level was also indicative of fewer recurrences consistently. In colon cancer cells, OGN increased dimerization of EGFR, then triggered EGFR endocytosis and induced the recruitment of downstream components of the EGFR internalization machinery (Eps15 and epsin1). Above all, OGN reduced Zeb-1 expression via EGFR/Akt leading to inhibition of epithelial-mesenchymal transition. As results, in vitro and in vivo, the OGN expression was demonstrated to reduce cell proliferation, inhibit invasion of colon cancer cells then impede cancer progression.

Conclusions: There is a positive association between OGN level and prolonged survival in CRC. OGN plays a restrictive role in colorectal cancer progression by reduced activation of EGFR/AKT/Zeb-1.

Keywords: EGFR; EMT; Osteoglycin; Zeb-1.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology*
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition*
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Proportional Hazards Models
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • Xenograft Model Antitumor Assays
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism

Substances

  • Intercellular Signaling Peptides and Proteins
  • OGN protein, human
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt