Osteopontin (OPN/SPP1), a Mediator of Tumor Progression, Is Regulated by the Mesenchymal Transcription Factor Slug/SNAI2 in Colorectal Cancer (CRC)

Cells. 2022 May 31;11(11):1808. doi: 10.3390/cells11111808.

Abstract

In colorectal cancer (CRC), disease-related death is closely linked to tumor aggressiveness and metastasis. Gene expression profiling of patient tumors has suggested that a more mesenchymal phenotype, present in about one-fourth of all patients, is associated with increased aggressiveness. Accordingly, the mesenchymal transcription factor Slug/SNAI2 has been associated with decreased disease-free survival. To decipher the basis for the Slug-mediated phenotype, we conducted RNAseq experiments with a panel of HT-29 CRC cells expressing different levels of Slug, both in vitro and in tumor models. The results show that osteopontin, a secreted pleotropic protein involved in multiple steps of colorectal cancer progression, was highly upregulated by Slug in vitro, as well as in vivo. We further show that Slug is a direct regulator of osteopontin at the promoter level. The levels of secreted osteopontin were correlated with Slug expression, thereby linking the tumor phenotype to a biomarker available by liquid biopsies. The results also suggest that osteopontin neutralization may attenuate at least some of the Slug-mediated functions.

Keywords: Slug/SNAI2 transcription factor; colorectal cancer (CRC); epithelial–mesenchymal transition (EMT); osteopontin (OPN/SPP1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Colorectal Neoplasms* / pathology
  • Humans
  • Osteopontin / genetics
  • Osteopontin / metabolism
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism

Substances

  • SNAI2 protein, human
  • SPP1 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors
  • Osteopontin

Grants and funding

This research was supported by recurrent funding from INSERM (Institut National de la Santé et de la Recherche Medicale) and Sorbonne University. K.-A.S. have a doctoral fellowhip from doctoral school “Physiology, Physiopathology and Therapeutics” P2T-ED394, Sorbonne University. S.T. was supported by an unrestricted research grant from Leo Pharma, Greece and by the RSFN association, France.