Modified TLR-mediated downregulation of miR-125b-5p enhances CD248 (endosialin)-induced metastasis and drug resistance in colorectal cancer cells

Mol Carcinog. 2020 Feb;59(2):154-167. doi: 10.1002/mc.23137. Epub 2019 Nov 19.


CD248, also called endosialin or tumor endothelial marker-1, is markedly upregulated in almost all cancers, including colon cancers. Changes in microRNA profiles are one of the direct causes of cancer development and progression. In this study, we investigated whether a change in CD248 expression in colon cancer cells could induce drug resistance after chemotherapy, and we explored the relationship between miR-125b-5p levels and CD248 expression in Toll-like receptor (TLR)-modified chemoresistant colon cancer cells. TLR2/6 and TLR5 upregulation in drug-resistant colon cancer cells contributed to miR-125b-5p downregulation and specificity protein 1 (Sp1)-mediated CD248 upregulation via nuclear factor-kappa B (NF-κB) activation. Exposure to specific TLR2/6 or TLR5 ligands enhanced the expression of mesenchymal markers as well as the migratory activity of oxaliplatin- or 5-fluorouracil-resistant colon cancer cells. The transfection of a synthetic miR-125b-5p mimic into chemoresistant cells prevented Sp1 and CD248 activation and significantly impaired invasive activity. Furthermore, Sp1 or CD248 gene silencing as well as miR-125b-5p overexpression markedly reversed drug resistance and inhibited epithelial-mesenchymal transition in colon cancer cells. Taken together, these results suggest that changes in miR-125b-5p levels play an important role in Sp1-mediated CD248 expression and the development of drug resistance in TLR-mutated colon cancer cells.

Keywords: CD248; Sp1; TLR modification; chemoresistance; colon cancer; miR-125b-5p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Antigens, Neoplasm / genetics*
  • Antigens, Neoplasm / metabolism
  • Antimetabolites, Antineoplastic / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Fluorouracil / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • MicroRNAs / genetics*
  • NF-kappa B / metabolism
  • RNA Interference
  • Toll-Like Receptors / genetics*
  • Toll-Like Receptors / metabolism


  • Antigens, CD
  • Antigens, Neoplasm
  • Antimetabolites, Antineoplastic
  • CD248 protein, human
  • MIRN125 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • Toll-Like Receptors
  • Fluorouracil