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Modified TLR‐mediated downregulation of miR‐125b‐5p enhances CD248 (endosialin)‐induced metastasis and drug resistance in colorectal cancer cells
Author(s) -
Park GaBin,
Jeong JeeYeong,
Kim Daejin
Publication year - 2020
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.23137
Subject(s) - downregulation and upregulation , biology , colorectal cancer , metastasis , cancer research , drug resistance , microrna , cancer , drug , pharmacology , gene , genetics
Abstract 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.