FOXC2 Promotes Oxaliplatin Resistance by Inducing Epithelial-Mesenchymal Transition Via MAPK/ERK Signaling in Colorectal Cancer

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2020 Feb 29

PMID 32110058

Citations 22

Authors

Yihong Chen

Ganlu Deng

Yaojie Fu

Ying Han

Cao Guo

Ling Yin

Changjing Cai

Hong Shen

Shaobin Wu

Shan Zeng

Affiliations

Soon will be listed here.

Abstract

Background: Chemoresistance is a major obstacle to improving the survival rate of colorectal cancer (CRC) patients. Forkhead box protein C2 (FOXC2), a member of the forkhead box (Fox) transcription factor family, is reported to be an important regulator of epithelial-to-mesenchymal transition (EMT) and plays a key role in tumor progression. However, little is known about the effects of FOXC2 on oxaliplatin (OXA) resistance in CRC.

Methods: OXA-resistant cells were generated from HCT116 cells. CCK-8, colony formation, flow cytometry and Transwell assays were used to compare the characteristics of OXA-resistant HCT116/OXA cells and the corresponding parental HCT116 cells. The expression of FOXC2 was confirmed by qRT-PCR and Western blotting in HCT116/OXA and HCT116 cells. Gain- and loss-of-function assays were performed to evaluate the effects of FOXC2 on OXA sensitivity and EMT in HCT116/OXA and HCT116 cells both in vitro and in vivo, and the possible molecular mechanisms were investigated.

Results: The relative expression of FOXC2 was significantly increased in HCT116/OXA cells compared with the parental HCT116 cells. Upregulation of FOXC2 in HCT116 cells reduced OXA sensitivity and promoted EMT. However, knockdown of FOXC2 in HCT116/OXA cells markedly increased the in vitro and in vivo sensitivity of HCT116/OXA cells to OXA by regulating EMT progression. Furthermore, FOXC2 activated MAPK/ERK signaling, and blockade of ERK attenuated FOXC2-induced EMT and FOXC2-enhanced OXA resistance.

Conclusion: FOXC2 induced EMT to promote oxaliplatin resistance by activating the MAPK/ERK signaling pathway. FOXC2 may be a potential therapeutic target for overcoming OXA resistance in human CRC.

Citing Articles

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The expression of exosomal and cellular miRNAs in predicting oxaliplatin resistance in colorectal cancer cells: an in silico and in vitro study.

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Ma X, Tian F, Li J, Wu Z, Cao L Turk J Gastroenterol. 2024; 35(9):726-734.

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