<p>FOXC2 Promotes Oxaliplatin Resistance by Inducing Epithelial-Mesenchymal Transition via MAPK/ERK Signaling in Colorectal Cancer</p>

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-tomesenchymal 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 OXAresistant 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.

The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer

“…In fact, there have been only limited studies showing that OXA resistance can arise due to a direct dysregulation of molecules/genes involved in for instance the PI3K/AKT pathway [234]. Most studies have however shown that OXA acts on the signalling pathways indirectly (or via an alternative pathway) by targeting other molecules which can communicate with the targets involved in said signalling pathways [235][236][237]. In addition to this, miRNAs, lncRNAs and circRNAs have also shown to target specific pathways not commonly involved in CRC OXA resistance, as will be discussed below (Table 2).…”

Identifying 8-mRNAsi Based Signature for Predicting Survival in Patients With Head and Neck Squamous Cell Carcinoma via Machine Learning

“…KEGG enrichment pathways in the yellow module were mainly involved in ECM–receptor interactions, PI3K-Akt signaling pathways, and MAPK signaling pathways. These signaling pathways have been demonstrated to facilitate cell survival, self-renewal and apoptosis inhibition in many CSCs ( Huang et al, 2017 ; Chen et al, 2020 ; Liao et al, 2020 ; Qin et al, 2020 ).…”

YTHDF2 Inhibits Gastric Cancer Cell Growth by Regulating FOXC2 Signaling Pathway

“…In breast cancer, FOXC2 is involved in regulating the EMT process and breast cancer stem cells ( Hollier et al, 2013 ). In colorectal cancer, FOXC2 also induces EMT through MAPK/ERK signaling, thereby enhancing oxaliplatin resistance ( Chen et al, 2020 ). Analysis of GC clinical patients found that abnormal overexpression of FOXC2 was significantly associated with differentiation, depth of invasion, lymph node metastasis, tumor staging, and patient prognosis ( Zhu et al, 2013 ).…”