FBXW4 Acts as a Protector of FOLFOX-Based Chemotherapy in Metastatic Colorectal Cancer Identified by Co-Expression Network Analysis

BACKGROUND: FOLFOX chemotherapy is one of the most commonly used treatments for colorectal cancer (CRC) patients. However, the efficacy and tolerance of FOLFOX therapy varies between patients. The purpose of this study was to explore hub genes associated with primary chemotherapy-resistance and to explore the possible mechanisms involved from non-European patients. METHOD: A weighted gene co-expression network was constructed to identify gene modules associated with chemotherapy resistance in mCRC from China. RESULTS: A Gene Array Chip was used to detect mRNA expression in 11 mCRC patients receiving preoperative FOLFOX chemotherapy. The immune response was associated with chemotherapy-resistance in microarray data. Through the use of WGCNA, we demonstrated that the crucial functions enriched in chemotherapy-resistance modules were cell proliferation, MAPK signaling pathways, and PI3K signaling pathways. Additionally, we identified and validated FBXW4 as a new effective predictor for chemotherapy sensitivity and a prognostic factor for survival of CRC patients by using our own data and GSE69657. Furthermore, a meta-analysis of 15 Gene Expression Omnibus–sourced datasets showed that FBXW4 messenger RNA levels were significantly lower in CRC tissues than in normal colon tissues. An analysis of the data from the R2: Genomics Analysis and Visualization Platform showed that low FBXW4 expression was correlated with a significantly worse event- and relapse-free survival. Gene set enrichment analysis showed that the mechanism of FBXW4-mediated chemotherapy resistance may involve the DNA replication signal pathway and the cell cycle. CONCLUSION: FBXW4 is associated with chemotherapy resistance and prognosis of CRC probably by regulating DNA replication signaling pathways and the cell cycle.