Abstract
Objective: 5-fluorouracil- and oxaliplatin-based FOLFOX regimens are mainstay chemotherapeutics for colorectal cancer (CRC) but drug resistance represents a major therapeutic challenge. To improve patient survival, there is a need to identify resistance genes to better understand the mechanisms underlying chemotherapy resistance. Methods: Transcriptomic datasets were retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and combined with our own microarray data. Weighted gene co-expression network analysis (WGCNA) was used to dissect the functional networks and hub genes associated with FOLFOX resistance and cancer recurrence. We then conducted analysis of prognosis, profiling of tumor infiltrating immune cells, and pathway overrepresentation analysis to comprehensively elucidate the biological impact of the identified hub gene in CRC. Results: WGCNA analysis identified the complement component 3 (C3) gene as the only hub gene associated with both FOLFOX chemotherapy resistance and CRC recurrence after FOLFOX chemotherapy. Subsequent survival analysis confirmed that high C3 expression confers poor progression-free survival, disease-free survival, and recurrence-free survival. Further correlational analysis revealed significant negative association of C3 expression with sensitivity to oxaliplatin, but not 5-fluorouracil. Moreover, in silico analysis of tumor immune cell infiltration suggested the change of C3 expression could affect tumor microenvironment. Finally, gene set enrichment analysis (GSEA) revealed a hyperactivation of pathways contributing to invasion, metastasis, lymph node spread, and oxaliplatin resistance in CRC samples with C3 overexpression. Conclusion: Our results suggest that high C3 expression is a debilitating factor for FOLFOX chemotherapy, especially for oxaliplatin sensitivity, and C3 may represent a novel biomarker for treatment decision of CRC.
Highlights
Colorectal cancer (CRC) is a critical global medical issue
We combined transcriptomic data from public databases with our own work and found that complement component 3 (C3) gene was associated with oxaliplatin resistance via reprogramming the tumor immune microenvironment in CRC. These findings suggest C3 represents a potential predictive biomarker for the prognosis of oxaliplatin-based therapy in CRC patients
To identify key genes associated with specific clinical traits of colorectal cancer, we employed the weighted gene co-expression network analysis (WGCNA) method to identify gene module-trait correlations
Summary
Colorectal cancer (CRC) is a critical global medical issue. While CRC cases and deaths have decreased over the last decades due to improved screening efforts and novel therapies, it has been estimated that CRC still ranked third in overall morbidity and mortality in the United States in 2021. CRC is a heterogeneous disease with a complex etiology involving an interplay of defective DNA damage repair, somatic mutations, chromosomal instability, microsatellite instability, DNA methylation, and epigenetic alterations (Colussi et al, 2013; Turano et al, 2019; Xu et al, 2021), all of which are thought to contribute to the malignant transformation of intestinal epithelial cells These factors may influence treatment response and prognosis of CRC patients. APC mutations are thought to occur first, followed by KRAS mutation and subsequent TP53 inactivation, resulting in abnormal activation of the Wnt/β-catenin, PI3K/Akt, NF-κB, JAK/ STAT, and TGF-β/BMPs pathways (Prasad et al, 2010; Fearon, 2011; Vogelstein et al, 2013; Groner and von Manstein, 2017). We recently reported that the long non-coding RNA NONHSAT062994 acts as a tumor suppressor and inhibits CRC development via inactivation of Akt signaling (He et al, 2017)
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