Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer

Xiao-Shun He; Sheng-Yi Zou; Jia-Lu Yao; Wangjianfei Yu; Zhi-Yong Deng; Jing-Ru Wang; Wen-Juan Gan; Shan Wan; Xiao-Qin Yang; Hua Wu

doi:10.3389/fmolb.2021.763652

Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer

Front Mol Biosci. 2021 Oct 15:8:763652. doi: 10.3389/fmolb.2021.763652. eCollection 2021.

Authors

Xiao-Shun He¹, Sheng-Yi Zou², Jia-Lu Yao³, Wangjianfei Yu⁴, Zhi-Yong Deng⁵, Jing-Ru Wang¹, Wen-Juan Gan⁶, Shan Wan¹, Xiao-Qin Yang⁴, Hua Wu^{1

6}

Affiliations

¹ Department of Pathology, Medical College of Soochow University and The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
² Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
³ Department of Cardiology, the First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
⁴ Department of Bioinformatics, Medical College of Soochow University, Soochow University, Suzhou, China.
⁵ Department of Pathology, The First People's Hospital of Kunshan, Kunshan, China.
⁶ Department of Pathology, Dushu Lake Hospital Affiliated of Soochow University, Soochow University, Suzhou, China.

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.

Keywords: C3; colorectal cancer; oxaliplatin resistance; prognosis; transcriptomic analysis.