Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer.
Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer.
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转录组分析确定补体成分 3 是结直肠癌化疗耐药的潜在预测生物标志物
DOI：
10.3389/fmolb.2021.763652
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发表时间：
2021
影响因子：
5
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
He XS;Zou SY;Yao JL;Yu W;Deng ZY;Wang JR;Gan WJ;Wan S;Yang XQ;Wu H
目的：基于5-氟尿嘧啶和奥沙利铂的FOLFOX方案是结直肠癌（CRC）的主要化疗药物，但耐药性是一个主要的治疗挑战。为了提高患者的生存率，有必要确定耐药基因，以更好地了解化疗耐药的机制。研究方法：从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）检索转录组数据集，并与我们自己的微阵列数据相结合。加权基因共表达网络分析（WGCNA）用于剖析与FOLFOX耐药和癌症复发相关的功能网络和枢纽基因。然后，我们进行了预后分析，肿瘤浸润免疫细胞的分析，以及通路过度表达分析，以全面阐明所鉴定的枢纽基因在CRC中的生物学影响。结果如下：WGCNA分析确定补体成分3（C3）基因是与FOLFOX化疗耐药和FOLFOX化疗后CRC复发相关的唯一枢纽基因。随后的生存分析证实，高C3表达赋予差的无进展生存，无疾病生存，和无复发生存。进一步的相关性分析显示，C3表达与奥沙利铂敏感性呈显著负相关，但与5-氟尿嘧啶无关。肿瘤免疫细胞浸润的计算机模拟分析表明，C3表达的变化可能影响肿瘤微环境。最后，基因集富集分析（GSEA）显示，在C3过表达的CRC样本中，导致侵袭、转移、淋巴结扩散和奥沙利铂耐药的途径过度活化。结论：我们的研究结果表明，C3高表达是FOLFOX化疗的一个削弱因素，特别是奥沙利铂的敏感性，C3可能代表一种新的生物标志物，为CRC的治疗决策。
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.
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DOI：
10.4049/jimmunol.1501886
发表时间：
2016-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cho MS;Rupaimoole R;Choi HJ;Noh K;Chen J;Hu Q;Sood AK;Afshar-Kharghan V
通讯作者：
Afshar-Kharghan V
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
2.8
作者：
Martin J;Petrillo A;Smyth EC;Shaida N;Khwaja S;Cheow HK;Duckworth A;Heister P;Praseedom R;Jah A;Balakrishnan A;Harper S;Liau S;Kosmoliaptsis V;Huguet E
通讯作者：
Huguet E
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S