Wang Tengyu, Zhen Qinghao, Wu Tong, Jin Lan, Yao Surui, Feng Yuyang, Chen Jinghua, Chen Chen, Huang Zhaohui
Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, 214122, China.
Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, China.
Mol Biol Rep. 2023 Apr;50(4):3167-3177. doi: 10.1007/s11033-023-08268-w. Epub 2023 Jan 25.
Colorectal cancer (CRC) is one of the cancers with high morbidity and mortality worldwide. Chemotherapy is commonly used for metastatic or more advanced CRC. The mechanism of CRC chemoresistance is still under active investigation. Therefore, we identify and validate differentially expressed genes (DEGs) between oxaliplatin/5-FU resistant and sensitive CRC cells.
Three datasets of colorectal cancer patients (GSE28691, GSE81006, and GSE77932) from the Gene Expression Omnibus (GEO) database were analyzed and volcano plots for DEGs were generated using the GEO2R tool. The intersection of three GEO datasets showed that GABRP was significantly upregulated in chemo-resistant CRC cells or patients with an adjusted p-value less than 0.01. The potential protein-protein interaction (PPI) network with GABRP was analyzed by the Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) website. The PPI network predicted ANKRD66, CLINT1, HAP1, PLCL1, GABARPAP, GABARAPL1, NSF, GABARAPL2, TRAK2, and CLIC3 had a high likelihood to interact with GABRP. Especially, GABARAP, GABARAPL1, ANKRD66, CLINT1, and CLIC3 were enriched as the most possibly associated proteins with GABRP among the networks. GABRP was significantly more expressed in both oxaliplatin/5-FU resistant CRC cells than in those counterpart sensitive CRC cells using quantitative PCR (qPCR) analysis. Consistently, TCGA, Oncomine, and Human Protein Atlas (HPA) databases confirmed that higher expression of GABRP was robustly found in CRC patients than those in other various cancer types or normal colon tissues.
We identify GABRP as a promising drug target to mediate oxaliplatin or 5-FU resistance in CRC. It provided the theoretical basis and potential clinical value for CRC patients.
结直肠癌（CRC）是全球发病率和死亡率较高的癌症之一。化疗常用于转移性或更晚期的结直肠癌。结直肠癌化疗耐药的机制仍在积极研究中。因此，我们鉴定并验证了奥沙利铂/5-氟尿嘧啶耐药和敏感的结直肠癌细胞之间的差异表达基因（DEGs）。
分析了来自基因表达综合数据库（GEO）的三个结直肠癌患者数据集（GSE28691、GSE81006和GSE77932），并使用GEO2R工具生成了DEGs的火山图。三个GEO数据集的交集显示，GABRP在化疗耐药的结直肠癌细胞或患者中显著上调，校正后的p值小于0.01。通过检索相互作用基因/蛋白质的搜索工具（STRING）网站分析了与GABRP潜在的蛋白质-蛋白质相互作用（PPI）网络。PPI网络预测ANKRD66、CLINT1、HAP1、PLCL1、GABARPAP、GABARAPL1、NSF、GABARAPL2、TRAK2和CLIC3与GABRP有很高的相互作用可能性。特别是，GABARAP、GABARAPL1、ANKRD66、CLINT1和CLIC3在网络中被富集为与GABRP最可能相关的蛋白质。使用定量PCR（qPCR）分析，GABRP在奥沙利铂/5-氟尿嘧啶耐药的结直肠癌细胞中均显著高于相应的敏感结直肠癌细胞。同样，TCGA、Oncomine和人类蛋白质图谱（HPA）数据库证实，与其他各种癌症类型或正常结肠组织相比，在结直肠癌患者中发现GABRP的表达更高。
我们鉴定出GABRP作为一种有前景的药物靶点，可介导结直肠癌对奥沙利铂或5-氟尿嘧啶的耐药性。它为结直肠癌患者提供了理论依据和潜在的临床价值。
