Comprehensive analysis identifies novel targets of gemcitabine to improve chemotherapy treatment strategies for colorectal cancer

Xinxin Zeng; Liyue Sun; Xiaomei Ling; Yuying Jiang; Ju Shen; Lei Liang; Xuhui Zhang

doi:10.3389/fendo.2023.1170526

Comprehensive analysis identifies novel targets of gemcitabine to improve chemotherapy treatment strategies for colorectal cancer

Front Endocrinol (Lausanne). 2023 Aug 17:14:1170526. doi: 10.3389/fendo.2023.1170526. eCollection 2023.

Authors

Xinxin Zeng¹, Liyue Sun¹, Xiaomei Ling², Yuying Jiang^{1

3}, Ju Shen^{1

3}, Lei Liang⁴, Xuhui Zhang¹

Affiliations

¹ Second Department of Oncology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
² Medical Research Center, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
³ Department of Radiation Oncology, Guangdong Medical University, Zhanjiang, China.
⁴ Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China.

Abstract

Background: Gemcitabine (GEM) is a second-line anticancer drug of choice for some colorectal cancer (CRC) patients, and GEM inability to be commonly available in the clinic due to the lack of clarity of the exact action targets.

Methods: The half maximal inhibitory concentration (IC50) of GEM treatment for 42 CRC cell lines were accessed from the Genomics of Drug sensitivity in Cancer (GDSC) database. High-throughput sequencing data of CRC patients were captured in The Cancer Genome Atlas (TCGA) and Weighted correlation network analysis (WGCNA) was conducted. Pearson correlations were derived for GEM potency-related genes. Differential analysis was conducted in the TCGA cohort to obtain CRC development-related genes (CDRGs), and univariate COX model analysis was performed on CDRGs overlapping with GEM potency-related genes to obtain CDRGs affecting CRC prognosis. Hub genes affecting GEM potency were identified by Spearman correlation.

Results: CALB2 and GPX3 were identified as potential targets for GEM treatment of CRC via prognostic analysis, which we also observed to be elevated with elevated clinical stage in CRC patients. The enhanced expression of CALB2 and GPX3 genes identified in the pathway analysis might inhibit the body metabolism as well as activate immune and inflammation related pathways. In addition, we found that CALB2 and GPX3 could also be considered as prognostic biomarkers in pan-cancer. Finally, we found that CALB2 and GPX3 were remarkably associated with the drug sensitivity of MG-132, Dasatinib, Shikonin, Midostaurin, MS-275, and Z-LNle-CHO, which were expected to be the drugs of choice for GEM combination.

Conclusion: CALB2 and GPX3 represent prognostic biomarkers for CRC and they might be potential action targets for GEM. Our study offered innovative ideas for GEM administration strategies.

Keywords: CALB2; GPX3; chemotherapy; colorectal cancer; combination drug; gemcitabine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Cell Line
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Dasatinib
Gemcitabine*
Humans

Substances

Gemcitabine
Dasatinib
Biomarkers

Grants and funding

This work was supported by Natural Science Foundation of China (No.81973718), Guangdong Natural Science Foundation (No.2021A1515011297), Guangzhou Science and Technology Plan Projects (No.202201020483 & No.202201010786) and the Foundation of Guangdong Second Provincial General Hospital (No.3DA2021015).