Identification of Genes Related to 5-Fluorouracil Based Chemotherapy for Colorectal Cancer

Abstract

BackgroundColorectal cancer (CRC) is one of the most common malignancies and its incidence and mortality are increasing yearly. 5-Fluorouracil (5-FU) has long been used as a standard first-line treatment for CRC patients. Although 5-FU-based chemotherapy is effective for advanced CRC, the consequent resistance remains a key problem and causes the poor prognosis of CRC patients. Thus, there is an urgent need to identify new biomarkers to predict the response to 5-FU-based chemotherapy.MethodsCRC samples were retrieved from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The immune-related genes were retrieved from the ImmPort database. Single-cell sequencing results from colorectal cancer were obtained by the ArrayExpress database. 5-FU resistance-related genes were filtered and validated by R packages. ESTIMATE algorithms were used to assess the tumor microenvironment (TME). KEGG and GO analysis were performed to explore the biological signaling pathway for resistant-response patients and sensitive-response patients in the tumor microenvironment. pRRophetic algorithms were used to predict 5-FU sensitivity. GSEA and GSVA analysis was performed to excavate the biological signaling pathway of the RBP7 gene.ResultsNine immune-related genes were identified to be associated with 5-FU resistance and poor disease-free survival (DFS) of CRC patients and the signature of these genes was developed in a DFS-prognostic model. Four immune-related genes were determined to be associated with 5-FU resistance and overall survival (OS) of CRC patients. The signature of these genes was developed an OS-prognostic model. ESTIMATE scores showed a significant difference between 5-FU resistant and 5-FU sensitive CRC patients. Resistant-response patients and sensitive-response patients to 5-FU based chemotherapy showed different GO and KEGG enrichment on the tumor microenvironment. RBP7, as a tumor immune microenvironment (TIME) related gene, was found to have the potential of predicting chemotherapy resistance and poor prognosis of CRC patients. GSEA analysis showed multiple signaling differences between the high and low expression of RBP7 in CRC patients. Hypoxia and TNFα signaling via NFκB gene sets were significantly different between chemotherapy resistant (RBP7High) and chemotherapy sensitive (RBP7Low) patients. Single-cell RNA-seq suggested RBP7 was centrally distributed in endothelial stalk cells, endothelial tip cells, and myeloid cells.ConclusionsImmune-related genes will hopefully be potential prognostic biomarkers to predict chemotherapy resistance for CRC. RBP7 may function as a tumor microenvironment regulator to induce 5-FU resistance, thereby affecting the prognosis of CRC patients.

ECM1 regulates the resistance of colorectal cancer to 5-FU treatment by modulating apoptotic cell death and epithelial-mesenchymal transition induction

“…For the treatment of CRC, 5-FU continues to be among the most popular and effective chemotherapeutic medicines ( Glimelius et al, 2021 ), and the adjuvant therapy based on 5-FU is essential to CRC patients in stage II-IV after radical surgery, which could prolong the survival time of CRC patients ( Wilkinson et al, 2010 ; Miller et al, 2019 ; Huang X et al, 2022 ). The emergence of chemoresistance remains a significant barrier to long-term benefit ( Xie et al, 2020 ).…”

Identification of cuproptosis-related miRNAs in triple-negative breast cancer and analysis of the miRNA–mRNA regulatory network

“…Our findings indicate an increased sensitivity to certain drugs among TNBC patients classified in the high-risk group. RBP7 may be used as a tumor microenvironment regulator to induce 5-fluorouracil resistance, affecting the prognosis of patients with colorectal cancer [ 55 ]. Docetaxel activates the antitumor immune response in a CGA/STING-dependent manner and promotes T-cell infiltration.…”

Cytoskeleton Related Protein KIF9：A Potential Biomarker of Prognosis, 5- Fluorouracil Chemoresistance and Response to Immunotherapy for Patients with Colorectal Cancer

“…Xingxing Huang and Xinbing Sui et al identi ed that some immune-related genes (HSPA8, RARB, RABEP2, ICAM2, CHGB, GALP, RBP7 et al) were associated with 5-Fu resistance and poor DFS and OS of CRC patients. And RBP7 may function as a tumor microenvironment regulator to induce 5-Fu resistance, thereby affecting the prognosis of CRC patients 25 . Besides, Guili Zheng and Qiang Wang et al found and demonstrated that CRC could obtain 5-Fu based chemotherapy by LINC01347/miR-328/LOXL2 axis, and LINC01347 could work as a prognostic biomarker and potential therapeutic target against 5-Fu based chemotherapy resistance of CRC 26 .…”