Frontiers in Immunology (Jun 2022)

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

  • Xingxing Huang,
  • Xingxing Huang,
  • Xingxing Huang,
  • Kun Ke,
  • Weiwei Jin,
  • Qianru Zhu,
  • Qianru Zhu,
  • Qianru Zhu,
  • Qicong Zhu,
  • Ruyi Mei,
  • Ruyi Mei,
  • Ruonan Zhang,
  • Ruonan Zhang,
  • Ruonan Zhang,
  • Shuxian Yu,
  • Shuxian Yu,
  • Lan Shou,
  • Lan Shou,
  • Xueni Sun,
  • Xueni Sun,
  • Jiao Feng,
  • Jiao Feng,
  • Ting Duan,
  • Ting Duan,
  • Yiping Mou,
  • Tian Xie,
  • Tian Xie,
  • Tian Xie,
  • Qibiao Wu,
  • Qibiao Wu,
  • Qibiao Wu,
  • Xinbing Sui,
  • Xinbing Sui,
  • Xinbing Sui

DOI
https://doi.org/10.3389/fimmu.2022.887048
Journal volume & issue
Vol. 13

Abstract

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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.

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