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Background: Drug resistance is the primary obstacle to advanced tumor therapy and the key risk factor for tumor recurrence and death. 5-Fluorouracil (5-FU) chemotherapy is the most common chemotherapy for individuals with colorectal cancer, despite numerous options. Methods: The Gene Expression Omnibus database was utilized to extract expression profile data of HCT-8 human colorectal cancer wild-type cells and their 5-FU-induced drug resistance cell line. These data were used to identify 5-FU resistance-related differentially expressed genes (5FRRDEGs), which intersected with the colorectal adenocarcinoma (COAD) transcriptome data provided by the Cancer Genome Atlas Program database. A prognostic signature containing five 5FRRDEGs (GOLGA8A, KLC3, TIGD1, NBPF1, and SERPINE1) was established after conducting a Cox regression analysis. We conducted nomogram development, drug sensitivity analysis, tumor immune microenvironment analysis, and mutation analysis to assess the therapeutic value of the prognostic qualities. Results: We identified 166 5FRRDEGs in patients with COAD. Subsequently, we created a prognostic model consisting of five 5FRRDEGs using Cox regression analysis. The patients with COAD were divided into different risk groups by risk score; the high-risk group demonstrated a worse prognosis than the low-risk group. Conclusion: In summary, the 5FRRDEG-based prognostic model is an effective tool for targeted therapy and chemotherapy in patients with COAD. It can accurately predict the survival prognosis of these patients as well as to provide the direction for exploring the resistance mechanism underlying COAD.
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BACKGROUND: Traditional Chinese medicine, JianpiJiedu decoction (JPJDF), has been utilized in colorectal cancer (CRC) treatment for over forty years. The potential of JPJDF to inhibit CRC through modulation of intestinal microbiota and their metabolites remains uncertain. AIMS: This study aims to further investigate the therapeutic mechanisms of JPJDF in CRC. METHODS: CAC mouse models were developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissues and contents underwent 16S rRNA gene sequencing and untargeted metabolomics analysis. Serum levels of IL-1ß and TNF-α were measured using ELISA. Immunohistochemistry was utilized to assess the expression of Ki67, ZO-1, Occludin, CD68, and CD206. Furthermore, western blotting was performed to evaluate the protein expression of AhR and NF-κB. RESULTS: JPJDF inhibited colorectal tumourigenesis in AOM/DSS treated mice, while also suppressing tumor cell proliferation and upregulating the expression of tight junction proteins. The results of 16S rRNA gene sequencing analysis revealed that JPJDF altered intestinal microbiota composition by increasing the abundance of beneficial bacteria. Additionally, JPJDF reduced tryptophan metabolites, effectively alleviating inflammation and significantly restoring intestinal barrier function in CAC mice. Molecular biology experiments confirmed that JPJDF suppressed the expression levels of AhR and M2-type tumor-associated macrophages, thereby promoting anti-tumor immunity and exerting inhibitory effects on CAC growth. CONCLUSION: JPJDF can regulate the tryptophan metabolism-AhR pathway by modulating the gut microbiota, reducing intestinal inflammation, improving intestinal barrier function, enhancing anti-tumor immunity, and effectively inhibiting CAC growth.
