Exploration of key pathogenic mechanisms and potential intervention targets of the traditional Chinese medicine Coptis chinensis in the treatment of cervical cancer based on network pharmacology and molecular docking techniques.

Abstract

Background: Traditional Chinese medicine (TCM) has shown potential in the treatment of cancer. This study investigated the molecular targets and mechanisms of Coptis chinensis in the treatment of cervical cancer using network pharmacology and bioinformatics.

Methods: Effective Coptis chinensis components were screened from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform based on the following criteria: drug-like properties (DLP) ≥0.18 and oral bioavailability (OB) ≥30%. Target genes were identified through DrugBank, while differentially expressed genes (DEGs) related to cervical cancer were sourced from the Gene Expression Omnibus (GEO) database (GSE7803) based on the following criteria: |log fold change| >2 and P<0.05. Common DEGs were identified through a Venn diagram analysis. The expression and prognostic relevance of the candidate genes were validated using The Cancer Genome Atlas (TCGA) database. Molecular docking was performed using Pubchem, Protein Data Bank (PDB), and CB-DOCK2. A gene set enrichment analysis (GSEA) was conducted to explore the potential mechanisms of DEGs. A retrospective analysis of cervical cancer patients (June 2021 to June 2022) was performed to examine the expression of key genes in the peripheral blood via enzyme-linked immunosorbent assay. A multivariate Cox regression was conducted to identify independent prognostic factors.

Results: In total, 10 effective Coptis chinensis compounds and 181 target genes were identified from the TCMSP database. The GEO analysis of GSE7803 identified 109 DEGs. The Venn diagram analysis identified the following seven shared DEGs: AR, MAOB, CDKN2A, TOP2A, CXCL8, matrix metalloproteinase 1 (MMP1), and SPP1. MMP1 and SPP1 were confirmed to be upregulated candidate genes in cervical cancer tissues, and to be associated with a worse prognosis [overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI), P<0.05]. Molecular docking showed that MMP1 had high binding affinity with quercetin (-9.2) while that of SPP1 was lower (-6.3). The GSEA indicated that MMP1 was involved in the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), Janus kinase/signal transducer and activator of transcription (JAK/STAT), transforming growth factor-β (TGF-β), mitogen-activated protein kinase (MAPK), and hypoxia-inducible factor 1 (HIF1) pathways, and apoptosis. The retrospective analysis demonstrated that MMP1 expression was significantly decreased in the peripheral blood of patients receiving conventional chemotherapy and Coptis chinensis compared to those receiving chemotherapy alone. Multivariate Cox regression confirmed that high MMP1 expression and a lack of Coptis chinensis treatment were independent risk factors for a poor prognosis (P<0.05).

Conclusions: MMP1 could be a predictive biomarker for cervical cancer. Coptis chinensis may exert therapeutic effects through MMP1 regulation via multiple pathways. Our findings provide a theoretical foundation for the clinical application of MMP1.