The intestinal flora plays significant roles in the formation and development of CRC via producing carcinogenic toxins and metabolites, causing intestinal dysbiosis, and altering immune response [18]. However, current knowledge of the specific mechanism by which intestinal flora influences the pathogenesis of CRC remains limited. In this study, we utilized text mining to extract the intestinal flora-related genes. With further analyses of the functional enrichments and PPI network, we identified 8 key genes associated with intestinal flora and the development of CRC. Finally, candidate drugs targeting 4 key genes (CSF2, CXCL8, IL6R, and CXCL10) were derived using the DGIdb database.
To explore whether intestinal flora contributes to the development of CRC via regulating gene expression, we identified the DEGs between CRC and normal samples. The interaction of the DEGs and intestinal flora-related genes extracted by text mining was selected for further functional enrichments and PPI analyses. Functional enrichment of the 48 selected DEGs in the GO biological process and KEGG pathways highlight their role in immune response, inflammatory response, and intestinal function. Previous studies have confirmed that alteration of intestinal flora can promote CRC development by inducing inflammation, immune suppression, and attacking the gut barrier system [19–21]. Moreover, intestinal flora has been proven to promote tumorigenesis and chemoresistance of CRC via regulating gene expression [22–24]. Therefore, the mechanism of intestinal flora contributing to the development of CRC is complex and multifaceted.
Using the MCODE plug-in, we created the most significant cluster network, including 8 genes. 87.5% (7/8) of these genes enriched in the cytokine-cytokine receptor interaction pathway, indicating that interactions between the intestinal flora and immune system contribute to the development of CRC.
Drug resistance has been a Gordian knot in the treatment of cancer. Therefore, we identified a list of 24 drugs with the potential therapeutic efficacy against CRC. Among the 8 key genes, the potential gene targets of these drugs are CSF2, CXCL8, IL6R, and CXCL10, and most of the drugs were CSF2 and CXCL8 inhibitors. As a cytokine, CSF2 can stimulate the recruitment and maturation of dendritic cells to induce protective immunity and then exert anti-tumor effects [25]. Yet in the tumor microenvironment, CSF2 is often up-regulated and suppress the immune response, resulting in a poor prognosis for patients [25, 26]. Another cytokine, CXCL8, has been proven to be associated with chemoresistance of CRC [27]. The increased expression of CXCL8 induced by anti-cancer drugs, such as doxorubicin and cisplatin, can upregulate the expression of ATP-binding cassette transporters, resulting in poor chemotherapeutic response [27]. Moreover, a high level of CXCL8 predicted poor overall survival in patients with CRC [28], which is contrary to our findings in this study. Among the listed drugs, cetuximab was considered as a prospective drug for CRC therapy thanks to its ability to decrease CXCL8 expression other than inhibiting the epidermal growth factor receptor [29, 30].
IL6R is the receptor of IL-6, which forms a dimer with glycoprotein-130. IL-6 binds the IL6R to initiate the IL-6 signaling that transduces intracellular signals via activation of the JAK-STAT3 pathway [31]. Research has suggested that the IL-6 signaling pathway plays an important role in the development and chemoresistance of various cancers, including CRC [32–34]. Accordingly, IL6R has been proposed as a promising target for CRC treatment. IL6R antagonist antibody, tocilizumab, could significantly reduce viability and enhance the apoptosis of CRC cells by blocking the IL-6/STAT3 pathway [35].
CXCL10 is a member of interferon-inducible proteins, which is increasingly being considered as a pro-tumorigenic factor in various cancers, including CRC [36]. Besides, elevated serum CXCL10 was associated with liver metastasis and poor prognosis in CRC [37]. Thus, CXCL10 may be a potential therapeutic target for CRC.
In conclusion, we presented a novel method to explore the molecular mechanism underlying the effect of intestinal flora on CRC. Importantly, we identified 8 potential key genes and 24 candidate drugs. Ten of the 24 drugs have not been tested in CRC, which not only provides a theoretical basis for new trials but also provides new insights into targeting drug discovery.