Investigating the role of intracellular Enterococcus faecalis in hepatocellular carcinoma

Authors

• OY Mrad Bouali
• MA Clavijo-Salomon
• G Trinchieri

Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with gut dysbiosis exasperating cancer progression. The tumor-associated microenvironment including the intratumoral microbiome has been the subject of investigation due to its role in HCC progression and metastasis. Growing evidence has revealed the role Enterococcus faecalis may play in liver carcinogenesis, however its ability to translocate from the gut to the liver and reside inside cancer cells, and the effect this has on tumorigenesis, is not fully understood. We infected different human liver cancer cell lines with E. faecalis isolated from HCC tumors from Mdr2-/- mice and explored by RNAseq the effect of intracellular E. faecalis on the cells. Intracellular infection was verified and quantified using plaque assay. Pathway analysis showed upregulation of membrane trafficking, endocytosis, and neutrophil degranulation pathways. Upregulation of JUN, FOS, and STC1 genes in SK-Hep-1 cells indicates activation of signaling mechanisms, namely the JNK pathway, responsible for cell proliferation and innate immune activation. Interestingly, CXCL8 and CXCL6 gene expression increased only in infected cells and ELISA revealed 6-fold increases in both IL-8 and CXCL6 in SK-Hep-1 cell supernatant post-infection compared to controls, suggesting E. faecalis’ role in promoting chemokine secretion and subsequent neutrophil recruitment. RNAseq and flow cytometry also indicated increased MR1 expression in infected cells compared to controls indicating a potential involvement of the E. faecalis riboflavin pathway and MAIT cells. At present, we are using live-cell imaging of HCC spheroids to better understand how E. faecalis influences neutrophil recruitment and tumor aggressiveness.

Scientific Focus Area: Cancer Biology

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