Bernice Chen

Introduction. Colorectal cancer (CRC) is one of the most common types of cancer and leading cause of death amongst adults with cancer.¹ In recent years, connections between gut microbiota, specifically enterotoxigenic Bacteroides fragilis (ETBF), and CRC development have been found.² Two studies, in particular, have reported specific cell proliferation and tumor growth pathways involving ETBF and its downstream effectors. While one paper focuses on the activation of the NF-kB pathway through Bacteroides fragilis toxin (BFT) secretion by ETBF and the other discusses the activation of the mTOR pathway through lncRNA mediator (Bacteroides fragilis-associated lncRNA, or BFAL1), convergence of the two mechanisms have been found for various other cancers and aging.^3,4,5 More specifically, mTOR can activate NF-kB directly or through intermediary regulators, leading to inflammatory responses, inhibition of apoptosis, and cell proliferation.^5,6 Thus, these findings suggest that regulatory mechanisms in response to the colonization of ETBF in colonic epithelial cells could serve as a potential therapeutic target. Methods and Results. In Chung et. al., Apc^min mice were colonized with ETBF and their colons were divided into 6 adjacent sections from proximal to distal.³ Immunoblotting and RT-PCR were used to measure levels of NF-kB activation and chemokine production. Also, chemokine receptor CXCR2 was inhibited with pepducin and the resulting number of microadenomas was counted. Results showed that ETBF colonization led to NF-kB activation and CXCL chemokine production with highest levels of both in the distal colon. Furthermore, inhibiting CXCR2 led to decreased numbers of microadenomas, showing that adenoma formation is dependent on the chemokines. This shows that NF-kB activation leads to an inflammatory response and adenoma formation in the colon, especially the distal colon. In Bao et. al., BFAL1 knockdown with siRNA and ETBF treatment were performed on two CRC cell lines HCT116 and DLD-1.⁴ A CCK-8 assay was used to measure the resulting cell proliferation. Luciferase reporter assays were used to measure miRNA and RHEB levels. GSEA analysis was used to determine if mTOR-related genes were affected. Results showed that ETBF treatment led to increased cell proliferation and BFAL1 knockdown led to decreased cell proliferation. Also, BFAL1 overexpression led to decreased miR-155-5P and miR-200a-3P and increased RHEB levels and thus mTOR activation. These findings suggest that BFAL1 activates the mTOR pathway, leading to tumor growth. Conclusion. These studies show that ETBF promotes tumorigenesis and cell proliferation by activating the NF-kB and mTOR pathways, respectively. Targeting the downstream effectors of ETBF colonization of colonic epithelial cells could serve as a potential therapeutic target.

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