Transkingdom network reveals bacterial players associated with cervical cancer gene expression program

Cervical cancer is the fourth most common cancer in women worldwide with human papillomavirus (HPV) being the main cause of disease. Chromosomal amplifications have been identified as a source of upregulation of cervical cancer driver genes but cannot fully explain increased expression of immune genes in invasive carcinoma. Insight into additional factors that may tip the balance from making the immune system tolerate HPV to eliminate the virus may lead to markers for better diagnosis. We investigated whether microbiota affect molecular pathways in cervical carcinogenesis by performing microbiome analysis via sequencing 16S rRNA in tumor biopsies from 121 patients. While we detected a large number of intra-tumor taxa (289 OTUs), we focused on the thirty-eight most abundantly represented microbes. To search for microbes and host genes potentially involved in the interaction, we reconstructed a transkingdom network by integrating previously discovered cervical cancer gene expression network with our bacterial co-abundance network and employed bipartite betweenness centrality (BiBC). The top ranked microbes were represented by the families Bacillaceae, Halobacteriaceae, and Prevotellaceae. While we could not define the first two families to the species level, Prevotellaceae was assigned to Prevotella bivia . By co-culturing a cervical cancer cell line with P. bivia , we confirmed that three out of ten top predicted genes in the transkingdom network (LAMP3, STAT1, TAP1), all regulators of immunological pathways, were upregulated by this microorganism. Therefore, we propose that intra-tumor microbiota might contribute to cervical carcinogenesis through the induction of immune response drivers, including the well-known cancer gene LAMP3.