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

PeerJ. 2018 Sep 19;6:e5590. doi: 10.7717/peerj.5590. eCollection 2018.

Abstract

Cervical cancer is the fourth most common cancer in women worldwide with human papillomavirus (HPV) being the main cause the disease. Chromosomal amplifications have been identified as a source of upregulation for 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 immune tolerance of HPV to the elimination of the virus may lead to better diagnosis markers. 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 operational taxonomic units (OTUs)), we focused on the 38 most abundantly represented microbes. To search for microbes and host genes potentially involved in the interaction, we reconstructed a transkingdom network by integrating a previously discovered cervical cancer gene expression network with our bacterial co-abundance network and employed bipartite betweenness centrality. 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 the ten top predicted genes in the transkingdom network (lysosomal associated membrane protein 3 (LAMP3), STAT1, TAP1), all regulators of immunological pathways, were upregulated by this microorganism. Therefore, we propose that intra-tumor microbiota may contribute to cervical carcinogenesis through the induction of immune response drivers, including the well-known cancer gene LAMP3.

Keywords: Cervical cancer; LAMP3; Microbiome; Prevotella bivia; Transkingdom network.

Grant support

This research was supported by startup funds for Andrey Morgun and Natalia Shulzhenko from Oregon State University (OSU), United States, the Norwegian Cancer Society grant nr 107438—PR-2007-0179 (Heidi Lyng), seed grant from College of Pharmacy OSU (Andrey Morgun), DK103761 (Natalia Shulzhenko). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.