Abstract
The incidence of human cervix adenocarcinoma (CC) caused by papillomavirus genome integration into the host chromosome is the third most common cancer among women. Bacterial cyclodipeptides (CDPs) exert cytotoxic effects in human cervical cancer HeLa cells, primarily by blocking the PI3K/Akt/mTOR pathway, but downstream responses comprising gene expression remain unstudied. Seeking to understand the cytotoxic and anti-proliferative effects of CDPs in HeLa cells, a global RNA-Seq analysis was performed. This strategy permitted the identification of 151 differentially expressed genes (DEGs), which were either up- or down-regulated in response to CDPs exposure. Database analysis, including Gene Ontology (COG), and the Kyoto Encyclopedia of Genes and Genomes (KEGG), revealed differential gene expression on cancer transduction signals, and metabolic pathways, for which, expression profiles were modified by the CDPs exposure. Bioinformatics confirmed the impact of CDPs in the differential expression of genes from signal transduction pathways such as PI3K-Akt, mTOR, FoxO, Wnt, MAPK, P53, TGF-β, Notch, apoptosis, EMT, and CSC. Additionally, the CDPs exposure modified the expression of cancer-related transcription factors involved in the regulation of processes such as epigenetics, DNA splicing, and damage response. Interestingly, transcriptomic analysis revealed the participation of genes of the mevalonate and cholesterol biosynthesis pathways; in agreement with this observation, total cholesterol diminished, confirming the blockage of the cholesterol synthesis by the exposure of HeLa cells to CDPs. Interestingly, the expression of some genes of the mevalonate and cholesterol synthesis such as HMGS1, HMGCR, IDI1, SQLE, MSMO1, SREBF1, and SOAT1 was up-regulated by CDPs exposure. Accordingly, metabolites of the mevalonate pathway were accumulated in cultures treated with CDPs. This finding further suggests that the metabolism of cholesterol is crucial for the occurrence of CC, and the blockade of the sterol synthesis as an anti-proliferative mechanism of the bacterial CDPs, represents a reasonable chemotherapeutic drug target to explore. Our transcriptomic study supports the anti-neoplastic effects of bacterial CDPs in HeLa cells shown previously, providing new insights into the transduction signals, transcription factors and metabolic pathways, such as mevalonate and cholesterol that are impacted by the CDPs and highlights its potential as anti-neoplastic drugs.
Highlights
Human cervical cancer (CC) is the third leading cause of cancer death among women around the world, along with breast, lung and colorectal cancers [1] and the second leading cause of death in America
FPKM (Fragments Per Kilobase of transcript) was an indicator of gene expression; a fold change >1.49 and False Discovery Rate (FDR) < 0.01 were taken as the screening criteria in the process of gene detection/selection. Analysis of those < 43.3 million randomly derived sequence reads aligned to the human genome, revealed that this approach is reliable for studying gene expression changes as a result of the antiproliferative effects of bacterial CDPs in the HeLa cell line of human cervical cancer, in a global transcriptomewide fashion
In addition to the identification of the widely described differentially expressed genes (DEGs) and Differentially Expressed Transcription Factors (DETFs) associated with several types of cancer and transduction signaling pathways, we found a group of DEGs, including circRNAs, lncRNA, RNAs regulated by miRNAs, and transcription factors (TFs) which are related to fundamental processes such as epigenetics, splicing, and DNA-damage response (Supplementary Table S4)
Summary
Human cervical cancer (CC) is the third leading cause of cancer death among women around the world, along with breast, lung and colorectal cancers [1] and the second leading cause of death in America. CC arises in normal cervical epithelium as a progressive disease over the course of years, originated by human papillomavirus (HPV) infection. HPV infection results in host genome alterations, leading to the silencing of some tumor-suppressor factors and the induction of aberrant function of tumor-promoting factors [2]. The severity of the outcomes of CC development depends on the specific subtype of the HPV infection. The oncoproteins E5, E6, and E7, encoded by the HPV genome, are the major drivers of oncogenesis in the normal cervical epithelium [3], disrupting the normal function of the histocompatibility complex I (MHC class I), P53, Rb, Notch, Wnt, MAPK, PI3K/Akt/mTOR, STAT-associated pathways, as well as HSPs such as Hsp, Hsp, and Hsp27 [4], which are central players controlling normal cellular growth, differentiation, and immune function [5, 6]
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