Coordinated action of human papillomavirus type 16 E6 and E7 oncoproteins on competitive endogenous RNA (ceRNA) network members in primary human keratinocytes
Open Access
- 7 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 21 (1), 1-19
- https://doi.org/10.1186/s12885-021-08361-y
Abstract
Background miRNAs and lncRNAs can regulate cellular biological processes both under physiological and pathological conditions including tumour initiation and progression. Interactions between differentially expressed diverse RNA species, as a part of a complex intracellular regulatory network (ceRNA network), may contribute also to the pathogenesis of HPV-associated cancer. The purpose of this study was to investigate the global expression changes of miRNAs, lncRNAs and mRNAs driven by the E6 and E7 oncoproteins of HPV16, and construct a corresponding ceRNA regulatory network of coding and non-coding genes to suggest a regulatory network associated with high-risk HPV16 infections. Furthermore, additional GO and KEGG analyses were performed to understand the consequences of mRNA expression alterations on biological processes. Methods Small and large RNA deep sequencing were performed to detect expression changes of miRNAs, lncRNAs and mRNAs in primary human keratinocytes expressing HPV16 E6, E7 or both oncoproteins. The relationships between lncRNAs, miRNAs and mRNAs were predicted by using StarBase v2.0, DianaTools-LncBase v.2 and miRTarBase. The lncRNA-miRNA-mRNA regulatory network was visualized with Cytoscape v3.4.0. GO and KEEG pathway enrichment analysis was performed using DAVID v6.8. Results We revealed that 85 miRNAs in 21 genomic clusters and 41 lncRNAs were abnormally expressed in HPV E6/E7 expressing cells compared with controls. We constructed a ceRNA network with members of 15 lncRNAs – 43 miRNAs – 358 mRNAs with significantly altered expressions. GO and KEGG functional enrichment analyses identified numerous cancer related genes, furthermore we recognized common miRNAs as key regulatory elements in biological pathways associated with tumorigenesis driven by HPV16. Conclusions The multiple molecular changes driven by E6 and E7 oncoproteins resulting in the malignant transformation of HPV16 host cells occur, at least in part, due to the abnormal alteration in expression and function of non-coding RNA molecules through their intracellular competing network.Keywords
This publication has 66 references indexed in Scilit:
- Deregulation of miR-21 and miR-29a in Cervical Cancer Related to HPV InfectionMicroRNA, 2019
- miRBase: from microRNA sequences to functionNucleic Acids Research, 2018
- LINC01101 and LINC00277 expression levels as novel factors in HPV‐induced cervical neoplasiaJournal of Cellular and Molecular Medicine, 2017
- Dysregulated expression of long noncoding RNAs in gynecologic cancersMolecular Cancer, 2017
- LncRNAs: key players and novel insights into cervical cancerTumor Biology, 2015
- Novel MicroRNA signatures in HPV-mediated cervical carcinogenesis in Indian womenTumor Biology, 2015
- MicroRNAs as biomarkers of cervical cancer development: a literature review on miR-125b and miR-34aMolecular Biology Reports, 2014
- Effects of human papillomavirus (HPV) type 16 oncoproteins on the expression of involucrin in human keratinocytesVirology Journal, 2012
- Dysregulation of microRNAs in cancer: Playing with fireFEBS Letters, 2010
- Papillomaviruses and cancer: from basic studies to clinical applicationNature Reviews Cancer, 2002