Comprehensive analysis of ceRNA networks in HPV16- and HPV18-mediated cervical cancers reveals XIST as a pivotal competing endogenous RNA

Abstract

Cervical cancer (CC) is one of the most common cancers in women worldwide, being closely related to high-risk human papillomavirus (HR-HPVs). After a particular HR-HPV infects a cervical cell, transcriptional changes in the host cell are expected, including the regulation of lncRNAs, miRNAs, and mRNAs. Such transcripts may work independently or integrated in complex molecular networks - as in competing endogenous RNA (ceRNA) networks. In our research, we gathered transcriptome data from samples of HPV16/HPV18 cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), from The Cancer Genome Atlas (TCGA) project. Using GDCRNATools, we identified ceRNA networks that differentiate HPV16- from HPV18-mediated CESC. For HPV16-CESC, three lncRNA-mRNA co-expressed pairs were reported, all led by the X-inactive specific transcript (XIST): XIST | DLG5, XIST | LGR4, and XIST | ZNF81. The XIST | LGR4 and XIST | ZNF81 pairs shared 11 miRNAs, suggesting an increased impact on their final biological effect. XIST also stood out as an important lncRNA in HPV18-CESC, leading 35 of the 42 co-expressed pairs. Some mRNAs, such as ADAM9 and SLC38A2, emerged as important players in the ceRNA regulatory networks due to sharing a considerable amount of miRNAs with XIST. Furthermore, some XIST-associated axes, namely XIST | miR-23a-3p | LGR4 and XIST | miR-30b-5p or miR-30c-5p or miR-30e-5p I ADAM9, had a significant impact on the overall survival of HPV16- and HPV18-CESC patients, respectively. Together, these data suggest that XIST has an important role in HPV-mediated tumorigenesis, which may implicate different molecular signatures between HPV16 and HPV18-associated tumors.