Oncogenic HPV promotes the expression of the long noncoding RNA lnc-FANCI-2 through E7 and YY1

Abstract

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3′ untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.

Prevalence and Genotype Distribution of Human Papillomavirus Infection among 12 076 Iranian Women

“…Chronic infection with HR-HPV subtypes, found in more than 99% of all cervical squamous cell carcinomas, is the major risk factor for the disease and is associated with cervical intraepithelial neoplasia (CIN) ( Hasanzadeh et al, 2019, Xue et al, 2021. The oncogenic activity of HR-HPV types is imputed to the random introduction of the virus genomic DNA into the host genome ( Al-Shabanah et al, 2013, Liu et al, 2021. HR-HPVs are associated with high-grade lesions and CC invasiveness ( Mchome et al, 2021 ).…”

Long Non-Coding RNA FGD5-AS1 Induced by Chlamydia trachomatis Infection Inhibits Apoptosis via Wnt/β-Catenin Signaling Pathway

“…For example, circulating lncRNA-HULC may be a candidate serum tumor marker for early diagnosis of gastric cancer and monitoring its progress and prognosis ( Gao et al., 2015 ). Oncogenic HPV can promote the expression of lnc-GANCI-2, which may be one of the infection markers of high-risk HPV ( Liu et al., 2021 ). However, there is no report on the utilization of lncRNAs as biomarkers for Ct infection.…”

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…Several lncRNAs previously found to be involved in cancer are also differentially expressed in cervical cancers compared to control samples. RNA interference-mediated silencing of E7 in HPV18-positive HeLa cells or expression of E6 in primary human keratinocytes resulted in altered expression of several lncRNAs compared to control cells [ 114 , 245 , 309 , 333 , 334 ]. One of the upregulated lncRNA in cervical cancers is HOTAIR.…”

“…E7 and to a lesser extent E6 elevated Fanconi anemia complementation group 1–2 (FANCI-2) lncRNA levels and this was dependent on YY1 binding sites in the promoter region of FANC-2 . E6 and E7 were found to reduce miR-29a levels, which targets transcription factor YY1 and E7 altered the activity of YY1 [ 309 ]. The exact role of FANCI-2 in HPV-induced cancer remains elusive.…”