Review
The interaction between human papilloma viruses related cancers and non-coding RNAs

https://doi.org/10.1016/j.prp.2022.153939Get rights and content

Abstract

Human papillomaviruses (HPVs) constitute a number of double-stranded DNA viruses with propensity to cause infection in squamous epithelial cells. Certain types of these viruses have been found to cause human cancers through delivering their oncoproteins E6 and E7. Since not all of infected patients develop malignant lesions, other factors might affect HPV-associate carcinogenic processes. A number of investigations have shown interaction between HPV-encoded proteins and a number of non-coding RNAs, principally microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Such interactions have been found to influence pathogenesis of HPV-related cancers. miR-21, miR-9, miR-143, miR-214 and let-7 are among miRNAs that contribute in the pathogenesis of HPV-related lesions. HOTAIR, SNHG8, SOX2OT, SNHG12, GABPB1-AS1, SOX21-AS1, DINO, HOST2, CCDST, FAM83H-AS1, TMPOP2 and CCEPR are examples of lncRNAs that contribute in this process. In the current review, we provide an outline of investigations that reported the impact of these transcripts in HPV-related cancers.

Introduction

Human papillomaviruses (HPVs) constitute a collection of small double-stranded DNA viruses with propensity to cause infection in squamous epithelial cells [99]. Certain types of HPVs have been found to contribute in the pathoetiology of anogenital and head and neck cancers [80]. Notably, as much as 4% of all human neoplasms have been associated with these viruses [80]. HPV infection is regarded as the principal reason for development of cervical cancer and genital warts [99]. While of genital HPV infections clear spontaneously, in about 10–20% of cases, persistent genital HPV infections occur. Most importantly, such infections can progress to grade 2/3 cervical intraepithelial neoplasm (CIN) and ultimately to invasive cervical cancer [60]. It is estimated that about one-third of CINs can progress to invasive cancers [73]. Without appropriate treatments, CINs undergo a continuum of growing cytological atypia. Almost all cases of high-grade CINs are caused by high-risk HPVs, i.e. HPV-16 and HPV-18 [22]. These viruses exert their oncogenic effects via their E6 and E7 genes, two oncoproteins that influence division and differentiation processes [26].

Current data have shown interaction between HPV-encoded proteins and a number of non-coding RNAs, principally microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). These two classes of RNAs have regulatory roles on expression of a wide range of genes. While both have regulatory roles, the mode of actions are different. miRNAs principally regulate gene expression at post-transcriptional level through binding with 3' UTR of transcripts, lncRNAs can affect gene expression at several levels, including chromatin structure, post transcription and transcriptional levels. Moreover, genetic variants within several lncRNAs have been shown to alter risk of several human disorders [89].

The interactions between non-coding RNAs and HPV-encoded proteins have been found to influence pathogenesis of HPV-related cancers. In the current review, we provide an outline of studies that reported the impact of these transcripts in HPV-related cancers.

Section snippets

miRNAs and HPV

miRNAs are small non-coding RNAs that regulate expression of genes mainly through binding with 3’ UTR of their targets. Such miRNA-mRNA interactions lead to either degradation of mRNA or suppression of its translation [77]. Several members of these transcripts have been found to affect pathogenesis of HPV-related cancers. For instance, exosomes originated from HPV-positive head and neck squamous cell carcinoma (HNSCC) cells have been reported to contain miR-9. These exosomes could induce M1

LncRNAs and HPV

LncRNAs can regulate expression of genes at different levels and through numerous mechanisms. LncRNAs actively interact with other RNA species. Moreover, they have been found to serve molecular decoy, scaffold, and enhancer RNAs [28]. The interaction between lncRNAs and HPV oncoproteins is implicated in the pathogenesis of HPV-related disorders. For instance, HOTAIR expression is up-regulated in HPV-16-positive cervical cancer cells, parallel with down-regulation of miR-214–3p. Notably, HPV-16

Discussion

HPV has been shown to affect carcinogenesis mainly through its oncoproteins E6 and E7 [76]. E6 has been shown to promote p53 degradation via interacting with the E3 ubiquitin ligase E6AP [131]. Meanwhile, E7 can bind to the pRb and dissociate the pRB/E2F complex [76]. However, the mechanisms of HPV-related carcinogenesis are more complex involving several other transcripts, particularly miRNAs and lncRNAs with either oncogenic or tumor suppressor roles. miR-148b-5p, miR-374a-3p, miR-375–3p,

Conclusion

Taken together, several miRNAs and lncRNAs partake in the pathogeensis of HPV-related cancers through having direct interactions with E6 or E7oncoproteins, affecting stability of targets of these oncoproteins or modulating activity of cancer-related pathways. Identification of the interactions between these non-coding RNAs and HPV oncoproteins could facilitate design of specific therapeutic modalities for HPV-related cancers. Although several valuable data has been obtained from above-mentioned

Ethics approval and consent to participant

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent forms were obtained from all study participants. The study protocol was approved by the ethical committee of Shahid Beheshti University of Medical Sciences. All methods were performed in accordance with the relevant

Funding

Not applicable.

CRediT authorship contribution statement

SGF and AR wrote the manuscript and revised it. MT supervised and designed the study. HS, DS, AB and BMH collected the data and designed the figures and tables. All authors read and approved the submitted version.

Declaration of Competing Interest

The authors declare they have no conflict of interest.

Acknowledgement

This study was financially supported by Grant from Medical School of Shahid Beheshti University of Medical Sciences.

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