Expression and molecular regulation of non-coding RNAs in HPV-positive head and neck squamous cell carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy worldwide. Accumulating evidence suggests that persistent HPV infection is closely related to a subset of HNSCC types, and the incidence of human papillomavirus (HPV)-positive HNSCC has been annually increasing in recent decades. Although the carcinogenesis of HPV-positive HNSCC has not been completely elucidated, it has been well confirmed that E6 and E7, the main viral oncoproteins are responsible for the maintenance of malignant transformation, promotion of cell proliferation, and increase in tumor invasion. Moreover, compared with HPV-negative HNSCC, HPV-positive HNSCC shows some special clinical-pathological features, which are possibly related to HPV infection and their specific regulatory mechanisms. Non-coding RNA (ncRNA) is a class of RNA lacking the protein-coding function and playing a critical regulatory role via multiple complex molecular mechanisms. NcRNA is an important regulatory pattern of epigenetic modification, which can exert significant effects on HPV-induced tumorigenesis and progression by deregulating downstream genes. However, the knowledge of ncRNAs is still limited, hence, a better understanding of ncRNAs could provide some insights for exploring the carcinogenesis mechanism and identifying valuable biomarkers in HPV-positive HNSCC. Therefore, in this review, we mainly focused on the expression profile of ncRNAs (including lncRNA, miRNA, and circRNA) and explored their regulatory role in HPV-positive HNSCC, aiming to clarify the regulatory mechanism of ncRNAs and identify valuable biomarkers for HPV-positive HNSCC.

Keywords: circular RNAs; head and neck squamous cell carcinoma; human papillomavirus; long non-coding RNAs; microRNAs; non--coding RNAs.

Figure 1

Classification of non-coding RNAs. Precursor miRNAs and siRNAs are transcribed and processed into mature miRNAs and siRNAs, respectively, which exert their function in the nucleus and cytoplasm. Precursor piRNAs are processed into mature piRNAs that form piRNA-PIWI complexes by combining them with PIWI proteins in the cytoplasm. TRNA intron splicing can lead to RNA cyclization, producing tricRNA. CircRNAs are divided into three main categories: intron-derived circular intronicRNAs (ciRNAs), exon-derived exonic circRNAs (ecircRNAs), and exon-intron circRNAs (EIcircRNAs). EIcircRNAs are mainly located in the nucleus, while ecircRNAs and tricRNAs are synthesized in the nucleus and will be exported to the cytoplasm. Most lncRNAs are located in the nucleus, and rarely encode proteins, while some are located in the cytoplasm.

Figure 2

Main mechanisms involved in the malignant transformation and biological behaviors induced by viral oncoproteins E6/E7 in HPV-positive HNSCC. Oncoproteins E6 and E7 can inactivate tumor suppressor proteins p53 and pRb involved in the cell cycle, genome stability, and epigenetic modifications, as well as affect mutation and epigenetic changes of the host genome. E6 and E7 regulated the levels of miRNAs mainly by releasing p53 and E2F, thus, affecting miRNA expression, while miRNAs can activate or suppress downstream genes and key signal pathways involved in biological behaviors.

Figure 3

Main mechanisms of miRNAs expression regulation by E6/E7 in HPV-positive HNSCC and cervical cancer. E6 and E7 regulate the levels of miRNAs mainly by binding or releasing the transcription factors of miRNAs, such as c-Myc, p53, and E2F. The degradation of cellular transcription factor p53 is induced by E6, which can bind the promoter region of miRNAs. HPV E6 oncoprotein destabilizes p53, which contributes to the deregulated miRNAs. The degradation of pRb induced by E7 leads to the release of E2F from the pRB-E2F complex, and E2F binds to its binding site in miRNA promoter region, thus, affecting miRNA expression.

Figure 4

Competing endogenous RNAs (CeRNAs) networks and mechanisms. CeRNAs link the function of protein-coding mRNAs with miRNAs, lncRNAs, circRNAs, and pseudogenic RNAs. CeRNAs target binding (sponge) MREs (pseudogene transcripts, lncRNA, miRNAs, and circRNA) to revive the inhibition of downstream target genes, and this regulatory mode constitutes the ceRNA mechanism.