Noncoding RNAs in oral cancer

Abstract

Oral cancer (OC) is the most prevalent subtype of cancer arising in the head and neck region. OC risk is mainly attributed to behavioral risk factors such as exposure to tobacco and excessive alcohol consumption, and a lesser extent to viral infections such as human papillomaviruses and Epstein-Barr viruses. In addition to these acquired risk factors, heritable genetic factors have shown to be associated with OC risk. Despite the high incidence, biomarkers for OC diagnosis are lacking and consequently, patients are often diagnosed in advanced stages. This delay in diagnosis is reflected by poor overall outcomes of OC patients, where 5-year overall survival is around 50%. Among the biomarkers proposed for cancer detection, noncoding RNA (ncRNA) can be considered as one of the most promising categories of biomarkers due to their role in virtually all cellular processes. Similar to other cancer types, changes in expressions of ncRNAs have been reported in OC and a number of ncRNAs have diagnostic, prognostic, and therapeutic potential. Moreover, some ncRNAs are capable of regulating gene expression by various mechanisms. Therefore, elucidating the current literature on the four main types of ncRNAs namely, microRNA, lncRNA, snoRNA, piwi-RNA, and circular RNA in the context of OC pathogenesis is timely and would enable further improvements and innovations in diagnosis, prognosis, and treatment of OC. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

Keywords: diagnosis; noncoding RNA; oral cancer; prognosis; therapeutics.

FIGURE 1

Pathogenesis of oral cancer (OC). The normal oral epithelia undergoes molecular changes following considerable exposure to carcinogens. More importantly, individuals with genetic and epigenetic predisposition are more prone for these epithelial transformations. Furthermore, genetic and epigenetic alterations, chromosomal abnormalities and other molecular interactions would lead to initiation, promotion, and progression to invasive OC.

FIGURE 2

An overview of biogenesis of microRNA. The initial step of miRNA biogenesis is the production of primary miRNA (pri‐microRNA) from transcription of miRNA genes by RNA polymerase II or RNA polymerase III. The specific hairpin loop of pri‐microRNA is recognized and cleaved by Drosha, Dicer along with DGCR8, forming a microprocessor complex generating 70–100 nucleotide pre‐microRNA. Consequently, the pre‐microRNAs are transported to the cytoplasm from the nucleus by Exportin5 and Ran‐GTP complex and converted to microRNA duplexes (19–24 nucleotides) by the RNA III endonuclease Dicer. The double‐stranded miRNA is unwound by a helicase enzyme to form mature miRNA. Consequently, the mature miRNA is combined with the Argonaute family of proteins giving rise to the RISC. This complex is responsible for the biogenesis of functional miRNAs. The other single strand of the mature miRNA duplex, known as passenger miRNA, is usually degraded, but on some occasions, these passenger miRNAs escape the degradation process and act as mature miRNAs themselves

FIGURE 3

Overview of sources of different classes of long‐noncoding RNAs. The majority of lncRNAs are transcribed by RNA polymerase II. Different classes of lncRNAs are transcribed from different DNA elements such as promoters, enhancers, exons, and intergenic regions. The classes of lncRNAs are enhancer, intronic, bidirectional, antisense, promoter associated, exonic, and long intergenic lncRNAs.

FIGURE 4

Overview of the biogenesis of piRNA. Primary piRNAs are produced from piRNA clusters in the nucleus and transported to the cytoplasm. RNA Helicase Armitage resolves the secondary structures of primary piRNA followed by despiralization, conversion to pre‐piRNAs by the endonuclease Zucchini, loading onto piwi proteins and trimming by the 3′–5′ exonuclease Nibbler. The newly formed 3′ termini are methylated by small RNA 2′‐O‐methyltransferase Hen1. This process is called primary piRNA biogenesis. Alternatively, piRNAs can be produced by secondary biogenesis (ping–pong cycle). The Aub protein binds to the antisense piRNA strand and cleaves sense piRNA, leading to sense piRNAs loaded onto Ago3. The Ago3/piRNA complex then cleaves antisense piRNA precursors. This produces antisense piRNAs loaded onto Aub. This cleavage and trimming cycle is repeated many times to produce piRNAs.

FIGURE 5

Overview of biogenesis of circular RNA. The biogenesis of circRNAs occur in nucleus. Different classes of circRNAs can be produced from pre‐mRNA splicing catalyzed by debranching enzymes such as by spliceosome machinery or group I and II ribozyme. Exon–intron circRNA is produced as a result of pre‐mRNA splicing resulting in merging of exons with an intron placed in between on the other side. Subsequent removal of intron results in the formation of exonic circRNA. Circularization can be promoted by RNA binding proteins. Intronic circRNAs are produced from lariat portions of introns that are resistant to spliceosomic enzymes. The GU rich and C rich portions are merged together and subsequent trimming of the tail results in the formation of intronic circRNAs. C, cytosine‐rich region; GU, guanine, uracil rich region; P, circularization driven by intron pairing; Q, RBP‐mediated circularization; R, intron removal; RBP, RNA binding protein; S, circularization driven by lariat structures; T, tail trimming.

FIGURE 6

Summary of the role of ncRNAs in oral carcinogenesis. Noncoding RNAs can regulate cell proliferation, migration and invasion, cell apoptosis, and chemoresistance. The figure shows the different ncRNAs involving at different levels regulating OC. Red colored: Over‐expressed ncRNAs, Green colored: Under‐expressed ncRNAs. , snoRNAs; , lncRNAs; , circular RNAs; , microRNAs.