The Unforeseen Non-Coding RNAs in Head and Neck Cancer

Abstract

Previously ignored non-coding RNAs (ncRNAs) have become the subject of many studies. However, there is an imbalance in the amount of consideration that ncRNAs are receiving. Some transcripts such as microRNAs (miRNAs) or small interfering RNAs (siRNAs) have gained much attention, but it is necessary to investigate other "pieces of the RNA puzzle". These can offer a more complete view over normal and pathological cell behavior. The other ncRNA species are less studied, either due to their recent discovery, such as stable intronic sequence RNA (sisRNA), YRNA, miRNA-offset RNAs (moRNA), telomerase RNA component (TERC), natural antisense transcript (NAT), transcribed ultraconserved regions (T-UCR), and pseudogene transcript, or because they are still largely seen as non-coding transcripts with no relevance to pathogenesis. Moreover, some are still considered housekeeping RNAs, for instance small nucleolar RNAs (snoRNAs) and TERC. Our review summarizes the biogenesis, mechanism of action and potential role of less known ncRNAs in head and neck cancer, with a particular focus on the installment and progress for this particular cancer type.

Keywords: biological mechanisms; head and neck cancer; rare non-coding RNAs.

Figure 1

A schematic representation of the biogenesis and the main characteristics of some rare RNA species. The bidirectional arrow represents the length of the transcript, the red arrow stands for transcription and the blue arrow stands for RNA processing. (A) The enhancer RNA (eRNA) is transcribed from the enhancer DNA (eDNA) region. The transcription can be unidirectional; in this case, eRNA is polyadenylated, has a length of more than 4 kb and is named 1D-eRNA. If the eRNA is transcribed bidirectionally, it is not polyadenylated, has a length of less than 2 kb and is called 2D-eRNA. (B) The stable intronic RNA (sisRNA) is transcribed as primary messenger RNA (mRNA) transcript. After splicing, the intronic sequence remains stable thus forming the sisRNA. (C) The YRNA is transcribed from special regions of the DNA, called YDNA. The YRNA can remain in the nucleus or it can be cleaved into smaller fragments associated with Rho proteins. The smaller fragments are called small YRNA (sYRNA) and are sometimes exported into the cytoplasm. (D) From the promoter region of the RNA polymerase II (Pol II), the telomerase RNA component (TERC) is transcribed. TERC helps with telomerase activity. (E) From the antisense strand of protein-coding genes, the natural antisense transcript (NAT) is synthesized. NAT bears many similarities to the mRNA. (F) the small nucleolar RNA (snoRNA) can be originated from the intronic regions of protein-coding genes or from the promoter region of RNA Pol II. (G) From transporter genes, transfer RNA (tRNA) is formed; this transcript can be further fragmented and it forms the tRNA-derived fragments (tRFs). (H) The endogens are former protein-coding genes that have accumulated major mutations throughout evolution and become non-functional. The pseudogenes can be transcribed and the pseudogenes transcript bears many similarities to the mRNA. (I) The primary form of miRNA is processed by Argonaute (AGO) proteins. After processing, some part of the primary transcript remains in the nucleus, becomes stable and is very similar to miRNAs. These transcripts are named miRNA-offset RNA (moRNA). (J) Some regions of DNA, also considered non-functional, have high similarity across different species. These regions are called ultraconserved regions and can be transcribed. The transcribed ultraconserved region (T-UCR) is also similar in some aspects to mRNA.

Figure 2

The lesser-known non-coding RNAs (ncRNAs) analyzed in this review have different mechanisms of action. NAT and pseudogene transcripts function as miRNA sponge, esiRNA and miRNA sources and can possess coding capacity. moRNA, T-UCR and sisRNA regulate gene expression through post-translational interaction with different coding or non-coding RNA species. In the alternative-splicing process, in addition to snoRNA, sisRNA might also play a role. YRNA is implicated in DNA replication and in deciding the fate of misfolded RNA. T-UCR and eRNA control gene expression before transcription: T-UCR by modulating the methylation pattern of CpG island and eRNA by chromatin structural changes and interaction with the transcription factors. TERC, through association with telomerase, maintains the length of telomeres, thus enabling replicative immortality. sYRNA were shown to be implicated in cell apoptosis, but the exact mechanism remains unknown. In addition, tRFs are involved in cell proliferation through an unknown mechanism.

Figure 3

A short list of the most studied down-regulated and up-regulated rare ncRNAs in head and neck cancer discovered to this date.

Figure 4

Salivary exosome-mediated intracellular communication in oral cancer. (1) In the tumor cell, by the budding of membrane, the multivesicular endosome (MVE) is formed, containing small vesicles of 40–100 nm called exosomes. The MVE can have an endogenous or an exogenous origin. (2) The MVE can fuse with a lysosome and its content is destroyed. (3) The MVE can also fuse with the plasma membrane and release the exosomes in the saliva. (4) The exosomes circulate through the body fluids such as the saliva or the blood and reach a targeted cell. (5) In the targeted cell, the exosomes are recognized by the surface proteins and are internalized through endocytosis. (6) The exosome can also bind directly to the plasma membrane and release its content into the cytoplasm. (7) An exosome contains surface proteins necessary for the engulfment by the targeted cell. In its interior, the exosome contains ncRNAs, DNA fragment and other proteins. This cargo can influence the behavior of their targeted cell. The exosome can contain also viruses; hence, it can mediate the spreading of human papilloma virus or Epstein-Barr virus.