Small non-coding RNA and cancer

Abstract

The ENCODE project has reported that at least 80% of the human genome is biologically active, yet only a small part of human DNA encodes for protein. The massive amount of RNA transcribed but not translated into protein can be classified as housekeeping RNA (such as rRNA, tRNA) and regulatory RNA (such as miRNA, piRNA, lncRNA). Small non-coding RNAs, in particular, have been the focus of many studies in the last 20 years and their fundamental role in many human diseases is currently well established. Inter alia, their role in cancer development and progression, as well as in drug resistance, is being increasingly investigated. In this review, focusing our attention on recent research results, we provide an overview of the four large classes of small non-coding RNAs, namely, miRNAs, piRNAs, snoRNA and the new class of tRNA-derived fragments, highlighting their fundamental role in cancer and their potential as diagnostic and prognostic biomarkers.

Figure 1.

Estimated expression percentage of different RNA species in typical mammalian cells (Adapted from Palazzo et al.).

Figure 2.

Schematic representation of miRNA (left) and piRNA (right) biogenesis. Primary miRNAs (pri-miRNAs) product by RNA POL II can be monocistronic if they carry just one mir or polycistronic if they contain multiple miRNAs. While in the nucleus, pri-miRNAs are cleaved by the Drosha/DGR8 complex into 65nt precursor miRNAs (pre-miRNAs) and then exported by the Exportin5/RAN-GTP complex into the cytoplasm where they are in turn cleaved by the Dicer/TRBP/PACT complex which thus produces a miRNA duplex ready to be incorporated into the RISC complex; only one strand of the miRNA is preferentially selected to be coupled with the RISC complex. On the right, piRNA precursors are produced through the primary processing pathway, transcribed by POL II and exported into the cytosol where they are cut into mature piRNAs. Then, mature piRNAs in complex with PIWI proteins migrate to the nucleus where they silence TEs. In addition, MIWI2 and MILI coupled with mature piRNAs, cleave transcripts bearing sites complementary to the piRNA sequence, thus amplifying mature piRNA species through the ping-pong pathway.

Figure 3.

Schematic representation of t-RF and snoRNA biogenesis: (A) All t-RF-1s (including tsRNAs) derive from the maturation of tRNA. After Pol III transcription, the tRNA 5′ sequence (leader) is removed by RNase P, whereas the 3′ end (trailer) is cleaved by the tRNase Z enzyme. The stress (and starvation)-induced tRNA fragments termed tiRNA (tiRs) (or tRNA halves) are the result of the cleavage carried out by angiogenin and they are called 5’- or 3’- according to which segment of the anticodone loop they include. The enzymes responsible of cleaving all other tRFs are still unknown. (B) Small nucleolar RNAs (snoRNAs) are predominantly located in introns. The snoRNA biogenesis pathway is essentially represented by endonuclease cleavage after mRNA splicing. Lariats generated after mRNA splicing, and carrying snoRNA, are linearized by the Debranching RNA Lariats 1 protein (DBR1). snoRNAs can alternatively be directly excised by endonucleases from pre-mRNA before splicing. In both cases, exonucleases finally release the mature snoRNA.