The biogenesis and biological function of PIWI-interacting RNA in cancer

Abstract

Small non-coding RNAs (ncRNAs) are vital regulators of biological activities, and aberrant levels of small ncRNAs are commonly found in precancerous lesions and cancer. PIWI-interacting RNAs (piRNAs) are a novel type of small ncRNA initially discovered in germ cells that have a specific length (24-31 nucleotides), bind to PIWI proteins, and show 2'-O-methyl modification at the 3'-end. Numerous studies have revealed that piRNAs can play important roles in tumorigenesis via multiple biological regulatory mechanisms, including silencing transcriptional and posttranscriptional gene processes and accelerating multiprotein interactions. piRNAs are emerging players in the malignant transformation of normal cells and participate in the regulation of cancer hallmarks. Most of the specific cancer hallmarks regulated by piRNAs are involved in sustaining proliferative signaling, resistance to cell death or apoptosis, and activation of invasion and metastasis. Additionally, piRNAs have been used as biomarkers for cancer diagnosis and prognosis and have great potential for clinical utility. However, research on the underlying mechanisms of piRNAs in cancer is limited. Here, we systematically reviewed recent advances in the biogenesis and biological functions of piRNAs and relevant bioinformatics databases with the aim of providing insights into cancer diagnosis and clinical applications. We also focused on some cancer hallmarks rarely reported to be related to piRNAs, which can promote in-depth research of piRNAs in molecular biology and facilitate their clinical translation into cancer treatment.

Keywords: Biogenesis; Biomarker; Cancer hallmarks; Database; piRNAs.

Fig. 1

Biogenesis mechanisms and characteristics of piRNAs. (A) Five origins of primary piRNAs. It has been confirmed that the generation of piRNAs can be divided into five groups depending on their origin: (a) transposon-derived, (b) mRNA-derived, (c) tRNA-derived, (d) lncRNA-derived, and (e) snoRNA-derived piRNAs. (B) Sense and antisense transcripts of the primary piRNAs are produced by small nucleotide sequences from clusters of piRNA genes. (C) Primary piRNAs are cleaved by Zuc in the YB body, and the 5′ fragments of the intermediate sequence interact with a PIWI protein to form the piRNA/PIWI complex and thus intermediate piRNAs. The 2′-hydroxyl at the 3′-end of the intermediate piRNA is methylated by Hen1 to form a mature piRNA/PIWI complex. (D) The primary piRNA binds to AGO3 or AUB proteins through the “ping-pong cycle” to form complexes in the nucleus. Given the complementary piRNA sequences of these two complexes, the piRNA/AGO3 complex splits target RNA in the cytoplasm to produce corresponding new sequences, which can then be used as substrates to bind to AUB proteins in the nucleus to form new piRNA/AUB complexes. TSS transcription start site; Zuc zucchini

Fig. 2

Regulatory mechanisms and biological functions of piRNAs and piRNA/PIWI complexes. (A) TGS mainly occurs on PIWI proteins with low catalytic activity. The role of piRNAs in gene expression modification is similar to that of DNA methylation. (B) PTGS usually requires PIWI proteins to perform cleavage because it depends on target transcriptional fragments. Here, piRNAs play a role similar to that of miRNAs. (C) Both piRNAs and PAZ domains of PIWI proteins in the piRNA/PIWI complex can directly bind to some proteins and thus promote multiprotein interactions

Fig. 3

piRNAs involved in human cancers. piRNAs related to cancer hallmarks are shown in the circle. The other five tumor hallmarks (genome instability and mutation, avoidance of immune destruction, evasion of growth suppression, acquisition of replicative immortality, and tumor-promoting inflammation) were not found to involve piRNAs. Other aberrant piRNAs in human cancers are shown in the box. The piRNAs shown in black have an oncogenic role, the piRNAs in blue have a tumor-suppressive role, and those shown in yellow have reportedly controversial roles in the specific cancer type. Abbreviations: DLBCL, diffuse large B-cell lymphoma. ^aDifferent studies of piR-823 in specific cancer types