PIWI-RNAs Small Noncoding RNAs with Smart Functions: Potential Theranostic Applications in Cancer

Abstract

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a new class of small noncoding RNAs (ncRNAs) that bind components of the PIWI protein family. piRNAs are specifically expressed in different human tissues and regulate important signaling pathways. Aberrant expressions of piRNAs and PIWI proteins have been associated with tumorigenesis and cancer progression. Recent studies reported that piRNAs are contained in extracellular vesicles (EVs), nanosized lipid particles, with key roles in cell-cell communication. EVs contain several bioactive molecules, such as proteins, lipids, and nucleic acids, including emerging ncRNAs. EVs are one of the components of liquid biopsy (LB) a non-invasive method for detecting specific molecular biomarkers in liquid samples. LB could become a crucial tool for cancer diagnosis with piRNAs as biomarkers in a precision oncology approach. This review summarizes the current findings on the roles of piRNAs in different cancer types, focusing on potential theranostic applications of piRNAs contained in EVs (EV-piRNAs). Their roles as non-invasive diagnostic and prognostic biomarkers and as new therapeutic options have been also discussed.

Keywords: PIWI proteins; biomarkers; epidrugs; extracellular vesicles; ncRNAs; piRNAs.

Figure 1

Simplified representation of the currently proposed model of piRNA biogenesis. Two steps of piRNA biogenesis: (1) primary amplification cycle in nucleus and (2) secondary amplification cycle described as “ping-pong cycle” in cytoplasm. Abbreviations: Pol II: polymerase II; Zuc: endonuclease Zucchini; Aub: Aubergine protein; Ago 3: Argonauta 3 protein.

Figure 2

Homeostasis of piRNA in human cells. The degradation of human piRNAs depends on 5′-3′ exoribonuclease.

Figure 3

piRNA involvement in different biological processes, hallmarks of cancer, such as tumor progression, epigenetic regulation, transposon deregulation, DNA methylation, metastasis, genomic integrity, drug resistance, and stem cell maintenance.

Figure 4

Roles of the four members of PIWI protein family. PIWI1, PIWI2, PIWI3, and PIWI4 have several roles in the steps of cancer progression (such as proliferation, migration, invasion, cell survival, tumor escape, chemoresistance, self-renewal properties, metastasis, apoptosis, EMT: epithelial–mesenchymal transition) and epigenetic regulation (DNA methylation).

Figure 5

Schematic representation of the piRNAs localization in various cancer types. 1: Breast and ovarian cancer; 2: lung cancer; 3: prostate cancer; 4: renal cancer; 5: colon rectal cancer; 6: gastric cancer; 7: pancreatic and biliary cancer; 8: other cancer type.

Figure 6

Working hypothesis of piRNA use in diagnosis and therapies. The identification of EV-piRNAs collected by the blood of cancer patients can be useful as diagnostic biomarkers. The engineering of EVs, loading ectopic piRNA, may allow shuttling piRNA useful as new epidrugs.