Simple Summary P-element-induced wimpy testis-interacting RNAs (piRNAs) are a novel class of small regulatory RNAs that often bind to PIWI proteins. First identified in animal germ line cells, piRNAs have key roles in germ line development. New insights into the functions of PIWI-piRNA complexes demonstrate that they regulate protein-coding genes. Aberrant piRNA expression has been also associated with different diseases, including cancer. Recently, piRNAs have been described in extracellular vesicles. EVs are one of the components of liquid biopsy, a revolutionary technique for detecting specific molecular biomarkers. This review focuses on piRNAs as potential biomarkers in different cancer types. Furthermore, piRNAs contained in extracellular vesicles could represent a new route for early diagnosis and therapies in a personalized medicine approach. 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.

Approximately 90% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is the fourth leading cause of cancer death world-wide. Therapies for PDAC are largely ineffective due to the dense desmoplastic tumor microenvironment which prevents chemotherapeutic drugs and small molecule inhibitors from exerting effective anti-cancer effects. In this review, we will discuss the roles of TP53 and miRs on the PDAC tumor microenvironment and how loss of the normal functions of TP53 promote tumor progression. The TP53 gene is mutated in approximately 50% of pancreatic cancers. Often, these TP53 mutations are point mutations which confer additional functions for the TP53 proteins. These are called gain of function (GOF) mutations (mut). Another class of TP53 mutations are deletions which result in loss of the TP53 protein; these are referred to TP53-null mutations. We have organized this review into various components/properties of the PDAC microenvironment and how they may be altered in the presence of mutant TP53 and loss of certain miR expression.

In the recent years, a huge number of human transcripts have been found in the human genome that do not encode for proteins, which have been named non-coding RNAs (npcRNAs) containing secondary structures or short regions highly conserved within mammalian sequences. Long RNAs (antisense RNA, structured RNA, and long interspersed ncRNAs) and small RNAs (miRNAs, siRNAs, snoRNAs) have shown to exert many roles: functioning as regulators of other mRNAs, at transcriptional and post-transcriptional level, controlling protein ubiquitination and degradation, regulating epigenetic marks and affecting chromosome structure. One group of npcRNAs that is well-characterized, at the biochemical level, is represented by miRNAs. This group comprises a large class of small npcRNAs (~22-nucleotide RNAs) acting through base pairing to partially complementary sites in the 3'untranslated regions (3'UTR) of the targeted messenger RNA. Circular RNAs, competing endogenous RNAs (ceRNAs) acting as RNA sponges, natural antisense RNAs (NAT), enhancer RNAs (eRNAs), and RNA decoys are further expanding the wide array of functionalities exerted by ncRNAs. In the last case, as example, Growth Arrest Suppressor 5 (GAS5) forms a structured RNA tha is a decoy for the glucocorticoid receptor (GR), mimicking the DNA structure of the GR element (GRE). Long noncoding RNAs (lncRNAs) have emerged as key players in regulating various fundamental cellular processes. Many of the mechanisms that modify the 3' UTRs, or that affect differential splicing, make use of RNA regulation, antisense RNAs, and may involve RNP complexes. Many human ncRNAs have been characterized in terms of function or expression profiles. HOTAIR, described in detail in the review by Ge Shan, is a structured RNA that assemble several proteins to form an epigenetic regulation complex: it assembles Polycomb Repressive Complex (PRC) proteins and determines the silencing of specific genes. Terminal differentiation induced ncRNA (TINCR) destabilises ALU elements in mRNAs through the RNA binding protein Staufen 1 binding to polypurine tract. Thus, proteins involved in the functioning of ncRNAs are highly varied: RNA binding proteins, ribonucleoprotein complexes, alternative splicing proteins, alternative polyadenylation proteins, chromatin remodeling complexes, and gene activation and repression complexes (PRC) and enzymes positioning or eliminating histone marks. Then, it is clear that the changes determined in several diseases and in cancer are caused non only by mutated genes but also by epigenetic deregulation and by alternative spliced genes and alternative polyA tails that evade microRNA recognition. Concerning miRs, the varied presence of Argonaute family of proteins and the link with diseases are well detailed in more than one review in this special issue.