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The Emerging Role of PIWI-Interacting RNAs (piRNAs) in Gastrointestinal Cancers: An Updated Perspective.

ABSTRACT: Gastrointestinal (GI) cancers produce ~3.4 million related deaths worldwide, comprising 35% of all cancer-related deaths. The high mortality among GI cancers is due to late diagnosis, the presence of metastasis and drug resistance development. Additionally, current clinical markers do not adequately guide patient management, thereby new and more reliable biomarkers and therapeutic targets are still needed for these diseases. RNA-seq technology has allowed the discovery of new types of RNA transcripts including PIWI-interacting RNAs (piRNAs), which have particular characteristics that enable these molecules to act via diverse molecular mechanisms for regulating gene expression. Cumulative evidence has described the potential role of piRNAs in the development of several tumor types as a likely explanation for certain genomic abnormalities and signaling pathways' deregulations observed in cancer. In addition, these piRNAs might be also proposed as promising diagnostic or prognostic biomarkers or as potential therapeutic targets in malignancies. This review describes important topics about piRNAs including their molecular characteristics, biosynthesis processes, gene expression silencing mechanisms, and the manner in which these transcripts have been studied in samples and cell lines of GI cancers to elucidate their implications in these diseases. Moreover, this article discusses the potential clinical usefulness of piRNAs as biomarkers and therapeutic targets in GI cancers.

SUBMITTER: Riquelme I

PROVIDER: S-EPMC8750603 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Piwi-interacting RNAs (piRNAs) are a class of small RNAs primarily responsible for silencing transposons in the animal germ line. The ping-pong cycle, the posttranscriptional silencing branch of the piRNA pathway, relies on piRNAs produced from endogenous transposon remnants to direct cleavage of transposon RNA via association with Piwi-family Argonaute proteins. In some mosquito species and mosquito-derived cell lines expressing a functionally expanded group of Piwi-family Argonaute proteins, both RNA and DNA viruses are targeted by piRNAs in a manner thought to involve direct processing of exogenous viral RNA into piRNAs. Whether viruses are targeted by piRNAs in nonmosquito species is unknown. Partial integrations of DNA and nonretroviral RNA virus genomes, termed endogenous viral elements (EVEs), are abundant in arthropod genomes and often produce piRNAs that are speculated to target cognate viruses through the ping-pong cycle. Here, we describe a Diaphorina citri densovirus (DcDV)-derived EVE in the genome of Diaphorina citri We found that this EVE gives rise to DcDV-specific primary piRNAs and is unevenly distributed among D. citri populations. Unexpectedly, we found that DcDV is targeted by ping-pong-dependent virus-derived piRNAs (vpiRNAs) in D. citri lacking the DcDV-derived EVE, while four naturally infecting RNA viruses of D. citri are not targeted by vpiRNAs. Furthermore, a recombinant Cricket paralysis virus containing a portion of the DcDV genome corresponding to the DcDV-derived EVE was not targeted by vpiRNAs during infection in D. citri harboring the EVE. These results demonstrate that viruses can be targeted by piRNAs in a nonmosquito species independently of endogenous piRNAs.IMPORTANCE Small RNAs serve as specificity determinants of antiviral responses in insects. Piwi-interacting RNAs (piRNAs) are a class of small RNAs found in animals, and their primary role is to direct antitransposon responses. These responses require endogenous piRNAs complementary to transposon RNA. Additionally, piRNAs have been shown to target RNA and DNA viruses in some mosquito species. In contrast to transposons, targeting of viruses by the piRNA pathway in these mosquito species does not require endogenous piRNAs. Here, we show that piRNAs target a DNA virus, but not RNA viruses, in an agricultural insect pest. We found that targeting of this DNA virus did not require endogenous piRNAs and that endogenous piRNAs did not mediate targeting of an RNA virus with which they shared complementary sequence. Our results highlight differences between mosquitoes and our experimental system and raise the possibility that DNA viruses may be targeted by piRNAs in other species.

Project description:Purpose: The aim of this study is to identify known and novel small RNAs (Piwi-interacting RNAs and microRNAs) in normal ovary and epithelial ovarian malignancies by adopting high-throughput RNA sequencing (RNA-Seq) and unveil their possible functions in neoplastic pathways of the two most frequently observed and highly lethal subtypes of epithelial ovarian cancers, endometrioid ovarian cancer (ENOCa) and serous ovarian cancer (SOCa). The study has been performed in normal ovarian tissues as well as malignant tissues of these cancer subtypes. Methods: 1 µg of total RNA was used as the starting material for library preparation as prescribed by Illumina Truseq small RNA library protocol. Small RNA sequencing was carried out by Genotypic Technology, Bangalore, India on Illumina Next-Seq 500 platform. Library preparation was done by performing 3' and 5' adapter ligation followed by reverse transcription of cDNA and amplification of the library. The construct of the library was fractionated to select 16-40 nucleotide insert of small RNAs using PAGE. The quality check of the library was done in Agilent Technologies 2100 Bioanalyzer using a DNA-specific chip, such as High Sensitivity DNA. The sequence reads that passed through Quality Check by FastQC and aligned to the human genome (hg19) were further analysed using in-house pipelines and set of known and novel piRNAs and miRNAs were identified. The sets of known piRNAs and miRNAs identified were assessed for their involvement in neoplastic processes of ovarian cancer subtypes by performing target analysis and GO enrichment studies. Results: Using an in-house prediction pipeline, we mapped about 10-15 million sequence reads per sample to the human genome (hg19) and detected 256, 234 and 219 annotated piRNAs in ENOCa, SOCa, and normal ovary respectively; whereas the average number of known miRNAs present in each sample was estimated to be 480. The annotated piRNAs obtained from each sample exhibited varied length distribution between 26-32 nts. Conclusions: For the first time, our study reported the presence of piRNAs in ENOCa, SOCa and normal ovarian tissue from the next-gen sequencing of small RNAs of 16-40 nts length. The extensive catalogue of human EOCa small RNAs (both piRNAs and miRNAs) detected in this study provides a useful resource to dissect complex neoplastic events that are possibly mediated by these ncRNAs, especially by piRNAs. Moreover, these piRNAs could be used as probable small RNA biomarkers for the EOCa.

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The Emerging Role of PIWI-Interacting RNAs (piRNAs) in Gastrointestinal Cancers: An Updated Perspective.

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