Cancer remains elusive in many aspects, especially in its causes and control. After protein profiling, genetic screening, and mutation studies, scientists now have turned their attention to epigenetic modulation. This new arena has brought to light the world of noncoding RNA (ncRNA). Although very complicated and often confusing, ncRNA domains are now among the most attractive molecular markers for epigenetic control of cancer. Long ncRNA and microRNA (miRNA) have been studied best among the noncoding genome and huge data have accumulated regarding their inhibitory and promoting effects in cancer. Another sector of ncRNAs is the world of PIWI-interacting RNAs (piRNAs). Initially discovered with the asymmetric division of germline stem cells in the Drosophila ovary, piRNAs have a unique capability to associate with mammalian proteins analogous to P-element induced wimpy testis (PIWI) in Drosophila and are capable of silencing transposons. After a brief introduction to its discovery timelines, the present narrative review covers the biogenesis, function, and role of piRNAs in lung cancer. The effects on lung cancer are highlighted under sections of cell proliferation, stemness maintenance, metastasis, and overall survival, and the review concludes with a discussion of recent discoveries of another class of small ncRNAs, the piRNA-like RNAs (piR-Ls).
Lung cancer causes the highest mortality in cancer-related deaths worldwide . One of the major causes of lung cancer is tobacco smoking, which may be associated with socioeconomic status [2, 3]. While raising awareness is necessary to control the growing incidence of lung cancer, understanding the cellular networks and discovering new targets for therapies are also important. In recent trends, scientists have examined the pool of noncoding RNAs (ncRNAs) and their specific roles in epigenetic regulation. So far, the most studied ncRNAs are microRNAs (miRNAs) and their regulatory roles in various cancers, including lung cancer, have been established .
P-element induced wimpy testis (PIWI) proteins belong to the Argonaute family of proteins , which were first discovered in Drosophila melanogaster ovarian germ cells and follicular cells . By interacting with Tudor domain-containing proteins (TDRDs), PIWI proteins mediate the biogenesis of PIWI-interacting RNAs (piRNAs), thereby silencing transposons . Three types of PIWI subfamily proteins are found in Drosophila—piwi, which localizes in the nucleus of germ and gonadal somatic cells, Aubergine (aub), and Archipelago 3 or Argonaute 3 (ago3), which are both expressed in nuages, or germline granules, which are special cytoplasmic compartments in Drosophila melanogaster. All these proteins are involved in the biogenesis of piRNAs in Drosophila flies . PIWI proteins use piRNAs as their guide to the specific DNA sequences for transposon silencing and gene regulation as well as playing major roles in their biogenesis . Orthologs of Drosophila piwi proteins have been found in mice, zebrafish, C. elegans, and humans, in which they have similar roles in maintaining male and female fertility (Figure 1). In the human, genome 4 piwi orthologs (PIWIL1/HIWI, PIWIL2/HILI, PIWIL3, and PIWIL4/HIWI2) have been identified . The first evidence of human PIWI association with cancer was studied in seminomas . Aberrant expression of 1 or more of these 4 proteins is common, especially in breast, prostate, and colorectal carcinomas (Table 1). Limited findings have emerged in the case of lung cancer [4, 60,61,62]. Various studies have found interesting patterns of human PIWI-like protein expression and regulatory effects in lung cancers . Human PIWIs and piRNAs may be important biomarkers and therapeutic targets for various cancers [64, 65].
Important discoveries of PIWI/piRNA expression in various cancers†
Inhibition of apoptosis and promotion of proliferation via Stat3/Bcl-XL signaling pathway 
Lung cancer until 2021 and other cancers until 2019. PIWI, PIWI protein (human); piRNA, Piwi protein-interacting RNA; PIWIL1, PIWI-like 1 protein (human) or HIWI protein (human); PIWIL2, HILI protein (human); PIWIL3, HIWI3 protein (human); and PIWIL4, HIWI2 protein (human); ncRNA, non-coding RNA.
The present narrative review aims to introduce the details of piRNA biogenesis and function and then detail the various discoveries as a timeline of events. The review aims to summarize the emerging roles of a relatively new group of sncRNAs, piRNAs, and their interacting PIWI family proteins in lung cancer. Finally, a correlation between the hallmarks of cancer and the piRNA/PIWI family of proteins has been attempted.
We used PubMed (MEDLINE inclusive), Google Scholar, Web of Science, and Scopus as principal online databases. To explore the literature related to PIWI RNA, the keyword “PIWI RNA” was used. To elaborate on its role in cancer the keywords “PIWI RNA” and “cancer” were used. Keywords “PIWI RNA” and “lung cancer” were used to narrow the specification to lung neoplasms. The genesis and logic for separation of dates to demark “PIWI RNA” and “cancer” and “PIWI RNA” and “lung cancer” as detailed in Table 1 was lung cancer until end 2021 and other cancers until 2019. This delimited the information and references related to PIWI RNA and cancers other than lung cancer to 2019. Preference was given to citation of references published in the past 5 years. The reference lists of identified articles were further examined for relevant publications. We have arranged our gathered information using the subtitles indicated in the review and further cross-verified each subheading content with appropriate keywords. We have assembled information for readers for ready reference and have added our personal comments summarizing information acquired along with an attempt to collate piRNA with the basics of cancer biology.
Biogenesis of piRNA
The pathway for piRNA generation is rather complicated and largely uncharted. However, studies conducted so far have confirmed 2 distinct pathways operate in the case of germline and gonadal somatic cells of Drosophila. Precursors of piRNAs are mainly transcribed from gene clusters flamenco and traffic jam. Flamenco is one of the major clusters for piRNA biogenesis in the somatic support cells of the Drosophila ovary and produces piRNA precursors. The cluster resides in the perichromatin region of the X chromosome in Drosophila. An approximately 180 kb stretch of the cluster transcribes into nascent piRNAs, which typically span about 150 kb. The transcripts are generated from a single strand of the DNA by unidirectional transcription orientation in the antisense direction. Partial or an entire loss of flamenco in Drosophila leads to malfunctioning in transposable element (TE) management [66, 67]. A similar, piRNA-producing locus in chromosome 2 in Drosophila is called traffic jam, whose primary function was identified as a crucial factor in gonadal morphogenesis in these flies. Loss of traffic jam leads to blockade in the differentiation of somatic cells into germ cells and ultimately the formation of follicular cells in Drosophila ovaries . Although these 2 clusters are the widely studied and important sources of piRNA, other sources such as intergenic regions and transposons are also noted . In these piRNA regions in the DNA, trimethylated lysine 9 of histone 3 (H3K9Me3) marks are abundant and contribute to piRNA expression . In germ cells, piRNA clusters, to be transcribed, require a protein complex consisting of Rhino, Deadlock, and Cutoff (RDC) proteins . TREX is another complex needed for the dual stranded cluster transcription recruited to the DNA in RDC dependent manner . The length of mature piRNAs varies from 24 to 32 nucleotides .
Zucchini mediated pathway
In the gonadal somatic cells and follicular cells, after transcription, the precursors of piRNAs are transported from the nucleus to the Yb body (containing Piwi, Armitage (Armi), Tudor, Vreteno (Vret), RNA helicase Sister of Yb (SoYb)) in the cytosol . Then premature piRNAs are processed at the 5′ end by a mitochondrial membrane endonuclease called Zucchini (Zuc) . Subsequently, they are loaded onto Piwi by Shutdown and Hsp83 and their 3′ end is trimmed by a slicer enzyme . Piwi has a bias for 5′ U. Aub and Ago3 proteins are not used in this pathway. This processed piRNA is further trimmed by a protein called Nibbler . Ultimately, it is methylated at the 2′ O position by a methyltransferase Hen1 (HENMT1 in mice) . This last step is believed to increase the stability of the piRNA. Processed and mature piRNAs are then transferred back to the nucleus.
The secondary amplification of piRNAs occurs in germ cells with the help of AUB and AGO3 proteins via the ping-pong pathway, which also leads to post-transcriptional gene silencing (PTGS). The ping-pong pathway starts with the loading of nascent piRNAs, transcribed from the clusters to Aub. Aub shows a 5′U bias for piRNAs and Ago3 shows a bias for adenine at the 10th position. The 5′ end is loaded on Aub with the help of the Shu and Hsp83 and then trimmed and methylated as described above for the Zuc mediated pathway . piRNAs loaded onto Aub are antisense to specific TE mRNA and they eventually guide Aub to their complementary TE mRNA in the cytosol for targeted destruction. This process also generates the 5′ piRNA precursor. The primary piRNA precursor is loaded onto Ago3 and processed into secondary piRNA precursors. The secondary piRNA precursor is sense to TE and antisense to unprocessed piRNA; accordingly they cleave the newly attached piRNA precursors and continue the loop of transposon silencing and mature piRNA production .
piRNAs save the germ cells from mutations by TE. The mechanism of piRNA biogenesis in Drosophila and many other species is itself a process of degrading TE at the post-transcriptional level. Mutations in Aub and Ago3 lead to an elevated level of transposons in the germ cells . As discussed earlier for the ping-pong pathway, a piRNA targets a transposon with opposite orientation and degrades it into a new piRNA. Together these processes serve to slice TE and amplify piRNA. The transposon-containing regions of the DNA generate piRNAs, which in turn upon maturation, recruit Piwi and other proteins to silence the TE region [79, 80]. Other species, such as mice and zebrafish, also show a similar function for their PIWI family proteins. Knocking down of Piwi orthologs increased the abundance of transposons in these species .
piRNA mediated epigenetic regulation and transcriptional silencing
Piwi and Aub conduct position effect variegation in which a stretch of euchromatin is converted to heterochromatin to variable extents among cells within the same tissue . Piwi interacts with heterochromatin protein 1a (HP1a) to promote heterochromatin formation . It is shown by studies in Drosophila that Piwi helps in loading the H3K9Me3 mark on DNA and converts stretches of DNA into heterochromatin. So, the loss of Piwi makes TE available for pol II . In mice, Mili and Miwi2 (mouse orthologs of PIWI) together promote retrotransposon silencing by CpG DNA methylation in male germ-line cells and piRNA alone can also regulate DNA methylation in these germ cells [81, 85].
Reproduction and development
PIWI proteins have stem cell maintaining properties for which their role in germline development and maintenance is well observed. Knockdown studies have shown anomalies in development. For instance, in Drosophila both male and female piwi protein-coding gene mutants fail to form primordial germ cells and renew germline stem cells, which leads to sterility . Aub protein-coding gene mutation leads to compromised PTGS and DNA damage accumulation also resulting in sterility . Females with mutant ago3 lay fewer eggs and most of the time are sterile . Similar results were also obtained from studies on mice. PIWI orthologs, Mili, Miwi2, and Miwi mutant mice show defects in PTGS and spermatogenesis . Zebrafish PIWI-like proteins Zili and Ziwi mutations decrease the number of germ cells and increase apoptosis of germ cells respectively . Mutations in other piRNA biogenesis proteins such as Tudor, Vret, and Tej also result in DNA damage and defects in development [74, 79]. piRNA clusters from the chromosomes of Drosophila germ cells play a crucial role in maintaining the integrity of the telomeric regions. Loss of piRNAs in germ cells results in decreased levels of HP1a, Rhino and H3K9Me3 association with the telomeric region and disputed nuclear positioning of the telomere . In silkworms and other insects, PIWI has a role in sex determination. Loss of Bmsiwi (insect PIWI) and histone methyltransferase BmAsh2 causes female-to-male sexual reversal .
Translational regulation by PIWI–piRNA pathway
piRNAs can be formed from the 3′UTR region of many protein-coding genes such as vas, traffic jam, and nanos and control the mRNA turnover and protein level expression of these genes. Drosophila flies with piwi mutant flies produce an excess of these gene products, which accumulate in the cell eventually damaging the DNA [70, 92, 93]. Mouse PIWIs interact with eIF4e, which forms a cluster of proteins to control translation .
Although very little evidence has been found so far, studies are suggesting a greater somatic function of the PIWI/piRNA pathway. In the early stages of embryogenesis, Drosophila piwi is needed for chromatin structure maintenance and cell cycle progression . piwi is also found on chromosomes of the salivary gland that mediate epigenetic regulation . Loss of piwi proteins in Drosophila intestinal stem cells impairs the gut regenerative capacity of these flies . In Aplysia, piRNA-mediated DNA methylation is needed for neuronal plasticity . In various arthropods, the PIWI-piRNA pathway may perform as an antiviral defense mechanism in mosquitoes and silkworms . In a rat model of diabetes, activities of pancreatic β-cells may be regulated by piRNAs. β-Cells express thousands of piRNAs and their expression changed when rat Piwi proteins were downregulated, resulting in defective insulin secretion . Besides all these major and minor functions of the PIWI–piRNA pathway in various animals, aberrant expression in human cancers has been reported (Table 1), which will be discussed in detail in the following sections.
Role of PIWI–piRNA in lung cancer
Induced expression of PIWIL2 in A549 cells results in increased cell proliferation by elevated expression of CDK2 and cyclin A, both in vitro and in vivo. Similar results are obtained from H460 cells in vitro. By contrast, RNAi-mediated depletion of the protein results in cell cycle arrest (G2/M) and increased apoptosis . An increase in PIWIL1 activity induces cell proliferation in A549 cells and decreases in H1299 cell proliferation when knocked down and increases the colony-forming capacity of tumor cells [63, 102].
A positive correlation of cell proliferation with aberrant expression of piRNAs can be postulated. piR-651 is one example of such piRNAs whose expression is altered significantly in many cancers including in lung cancer patient samples and cancer cell lines such as NCIH446 and 95-D . piR-651 maintains the cell population by keeping proapoptotic proteins in check . Inhibition of piR-651 decreases cell proliferation and increases apoptosis in A549 and HCC827 cells. piR-651 negatively regulates proapoptotic proteins while increasing the activities of antiapoptotic proteins . piR-651 helps cyclin D1 and CDK-4 overexpression and upregulates proliferation of transfected A549 cells both in vitro and in vivo . The expression of RASSF1C has been shown to regulate certain piRNA expression and cancer progression. Upregulation of this oncoprotein correlated with overexpression of piR-52200 and underexpression of piR-35127 inpatient samples while piR-34871 and piR-46545 were additionally up- and downregulated respectively in the non-small-cell lung cancer (NSCLC) cell line H1299 along with the previous 2 piRNAs. In vitro, overexpressing underexpressed and knocking down overexpressed piRNAs decreases cell proliferation. Specifically, knock down of piR-52200 in A549 cells, piR-34871 in HT520 cells decreases cell proliferation significantly. By contrast, H1299 responded in most knockdown and overexpression studies. A low level of colony formation was observed in normal lung tissues after manipulation of piRNA expression . piR-55490 acted as an anticancer agent in vitro and in xenograft studies. In lung cancer cell lines such as A549, H460, and H1299, piR-55490 expression was originally suppressed and upon overexpression, these cell lines showed decreased proliferation. It is postulated that piR-55490 binds to mTOR and degrades it decreasing tumor cell proliferation . Two piRNAs overlapping in the 15th chromosome and sharing a common single nucleotide polymorphism, rs11639347, piR-5247, and piR-5671, increase proliferation of A549 cells .
Human PIWI proteins are now proven to maintain the stemness of certain cell populations when present in testis. Hiwi inhibition resulted in the loss of ALDH-1 (cancer cell marker) positive cells and decreased tumor mass in immunocompromised mice when injecting SSClo Aldebr stem cells isolated from an SPC-A1 cell line . Overexpression of RASSF1C promotes CD133+ (stem cell marker) A549 cell tumor sphere formation. RASSF1C induces PIWIL1 expression, which maintains stem cell properties and regulates the wnt/β-catenin pathway. Coexpression of RASSF1C and IGFBP-5 reduces PIWIL1 expression .
The interplay between PIWIs and piRNAs aids more than one hallmark of cancer. Inhibition of piR-651 decreases migration of highly invasive cell lines 95-D, A549, and HCC827 cells [106, 107]. Inhibition of PIWIL1 interferes with metastatic activity in H1299 cells, while increased expression induces A549 cell migration .
Human case study databases like The Cancer Genome Atlas (TCGA) show a positive correlation between PIWIL1 expression and poor overall survival of patients . Patient samples show similar results, increased PIWIL1 correlating to shorter time to relapse (TTR) and shorter overall survival. Whereas, decreased PIWIL4 correlated with shorter TTR and less overall survival . Patients with higher piR-55490 expression have longer overall survival .
piRNA-like short noncoding RNA
Studies in NSCLC and lung squamous cell carcinoma (LSCC) have revealed another class of sncRNAs, the piRNA-Like RNAs (piR-Ls). These RNAs have similar as well as distinguishing features to piRNAs. Two variants have been discovered to date, piR-L-138 and piR-L-163, and both are similar to piRNAs in length. However, 2 major differences are that, unlike piRNAs, they are expressed in adult tissues, and they bind directly to phosphorylated protein targets (p-proteins) to regulate their functional efficacy. Therefore, they are designated as protein functional effector sncRNAs (pfeRNAs). piR-L-138 expression in LSCC increases after cisplatin-based chemotherapy, which eventually leads to chemoresistance by the tumor cells. By contrast, targeting piR-L-138 in LSCC cell lines such as H157 and SKMES-1 increases apoptosis. piR-L-138 regulates p60MDM2 to control cell proliferation [111, 58]. Another study showed piR-L-163 binds to Ezrin, Radixin, and Moesin (p-ERM), which in turn increases the binding capacity of p-ERM to EBP50 and F acting. Blocking piR-L-163 induces cell growth and invasion revealing it as a negative regulator of tumor progression .
piRNA biomarker and chemoresistance
Cancer prognosis is related to 2 important facets namely early detection and delayed chemoresistance. In a study with 20 pairs of malignant and nonmalignant tissues, piR-hsa-211106 was downregulated in all malignant tissues as it prevented metastasis and induced apoptosis in lung cancer cells . This piRNA interacts with pyruvate carboxylase, which prevents cisplatin resistivity in lung cancer cells .
Lin et al.  and Li et al.  demonstrated that piRNAs can also be used for diagnosis of lung cancer. Sputum from 32 lung cancer patients was used as a source of epithelial cells from the bronchus and cRNA was profiled . Lung cancer patients had upregulated piR-004987 and piR-020809 expression and downregulated expression of piR-023338 and piR-011186 . Li et al.  examined 19 lung tissues from lung cancer patients and compared their piRNA profile with noncancerous lung tissues (from different sites in the same patients). They found 10 piRNAs unregulated in cancerous tissues compared with noncancerous tissue samples (see Table 1). Of these, 2 exosomal piRNAs, namely piR-hsa-26925 and piR-hsa-5444, were found in patient sera. Exosomes are double-layered lipid extracellular vesicles containing macromolecules like nucleic acids (in this case piRNA) used for cell-to-cell communication. Thus, such exosomes identifiable from sera can act as diagnostic markers for lung cancer.
Accumulated data supports the importance of piRNAs in lung and other cancers. Presently we have emphasized lung cancer as it still reigns among all types of cancers in terms of the highest mortality in cancer-related deaths worldwide . Lung cancer management, like any other cancer, revolves around both diagnoses and treatment. For both these factors, detailed molecular understanding of the disease is necessary for an effective outcome. piRNA contributes to cardinal features of cancer development, namely, cell proliferation, stemness maintenance, and metastasis; thus, also reflecting overall survival. Better understanding and clinical interpretation of these noncoding RNAs will not only aid in the understanding of the molecular perturbations, but may also provide insight into the selection of treatment modalities. More detailed screening and identification of anomalous expression of piRNAs may not only help in diagnosis, but also predict the prognosis of the disease. To collate the basics of cancer biology with the advances with knowledge of PIWI proteins or piRNAs, we merged our gathered information with the “Emerging hallmarks and enabling characteristics” as delineated by Hanahan and Weinberg [113, 105]. A diagrammatic representation of how the present finding of PIWI proteins or piRNA integrates with the hallmarks of cancer is depicted in Figure 2. Those PIWI proteins or piRNA that are positively regulated with the hallmarks may serve as a target for lung cancer therapy or as diagnostic or prognostic markers. By contrast, negatively regulated PIWI proteins or piRNA may serve as therapeutic options.
Cai Z, Liu Q. Understanding the Global Cancer Statistics 2018: implications for cancer control. Sci China Life Sci. 2021; 64:1017–20.CaiZLiuQUnderstanding the Global Cancer Statistics 2018: implications for cancer control20216410172010.1007/s11427-019-9816-131463738Search in Google Scholar
Wong MCS, Lao XQ, Ho K-F, Goggins WB, Tse SLA. Incidence and mortality of lung cancer: global trends and association with socioeconomic status. Sci Rep. 2017; 7:14300. doi: 10.1038/s41598-017-14513-7WongMCSLaoXQHoK-FGogginsWBTseSLAIncidence and mortality of lung cancer: global trends and association with socioeconomic status201771430010.1038/s41598-017-14513-7566273329085026DOI öffnenSearch in Google Scholar
Nargis N, Yong H-H, Driezen P, Mbulo L, Zhao L, Fong GT, et al. Socioeconomic patterns of smoking cessation behavior in low and middle-income countries: emerging evidence from the Global Adult Tobacco Surveys and International Tobacco Control Surveys. PLoS One. 2019; 14:e02202232019. doi: 10.1371/journal.pone.0220223NargisNYongH-HDriezenPMbuloLZhaoLFongGTSocioeconomic patterns of smoking cessation behavior in low and middle-income countries: emerging evidence from the Global Adult Tobacco Surveys and International Tobacco Control Surveys201914e0220223201910.1371/journal.pone.0220223673086931490958DOI öffnenSearch in Google Scholar
Sonea L, Buse M, Gulei D, Onaciu A, Simon I, Braicu C, Berindan-Neagoe I. Decoding the emerging patterns exhibited in non-coding RNAs characteristic of lung cancer with regard to their clinical significance. Curr Genomics. 2018; 19:258–78.SoneaLBuseMGuleiDOnaciuASimonIBraicuCBerindan-NeagoeIDecoding the emerging patterns exhibited in non-coding RNAs characteristic of lung cancer with regard to their clinical significance2018192587810.2174/1389202918666171005100124593044829755289Search in Google Scholar
Litwin M, Szczepańska-Buda A, Piotrowska A, Dzięgiel P, Witkiewicz W. The meaning of PIWI proteins in cancer development. Oncol Lett. 2017; 13:3354–62.LitwinMSzczepańska-BudaAPiotrowskaADzięgielPWitkiewiczWThe meaning of PIWI proteins in cancer development20171333546210.3892/ol.2017.5932543146728529570Search in Google Scholar
Lin H, Spradling AC. A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary. Development. 1997; 124:2463–76.LinHSpradlingACA novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary199712424637610.1242/dev.124.12.24639199372Search in Google Scholar
Gan B, Chen S, Liu H, Min J, Liu K. Structure and function of eTudor domain containing TDRD proteins. Crit Rev Biochem Mol Biol. 2019; 54:119–32.GanBChenSLiuHMinJLiuKStructure and function of eTudor domain containing TDRD proteins2019541193210.1080/10409238.2019.160319931046474Search in Google Scholar
Huang X, Tóth KF, Aravin AA. piRNA biogenesis in Drosophila melanogaster. Trends Genet. 2017; 33:882–94.HuangXTóthKFAravinAApiRNA biogenesis in Drosophila melanogaster2017338829410.1016/j.tig.2017.09.002577312928964526Search in Google Scholar
Yu T, Koppetsch BS, Pagliarani S, Johnston S, Silverstein NJ, Luban J, et al. The piRNA response to retroviral invasion of the koala genome. Cell. 2019; 179:632–643.e12. doi: 10.1016/j.cell.2019.09.002YuTKoppetschBSPagliaraniSJohnstonSSilversteinNJLubanJThe piRNA response to retroviral invasion of the koala genome2019179632643.e1210.1016/j.cell.2019.09.002680066631607510DOI öffnenSearch in Google Scholar
Cox DN, Chao A, Baker J, Chang L, Qiao D, Lin H. A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes Dev. 1998; 12:3715–27.CoxDNChaoABakerJChangLQiaoDLinHA novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal19981237152710.1101/gad.12.23.37153172559851978Search in Google Scholar
Reinke V, Smith HE, Nance J, Wang J, Van Doren C, Begley R, et al. A global profile of germline gene expression in C. elegans. Mol Cell. 2000; 6:605–16.ReinkeVSmithHENanceJWangJVan DorenCBegleyRA global profile of germline gene expression in C. elegans200066051610.1016/S1097-2765(00)00059-9Search in Google Scholar
Kuramochi-Miyagawa S, Kimura T, Yomogida K, Kuroiwa A, Tadokoro Y, Fujita Y, et al. Two mouse piwi-related genes: miwi and mili. Mech Dev. 2001; 108:121–33.Kuramochi-MiyagawaSKimuraTYomogidaKKuroiwaATadokoroYFujitaYTwo mouse piwi-related genes: miwi and mili20011081213310.1016/S0925-4773(01)00499-3Search in Google Scholar
Sharma AK, Nelson MC, Brandt JE, Wessman M, Mahmud N, Weller KP, Hoffman R. Human CD34+ stem cells express the hiwi gene, a human homologue of the Drosophila gene piwi. Blood. 2001; 97:426–34.SharmaAKNelsonMCBrandtJEWessmanMMahmudNWellerKPHoffmanRHuman CD34+ stem cells express the hiwi gene, a human homologue of the Drosophila gene piwi2001974263410.1182/blood.V97.2.426Search in Google Scholar
Qiao D, Zeeman A-M, Deng W, Looijenga LHJ, Lin H. Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas. Oncogene. 2002; 21:3988–99.QiaoDZeemanA-MDengWLooijengaLHJLinHMolecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas20022139889910.1038/sj.onc.1205505Search in Google Scholar
Mochizuki K, Fine NA, Fujisawa T, Gorovsky MA. Analysis of a piwi-related gene implicates small RNAs in genome rearrangement in Tetrahymena. Cell. 2002; 110:689–99.MochizukiKFineNAFujisawaTGorovskyMAAnalysis of a piwi-related gene implicates small RNAs in genome rearrangement in Tetrahymena20021106899910.1016/S0092-8674(02)00909-1Search in Google Scholar
Tan CH, Lee TC, Weeraratne SD, Korzh V, Lim TM, Gong Z. Ziwi, the zebrafish homologue of the Drosophila piwi: co-localization with vasa at the embryonic genital ridge and gonad-specific expression in the adults. Mech Dev. 2002; 119(Suppl 1):S221–4.TanCHLeeTCWeeraratneSDKorzhVLimTMGongZZiwi, the zebrafish homologue of the Drosophila piwi: co-localization with vasa at the embryonic genital ridge and gonad-specific expression in the adults2002119Suppl 1S221410.1016/S0925-4773(03)00120-5Search in Google Scholar
Girard A, Sachidanandam R, Hannon GJ, Carmell MA. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature. 2006; 442(7099):199–202.GirardASachidanandamRHannonGJCarmellMAA germline-specific class of small RNAs binds mammalian Piwi proteins2006442709919920210.1038/nature0491716751776Search in Google Scholar
Lee JH, Schütte D, Wulf G, Füzesi L, Radzun HJ, Schweyer S, et al. Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway. Human Mol Genet. 2005; 15:201–11.LeeJHSchütteDWulfGFüzesiLRadzunHJSchweyerSStem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway2005152011110.1093/hmg/ddi43016377660Search in Google Scholar
Liu X, Sun Y, Guo J, Ma H, Li J, Dong B, et al. Expression of hiwi gene in human gastric cancer was associated with proliferation of cancer cells. Int J Cancer. 2006; 118:1922–9.LiuXSunYGuoJMaHLiJDongBExpression of hiwi gene in human gastric cancer was associated with proliferation of cancer cells20061181922910.1002/ijc.2157516287078Search in Google Scholar
Taubert H, Greither T, Kaushal D, Würl P, Bache M, Bartel F, et al. Expression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft-tissue sarcoma. Oncogene. 2007; 26:1098–100.TaubertHGreitherTKaushalDWürlPBacheMBartelFExpression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft-tissue sarcoma200726109810010.1038/sj.onc.120988016953229Search in Google Scholar
Grochola LF, Greither T, Taubert H, Möller P, Knippschild U, Udelnow A, et al. The stem cell-associated Hiwi gene in human adenocarcinoma of the pancreas: expression and risk of tumour-related death. Br J Cancer. 2008; 99:1083–8.GrocholaLFGreitherTTaubertHMöllerPKnippschildUUdelnowAThe stem cell-associated Hiwi gene in human adenocarcinoma of the pancreas: expression and risk of tumour-related death2008991083810.1038/sj.bjc.6604653256707218781170Search in Google Scholar
He W, Wang Z, Wang Q, Fan Q, Shou C, Wang J, et al. Expression of HIWI in human esophageal squamous cell carcinoma is significantly associated with poorer prognosis. BMC Cancer. 2009; 9:426. doi: 10.1186/1471-2407-9-426HeWWangZWangQFanQShouCWangJExpression of HIWI in human esophageal squamous cell carcinoma is significantly associated with poorer prognosis2009942610.1186/1471-2407-9-426280151919995427DOI öffnenSearch in Google Scholar
He G, Chen L, Ye Y, Xiao Y, Hua K, Jarjoura D, et al. Piwil2 expressed in various stages of cervical neoplasia is a potential complementary marker for p16INK4a. Am J Transl Res. 2010; 2:156–69.HeGChenLYeYXiaoYHuaKJarjouraDPiwil2 expressed in various stages of cervical neoplasia is a potential complementary marker for p16INK4a2010215669Search in Google Scholar
Liu JJ, Shen R, Chen L, Ye Y, He G, Hua K, et al. Piwil2 is expressed in various stages of breast cancers and has the potential to be used as a novel biomarker. Int J Clin Exp Pathol. 2010; 3:328–37.LiuJJShenRChenLYeYHeGHuaKPiwil2 is expressed in various stages of breast cancers and has the potential to be used as a novel biomarker2010332837Search in Google Scholar
Sun G, Wang Y, Sun L, Luo H, Liu N, Fu Z, You Y. Clinical significance of Hiwi gene expression in gliomas. Brain Res. 2011; 1373:183–8.SunGWangYSunLLuoHLiuNFuZYouYClinical significance of Hiwi gene expression in gliomas20111373183810.1016/j.brainres.2010.11.09721138738Search in Google Scholar
Cheng J, Guo J-M, Xiao B-X, Miao Y, Jiang Z, Zhou H, Li Q-N. piRNA, the new non-coding RNA, is aberrantly expressed in human cancer cells. Clin Chim Acta. 2011; 412:1621–5.ChengJGuoJ-MXiaoB-XMiaoYJiangZZhouHLiQ-NpiRNA, the new non-coding RNA, is aberrantly expressed in human cancer cells20114121621510.1016/j.cca.2011.05.01521616063Search in Google Scholar
Yan ZE, Qu L-k, Lin M, Liu C-y, Bin D, Xing X-f, et al. HIWI expression profile in cancer cells and its prognostic value for patients with colorectal cancer. Chinese Med J (Engl). 2011; 124:2144–9.YanZEQuL-kLinMLiuC-yBinDXingX-fHIWI expression profile in cancer cells and its prognostic value for patients with colorectal cancer201112421449Search in Google Scholar
Cheng J, Deng H, Xiao B, Zhou H, Zhou F, Shen Z, Guo J. piR-823, a novel non-coding small RNA, demonstrates in vitro and in vivo tumor suppressive activity in human gastric cancer cells. Cancer Lett. 2012; 315:12–7.ChengJDengHXiaoBZhouHZhouFShenZGuoJpiR-823, a novel non-coding small RNA, demonstrates in vitro and in vivo tumor suppressive activity in human gastric cancer cells201231512710.1016/j.canlet.2011.10.00422047710Search in Google Scholar
Li D, Sun X, Yan D, Huang J, Luo Q, Tang H, Peng Z. Piwil2 modulates the proliferation and metastasis of colon cancer via regulation of matrix metallopeptidase 9 transcriptional activity. Exp Biol Med (Maywood). 2012; 237:1231–40.LiDSunXYanDHuangJLuoQTangHPengZPiwil2 modulates the proliferation and metastasis of colon cancer via regulation of matrix metallopeptidase 9 transcriptional activity201223712314010.1258/ebm.2012.01138023104504Search in Google Scholar
Chen C, Liu J, Xu G. Overexpression of PIWI proteins in human stage III epithelial ovarian cancer with lymph node metastasis. Cancer Biomark. 2013; 13:315–21.ChenCLiuJXuGOverexpression of PIWI proteins in human stage III epithelial ovarian cancer with lymph node metastasis2013133152110.3233/CBM-13036024440970Search in Google Scholar
Zhang H, Ren Y, Xu H, Pang D, Duan C, Liu C. The expression of stem cell protein Piwil2 and piR-932 in breast cancer. Surg Oncol. 2013; 22:217–23.ZhangHRenYXuHPangDDuanCLiuCThe expression of stem cell protein Piwil2 and piR-932 in breast cancer2013222172310.1016/j.suronc.2013.07.00123992744Search in Google Scholar
Wang D-W, Wang Z-H, Wang L-L, Song Y, Zhang G-Z. Overexpression of hiwi promotes growth of human breast cancer cells. Asian Pac J Cancer Prev. 2014; 15:7553–8.WangD-WWangZ-HWangL-LSongYZhangG-ZOverexpression of hiwi promotes growth of human breast cancer cells2014157553810.7314/APJCP.2014.15.18.7553Search in Google Scholar
Yan H, Wu Q-L, Sun C-Y, Ai L-S, Deng J, Zhang L, et al. piRNA-823 contributes to tumorigenesis by regulating de novo DNA methylation and angiogenesis in multiple myeloma. Leukemia. 2015; 29:196–206.YanHWuQ-LSunC-YAiL-SDengJZhangLpiRNA-823 contributes to tumorigenesis by regulating de novo DNA methylation and angiogenesis in multiple myeloma20152919620610.1038/leu.2014.13524732595Search in Google Scholar
Al-Janabi O, Wach S, Nolte E, Weigelt K, Rau TT, Stöhr C, et al. Piwi-like 1 and 4 gene transcript levels are associated with clinicopathological parameters in renal cell carcinomas. Biochim Biophys Acta. 2014; 1842:686–90.Al-JanabiOWachSNolteEWeigeltKRauTTStöhrCPiwi-like 1 and 4 gene transcript levels are associated with clinicopathological parameters in renal cell carcinomas201418426869010.1016/j.bbadis.2014.01.01424509249Search in Google Scholar
Liu W, Gao Q, Chen K, Xue X, Li M, Chen Q, et al. Hiwi facilitates chemoresistance as a cancer stem cell marker in cervical cancer. Oncol Rep. 2014; 32:1853–60.LiuWGaoQChenKXueXLiMChenQHiwi facilitates chemoresistance as a cancer stem cell marker in cervical cancer20143218536010.3892/or.2014.340125119492Search in Google Scholar
Xie Y, Yang Y, Ji D, Zhang D, Yao X, Zhang X. Hiwi downregulation, mediated by shRNA, reduces the proliferation and migration of human hepatocellular carcinoma cells. Mol Med Rep. 2014; 11:1455–61.XieYYangYJiDZhangDYaoXZhangXHiwi downregulation, mediated by shRNA, reduces the proliferation and migration of human hepatocellular carcinoma cells20141114556110.3892/mmr.2014.284725370791Search in Google Scholar
Chu H, Hui G, Yuan L, Shi D, Wang Y, Du M, et al. Identification of novel piRNAs in bladder cancer. Cancer Lett. 2015; 356:561–7.ChuHHuiGYuanLShiDWangYDuMIdentification of novel piRNAs in bladder cancer2015356561710.1016/j.canlet.2014.10.00425305452Search in Google Scholar
Fu A, Jacobs DI, Hoffman AE, Zheng T, Zhu Y. PIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome. Carcinogenesis. 2015; 36:1094–102.FuAJacobsDIHoffmanAEZhengTZhuYPIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome201536109410210.1093/carcin/bgv105500615226210741Search in Google Scholar
Yang Y, Zhang X, Song D, Wei J. Piwil2 modulates the invasion and metastasis of prostate cancer by regulating the expression of matrix metalloproteinase-9 and epithelial-mesenchymal transitions. Oncol Lett. 2015; 10:1735–40.YangYZhangXSongDWeiJPiwil2 modulates the invasion and metastasis of prostate cancer by regulating the expression of matrix metalloproteinase-9 and epithelial-mesenchymal transitions20151017354010.3892/ol.2015.3392453327926622742Search in Google Scholar
Müller S, Raulefs S, Bruns P, Afonso-Grunz F, Plötner A, Thermann R, et al. Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. Mol Cancer. 2015; 14:94. doi: 10.1186/s12943-015-0358-5MüllerSRaulefsSBrunsPAfonso-GrunzFPlötnerAThermannRNext-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer2015149410.1186/s12943-015-0358-5441753625910082DOI öffnenSearch in Google Scholar
Chu H, Xia L, Qiu X, Gu D, Zhu L, Jin J, et al. Genetic variants in noncoding PIWI-interacting RNA and colorectal cancer risk. Cancer. 2015; 121:2044–52.ChuHXiaLQiuXGuDZhuLJinJGenetic variants in noncoding PIWI-interacting RNA and colorectal cancer risk201512120445210.1002/cncr.2931425740697Search in Google Scholar
Wang Y, Jiang Y, Ma N, Sang B, Hu X, Cong X, Liu Z. Overexpression of Hiwi inhibits the growth and migration of chronic myeloid leukemia cells. Cell Biochem Biophys. 2015; 73:117–24.WangYJiangYMaNSangBHuXCongXLiuZOverexpression of Hiwi inhibits the growth and migration of chronic myeloid leukemia cells2015731172410.1007/s12013-015-0651-325701408Search in Google Scholar
Chen YJ, Xiong XF, Wen SQ, Tian L, Cheng WL, Qi YQ. Expression and clinical significance of PIWIL2 in hilar cholangiocarcinoma tissues and cell lines. Genet Mol Res. 2015; 14:7053–61.ChenYJXiongXFWenSQTianLChengWLQiYQExpression and clinical significance of PIWIL2 in hilar cholangiocarcinoma tissues and cell lines20151470536110.4238/2015.June.26.1526125915Search in Google Scholar
Busch J, Ralla B, Jung M, Wotschofsky Z, Trujillo-Arribas E, Schwabe P, et al. Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas. J Exp Clin Cancer Res. 2015; 34:61. doi: 10.1186/s13046-015-0180-3BuschJRallaBJungMWotschofskyZTrujillo-ArribasESchwabePPiwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas2015346110.1186/s13046-015-0180-3446720526071182DOI öffnenSearch in Google Scholar
Chen Z, Che Q, Jiang F-Z, Wang H-H, Wang F-Y, Liao Y, Wan X-P. Piwil1 causes epigenetic alteration of PTEN gene via upregulation of DNA methyltransferase in type I endometrial cancer. Biochem Biophys Res Commun. 2015; 463:876–80.ChenZCheQJiangF-ZWangH-HWangF-YLiaoYWanX-PPiwil1 causes epigenetic alteration of PTEN gene via upregulation of DNA methyltransferase in type I endometrial cancer20154638768010.1016/j.bbrc.2015.06.02826056945Search in Google Scholar
Taubert H, Wach S, Jung R, Pugia M, Keck B, Bertz S, et al. Piwil 2 expression is correlated with disease-specific and progression-free survival of chemotherapy-treated bladder cancer patients. Mol Med. 2015; 21:371–80.TaubertHWachSJungRPugiaMKeckBBertzSPiwil 2 expression is correlated with disease-specific and progression-free survival of chemotherapy-treated bladder cancer patients2015213718010.2119/molmed.2014.00250453447425998509Search in Google Scholar
Wang Z, Liu N, Shi S, Liu S, Lin H. The role of PIWIL4, an Argonaute family protein, in breast cancer. J Biol Chem. 2016; 291:10646–58.WangZLiuNShiSLiuSLinHThe role of PIWIL4, an Argonaute family protein, in breast cancer2016291106465810.1074/jbc.M116.723239486591326957540Search in Google Scholar
Firmino N, Martinez VD, Rowbotham DA, Enfield KS, Bennewith KL, Lam WL. HPV status is associated with altered PIWI-interacting RNA expression pattern in head and neck cancer. Oral Oncol. 2016; 55:43–8.FirminoNMartinezVDRowbothamDAEnfieldKSBennewithKLLamWLHPV status is associated with altered PIWI-interacting RNA expression pattern in head and neck cancer20165543810.1016/j.oraloncology.2016.01.012480843926852287Search in Google Scholar
Jacobs DI, Qin Q, Lerro MC, Fu A, Dubrow R, Claus EB, et al. PIWI-interacting RNAs in gliomagenesis: evidence from post-GWAS and functional analyses. Cancer Epidemiol Biomarkers Prev. 2016; 25:1073–80.JacobsDIQinQLerroMCFuADubrowRClausEBPIWI-interacting RNAs in gliomagenesis: evidence from post-GWAS and functional analyses20162510738010.1158/1055-9965.EPI-16-004727197292Search in Google Scholar
Gambichler T, Kohsik C, Höh AK, Lang K, Käfferlein HU, Brüning T, et al. Expression of PIWIL3 in primary and metastatic melanoma. J Cancer Res Clin Oncol. 2017; 143:433–7.GambichlerTKohsikCHöhAKLangKKäfferleinHUBrüningTExpression of PIWIL3 in primary and metastatic melanoma2017143433710.1007/s00432-016-2305-227858163Search in Google Scholar
Sivagurunathan S, Arunachalam JP, Chidambaram S. PIWI-like protein, HIWI2 is aberrantly expressed in retinoblastoma cells and affects cell-cycle potentially through OTX2. Cell Mol Biol Lett. 2017; 22:17. doi: 10.1186/s11658-017-0048-ySivagurunathanSArunachalamJPChidambaramSPIWI-like protein, HIWI2 is aberrantly expressed in retinoblastoma cells and affects cell-cycle potentially through OTX22017221710.1186/s11658-017-0048-y557609528861107DOI öffnenSearch in Google Scholar
Vychytilova-Faltejskova P, Stitkovcova K, Radova L, Sachlova M, Kosarova Z, Slaba K, et al. Circulating PIWI-interacting RNAs piR-5937 and piR-28876 are promising diagnostic biomarkers of colon cancer. Cancer Epidemiol Biomarkers Prev. 2018; 27:1019–28.Vychytilova-FaltejskovaPStitkovcovaKRadovaLSachlovaMKosarovaZSlabaKCirculating PIWI-interacting RNAs piR-5937 and piR-28876 are promising diagnostic biomarkers of colon cancer20182710192810.1158/1055-9965.EPI-18-031829976566Search in Google Scholar
Jacobs DI, Qin Q, Fu A, Chen Z, Zhou J, Zhu Y. piRNA-8041 is downregulated in human glioblastoma and suppresses tumor growth in vitro and in vivo. Oncotarget. 2018; 9:37616–26.JacobsDIQinQFuAChenZZhouJZhuYpiRNA-8041 is downregulated in human glioblastoma and suppresses tumor growth in vitro and in vivo20189376162610.18632/oncotarget.26331634088530701019Search in Google Scholar
Gao C-L, Sun R, Li D-H, Gong F. PIWI-like protein 1 upregulation promotes gastric cancer invasion and metastasis. Onco Targets Ther. 2018; 11:8783–89.GaoC-LSunRLiD-HGongFPIWI-like protein 1 upregulation promotes gastric cancer invasion and metastasis20181187838910.2147/OTT.S186827628751230584336Search in Google Scholar
Eckstein M, Jung R, Weigelt K, Sikic D, Stöhr R, Geppert C, et al. Piwi-like 1 and-2 protein expression levels are prognostic factors for muscle invasive urothelial bladder cancer patients. Sci Rep. 2018; 8:17693. doi: 10.1038/s41598-018-35637-4EcksteinMJungRWeigeltKSikicDStöhrRGeppertCPiwi-like 1 and-2 protein expression levels are prognostic factors for muscle invasive urothelial bladder cancer patients201881769310.1038/s41598-018-35637-4628383830523270DOI öffnenSearch in Google Scholar
Heng ZS, Lee JY, Subhramanyam CS, Wang C, Thanga LZ, Hu Q. The role of 17β-estradiol-induced upregulation of Piwi-like 4 in modulating gene expression and motility in breast cancer cells. Oncol Rep. 2018; 40:2525–35.HengZSLeeJYSubhramanyamCSWangCThangaLZHuQThe role of 17β-estradiol-induced upregulation of Piwi-like 4 in modulating gene expression and motility in breast cancer cells20184025253510.3892/or.2018.6676615187830226541Search in Google Scholar
Li B, Hong J, Hong M, Wang Y, Yu T, Zang S, Wu Q. piRNA-823 delivered by multiple myeloma-derived extracellular vesicles promoted tumorigenesis through re-educating endothelial cells in the tumor environment. Oncogene. 2019; 38:5227–38.LiBHongJHongMWangYYuTZangSWuQpiRNA-823 delivered by multiple myeloma-derived extracellular vesicles promoted tumorigenesis through re-educating endothelial cells in the tumor environment20193852273810.1038/s41388-019-0788-430890754Search in Google Scholar
Roy J, Das B, Jain N, Mallick B. PIWI-interacting RNA 39980 promotes tumor progression and reduces drug sensitivity in neuroblastoma cells. J Cell Physiol. 2020; 235:2286–99.RoyJDasBJainNMallickBPIWI-interacting RNA 39980 promotes tumor progression and reduces drug sensitivity in neuroblastoma cells202023522869910.1002/jcp.2913631478570Search in Google Scholar
Tan L, Mai D, Zhang B, Jiang X, Zhang J, Bai R, et al. PIWI-interacting RNA-36712 restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA. Mol Cancer. 2019; 18:9. doi: 10.1186/s12943-019-0940-3TanLMaiDZhangBJiangXZhangJBaiRPIWI-interacting RNA-36712 restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA201918910.1186/s12943-019-0940-3633050130636640DOI öffnenSearch in Google Scholar
Lin Y, Holden V, Dhilipkannah P, Deepak J, Todd NW, Jiang F. A non-coding RNA landscape of bronchial epitheliums of lung cancer patients. Biomedicines. 2020; 8:88. doi: 10.3390/biomedicines8040088LinYHoldenVDhilipkannahPDeepakJToddNWJiangFA non-coding RNA landscape of bronchial epitheliums of lung cancer patients202088810.3390/biomedicines8040088723574432294932DOI öffnenSearch in Google Scholar
Liu Y, Dong Y, He X, Gong A, Gao J, Hao X, et al. piR-hsa-211106 inhibits the progression of lung adenocarcinoma through pyruvate carboxylase and enhances chemotherapy sensitivity. Front Oncol. 2021; 11:651915. doi: 10.3389/fonc.2021.651915LiuYDongYHeXGongAGaoJHaoXpiR-hsa-211106 inhibits the progression of lung adenocarcinoma through pyruvate carboxylase and enhances chemotherapy sensitivity202111651915.10.3389/fonc.2021.651915826094334249688DOI öffnenSearch in Google Scholar
Li J, Wang N, Zhang F, Jin S, Dong Y, Dong X, et al. PIWI-interacting RNAs are aberrantly expressed and may serve as novel biomarkers for diagnosis of lung adenocarcinoma. Thorac Cancer. 2021; 12:2468–77.LiJWangNZhangFJinSDongYDongXPIWI-interacting RNAs are aberrantly expressed and may serve as novel biomarkers for diagnosis of lung adenocarcinoma20211224687710.1111/1759-7714.14094844790534346164Search in Google Scholar
Fathizadeh H, Asemi Z. Epigenetic roles of PIWI proteins and piRNAs in lung cancer. Cell Biosci. 2019; 9:102. doi: 10.1186/s13578-019-0368-xFathizadehHAsemiZEpigenetic roles of PIWI proteins and piRNAs in lung cancer2019910210.1186/s13578-019-0368-x692584231890151DOI öffnenSearch in Google Scholar
Dana PM, Mansournia MA, Mirhashemi SM. PIWI-interacting RNAs: new biomarkers for diagnosis and treatment of breast cancer. Cell Biosci. 2020; 10:44. doi: 10.1186/s13578-020-00403-5DanaPMMansourniaMAMirhashemiSMPIWI-interacting RNAs: new biomarkers for diagnosis and treatment of breast cancer2020104410.1186/s13578-020-00403-5709245632211149DOI öffnenSearch in Google Scholar
Yu Y, Xiao J, Hann SS. The emerging roles of PIWI-interacting RNA in human cancers. Cancer Manag Res. 2019; 11:5895–909.YuYXiaoJHannSSThe emerging roles of PIWI-interacting RNA in human cancers201911589590910.2147/CMAR.S209300661201731303794Search in Google Scholar
Sokolova OA, Ilyin AA, Poltavets AS, Nenasheva VV, Mikhaleva EA, Shevelyov YY, Klenov MS. Yb body assembly on the flamenco piRNA precursor transcripts reduces genic piRNA production. Mol Biol Cell. 2019; 30:1544–54.SokolovaOAIlyinAAPoltavetsASNenashevaVVMikhalevaEAShevelyovYYKlenovMSYb body assembly on the flamenco piRNA precursor transcripts reduces genic piRNA production20193015445410.1091/mbc.E17-10-0591672469530943101Search in Google Scholar
Ishizu H, Kinoshita T, Hirakata S, Komatsuzaki C, Siomi MC. Distinct and collaborative functions of Yb and Armitage in transposon-targeting piRNA biogenesis. Cell Rep. 2019; 27:1822-35.e8. doi: 10.1016/j.celrep.2019.04.029.IshizuHKinoshitaTHirakataSKomatsuzakiCSiomiMCDistinct and collaborative functions of Yb and Armitage in transposon-targeting piRNA biogenesis201927182235.e810.1016/j.celrep.2019.04.02931067466DOI öffnenSearch in Google Scholar
Saito K, Inagaki S, Mituyama T, Kawamura Y, Ono Y, Sakota E, et al. A regulatory circuit for piwi by the large Maf gene traffic jam in Drosophila. Nature. 2009; 461:1296–9.SaitoKInagakiSMituyamaTKawamuraYOnoYSakotaEA regulatory circuit for piwi by the large Maf gene traffic jam in Drosophila20094611296910.1038/nature0850119812547Search in Google Scholar
Aguiar ERGR, de Almeida JPP, Queiroz LR, Oliveira LS, Olmo RP, de Faria IJDS, et al. A single unidirectional piRNA cluster similar to the flamenco locus is the major source of EVE-derived transcription and small RNAs in Aedes aegypti mosquitoes. RNA. 2020; 26:581–94.AguiarERGRde AlmeidaJPPQueirozLROliveiraLSOlmoRPde FariaIJDSA single unidirectional piRNA cluster similar to the flamenco locus is the major source of EVE-derived transcription and small RNAs in Aedes aegypti mosquitoes2020265819410.1261/rna.073965.119716135431996404Search in Google Scholar
Le Thomas A, Rogers AK, Webster A, Marinov GK, Liao SE, Perkins EM, et al. Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state. Genes Dev. 2013; 27:390–9.Le ThomasARogersAKWebsterAMarinovGKLiaoSEPerkinsEMPiwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state201327390910.1101/gad.209841.112358955623392610Search in Google Scholar
Chen P, Luo Y, Aravin AA. RDC complex executes a dynamic piRNA program during Drosophila spermatogenesis to safeguard male fertility. PLoS Genet. 2021; 17:e1009591. doi: 10.1371/journal.pgen.1009591ChenPLuoYAravinAARDC complex executes a dynamic piRNA program during Drosophila spermatogenesis to safeguard male fertility202117e100959110.1371/journal.pgen.1009591841236434473737DOI öffnenSearch in Google Scholar
Qi H, Watanabe T, Ku H-Y, Liu N, Zhong M, Lin H. The Yb body, a major site for Piwi-associated RNA biogenesis and a gateway for Piwi expression and transport to the nucleus in somatic cells. J Biol Chem. 2011; 286:3789–97.QiHWatanabeTKuH-YLiuNZhongMLinHThe Yb body, a major site for Piwi-associated RNA biogenesis and a gateway for Piwi expression and transport to the nucleus in somatic cells201128637899710.1074/jbc.M110.193888303038021106531Search in Google Scholar
Pane A, Wehr K, Schüpbach T. zucchini and squash encode two putative nucleases required for rasiRNA production in the Drosophila germline. Dev Cell. 2007; 12:851–62.PaneAWehrKSchüpbachTzucchini and squash encode two putative nucleases required for rasiRNA production in the Drosophila germline2007128516210.1016/j.devcel.2007.03.022194581417543859Search in Google Scholar
Olivieri D, Senti K-A, Subramanian S, Sachidanandam R, Brennecke J. The cochaperone shutdown defines a group of biogenesis factors essential for all piRNA populations in Drosophila. Mol Cell. 2012; 47:954–69.OlivieriDSentiK-ASubramanianSSachidanandamRBrenneckeJThe cochaperone shutdown defines a group of biogenesis factors essential for all piRNA populations in Drosophila2012479546910.1016/j.molcel.2012.07.021346380522902557Search in Google Scholar
Xie W, Sowemimo I, Hayashi R, Wang J, Burkard TR, Brennecke J, et al. Structure-function analysis of microRNA 3′-end trimming by Nibbler. Proc Natl Acad Sci U S A. 2020; 117:30370–79.XieWSowemimoIHayashiRWangJBurkardTRBrenneckeJStructure-function analysis of microRNA 3′-end trimming by Nibbler2020117303707910.1073/pnas.2018156117772015333199607Search in Google Scholar
Ding D, Chen C. Zucchini: the key ingredient to unveil piRNA precursor processing. Biol Reprod. 2020; 103:452–54.DingDChenCZucchini: the key ingredient to unveil piRNA precursor processing20201034525410.1093/biolre/ioaa090744277532524138Search in Google Scholar
Pippadpally S, Venkatesh T. Deciphering piRNA biogenesis through cytoplasmic granules, mitochondria and exosomes. Arch Biochem Biophys. 2020; 695:108597. doi: 10.1016/j.abb.2020.108597PippadpallySVenkateshTDeciphering piRNA biogenesis through cytoplasmic granules, mitochondria and exosomes202069510859710.1016/j.abb.2020.10859732976825DOI öffnenSearch in Google Scholar
Sokolova OA, Iakushev EIu, Stoliarenko AD, Mikhaleva EA, Gvozdev VA, Klenov MS. [The interplay of transposon silencing genes in the Drosophila melanogaster germline]. Mol Biol (Mosk). 2011; 45:633–41. [in Russian, English abstract]SokolovaOAIakushevEIuStoliarenkoADMikhalevaEAGvozdevVAKlenovMS[The interplay of transposon silencing genes in the Drosophila melanogaster germline]20114563341[in Russian, English abstract]10.1134/S0026893311030174Search in Google Scholar
Ozata DM, Gainetdinov I, Zoch A, O’Carroll D, Zamore PD. PIWI-interacting RNAs: small RNAs with big functions. Nat Rev Genet. 2019; 20:89–108.OzataDMGainetdinovIZochAO’CarrollDZamorePDPIWI-interacting RNAs: small RNAs with big functions2019208910810.1038/s41576-018-0073-330446728Search in Google Scholar
Russell SJ, LaMarre J. Transposons and the PIWI pathway: genome defense in gametes and embryos. Reproduction. 2018; 156:R111–24.RussellSJLaMarreJTransposons and the PIWI pathway: genome defense in gametes and embryos2018156R1112410.1530/REP-18-021830037984Search in Google Scholar
Aravin AA, Sachidanandam R, Girard A, Fejes-Toth K, Hannon GJ. Developmentally regulated piRNA clusters implicate MILI in transposon control. Science. 2007; 316:744–7.AravinAASachidanandamRGirardAFejes-TothKHannonGJDevelopmentally regulated piRNA clusters implicate MILI in transposon control2007316744710.1126/science.114261217446352Search in Google Scholar
Pal-Bhadra M, Leibovitch BA, Gandhi SG, Chikka MR, Bhadra U, Birchler JA, Elgin SCR. Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery. Science. 2004; 303:669–72.Pal-BhadraMLeibovitchBAGandhiSGChikkaMRBhadraUBirchlerJAElginSCRHeterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery20043036697210.1126/science.109265314752161Search in Google Scholar
Teo RYW, Anand A, Sridhar V, Okamura K, Kai T. Heterochromatin protein 1a functions for piRNA biogenesis predominantly from pericentric and telomeric regions in Drosophila. Nat Commun. 2018; 9:1735. doi: 10.1038/s41467-018-03908-3TeoRYWAnandASridharVOkamuraKKaiTHeterochromatin protein 1a functions for piRNA biogenesis predominantly from pericentric and telomeric regions in Drosophila20189173510.1038/s41467-018-03908-3593567329728561DOI öffnenSearch in Google Scholar
Zhao K, Cheng S, Miao N, Xu P, Lu X, Zhang Y, et al. A Pandas complex adapted for piRNA-guided transcriptional silencing and heterochromatin formation. Nat Cell Biol. 2019; 21:1261–72.ZhaoKChengSMiaoNXuPLuXZhangYA Pandas complex adapted for piRNA-guided transcriptional silencing and heterochromatin formation20192112617210.1038/s41556-019-0396-031570835Search in Google Scholar
Watanabe T, Tomizawa SI, Mitsuya K, Totoki Y, Yamamoto Y, Kuramochi-Miyagawa S, et al. Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus. Science. 2011; 332:848–52.WatanabeTTomizawaSIMitsuyaKTotokiYYamamotoYKuramochi-MiyagawaSRole for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus20113328485210.1126/science.1203919336850721566194Search in Google Scholar
Théron E, Maupetit-Mehouas S, Pouchin P, Baudet L, Brasset E, Vaury C. The interplay between the Argonaute proteins Piwi and Aub within Drosophila germarium is critical for oogenesis, piRNA biogenesis and TE silencing. Nucleic Acids Res. 2018; 46:10052–65.ThéronEMaupetit-MehouasSPouchinPBaudetLBrassetEVauryCThe interplay between the Argonaute proteins Piwi and Aub within Drosophila germarium is critical for oogenesis, piRNA biogenesis and TE silencing201846100526510.1093/nar/gky695621271430113668Search in Google Scholar
Zhang Y, Liu W, Li R, Gu J, Wu P, Peng C, et al. Structural insights into the sequence-specific recognition of Piwi by Drosophila Papi. Proc Natl Acad Sci U S A. 2018; 115:3374–79.ZhangYLiuWLiRGuJWuPPengCStructural insights into the sequence-specific recognition of Piwi by Drosophila Papi201811533747910.1073/pnas.1717116115587967229531043Search in Google Scholar
Wenda JM, Homolka D, Yang Z, Spinelli P, Sachidanandam R, Pandey RR, Pillai RS. Distinct roles of RNA helicases MVH and TDRD9 in PIWI slicing-triggered mammalian piRNA biogenesis and function. Dev Cell. 2017; 41:623–637.e9. doi: 10.1016/j.devcel.2017.05.021WendaJMHomolkaDYangZSpinelliPSachidanandamRPandeyRRPillaiRSDistinct roles of RNA helicases MVH and TDRD9 in PIWI slicing-triggered mammalian piRNA biogenesis and function201741623637.e910.1016/j.devcel.2017.05.021548118628633017DOI öffnenSearch in Google Scholar
Zhu J, Zhang D, Liu X, Yu G, Cai X, Xu C, et al. Zebrafish prmt5 arginine methyltransferase is essential for germ cell development. Development. 2019; 146:dev179572. doi: 10.1242/dev.179572ZhuJZhangDLiuXYuGCaiXXuCZebrafish prmt5 arginine methyltransferase is essential for germ cell development2019146dev179572.10.1242/dev.17957231533925DOI öffnenSearch in Google Scholar
Radion E, Morgunova V, Ryazansky S, Akulenko N, Lavrov S, Abramov Y, et al. Key role of piRNAs in telomeric chromatin maintenance and telomere nuclear positioning in Drosophila germline. Epigenetics Chromatin. 2018; 11:40. doi: 10.1186/s13072-018-0210-4RadionEMorgunovaVRyazanskySAkulenkoNLavrovSAbramovYKey role of piRNAs in telomeric chromatin maintenance and telomere nuclear positioning in Drosophila germline2018114010.1186/s13072-018-0210-4604398430001204DOI öffnenSearch in Google Scholar
Li Z, You L, Yan D, James AA, Huang Y, Tan A. Bombyx mori histone methyltransferase BmAsh2 is essential for silkworm piRNA-mediated sex determination. PLoS Genet. 2018; 14:e1007245. doi: 10.1371/journal.pgen.1007245LiZYouLYanDJamesAAHuangYTanABombyx mori histone methyltransferase BmAsh2 is essential for silkworm piRNA-mediated sex determination201814e100724510.1371/journal.pgen.1007245584182629474354DOI öffnenSearch in Google Scholar
Robine N, Lau NC, Balla S, Jin Z, Okamura K, Kuramochi-Miyagawa S, et al. A broadly conserved pathway generates 3′UTR-directed primary piRNAs. Curr Biol. 2009; 19:2066–76.RobineNLauNCBallaSJinZOkamuraKKuramochi-MiyagawaSA broadly conserved pathway generates 3′UTR-directed primary piRNAs20091920667610.1016/j.cub.2009.11.064281247820022248Search in Google Scholar
Rouget C, Papin C, Boureux A, Meunier A-C, Franco B, Robine N, et al. Maternal mRNA deadenylation and decay by the piRNA pathway in the early Drosophila embryo. Nature. 2010; 467(7319):1128–32.RougetCPapinCBoureuxAMeunierA-CFrancoBRobineNMaternal mRNA deadenylation and decay by the piRNA pathway in the early Drosophila embryo2010467731911283210.1038/nature09465450574820953170Search in Google Scholar
Dai P, Wang X, Gou L-T, Li Z-T, Wen Z, Chen Z-G, et al. A translation-activating function of MIWI/piRNA during mouse spermiogenesis. Cell. 2019; 179:1566–81.e16. doi: 10.1016/j.cell.2019.11.022DaiPWangXGouL-TLiZ-TWenZChenZ-GA translation-activating function of MIWI/piRNA during mouse spermiogenesis2019179156681.e1610.1016/j.cell.2019.11.022813932331835033DOI öffnenSearch in Google Scholar
Mani SR, Megosh H, Lin H. PIWI proteins are essential for early Drosophila embryogenesis. Dev Biol. 2014; 385:340–9.ManiSRMegoshHLinHPIWI proteins are essential for early Drosophila embryogenesis2014385340910.1016/j.ydbio.2013.10.017391587924184635Search in Google Scholar
Bahn JH, Zhang Q, Li F, Chan T-M, Lin X, Kim Y, et al. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin Chem. 2015; 61:221–30.BahnJHZhangQLiFChanT-MLinXKimYThe landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva2015612213010.1373/clinchem.2014.230433433288525376581Search in Google Scholar
Lenart P, Novak J, Bienertova-Vasku J. PIWI-piRNA pathway: setting the pace of aging by reducing DNA damage. Mech Ageing Dev. 2018; 173:29–38.LenartPNovakJBienertova-VaskuJPIWI-piRNA pathway: setting the pace of aging by reducing DNA damage2018173293810.1016/j.mad.2018.03.00929580825Search in Google Scholar
Rajasethupathy P, Antonov I, Sheridan R, Frey S, Sander C, Tuschl T, Kandel ER. A role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity. Cell. 2012; 149:693–707.RajasethupathyPAntonovISheridanRFreySSanderCTuschlTKandelERA role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity201214969370710.1016/j.cell.2012.02.057344236622541438Search in Google Scholar
Kolliopoulou A, Santos D, Taning CNT, Wynant N, Vanden Broeck J, Smagghe G, Swevers L. PIWI pathway against viruses in insects. Wiley Interdiscip Rev RNA. 2019; 10:e1555. doi: 10.1002/wrna.1555KolliopoulouASantosDTaningCNTWynantNVanden BroeckJSmaggheGSweversLPIWI pathway against viruses in insects201910e155510.1002/wrna.155531183996DOI öffnenSearch in Google Scholar
Henaoui IS, Jacovetti C, Mollet IG, Guay C, Sobel J, Eliasson L, Regazzi R. PIWI-interacting RNAs as novel regulators of pancreatic beta cell function. Diabetologia. 2017; 60:1977–86.HenaouiISJacovettiCMolletIGGuayCSobelJEliassonLRegazziRPIWI-interacting RNAs as novel regulators of pancreatic beta cell function20176019778610.1007/s00125-017-4368-228711973Search in Google Scholar
Zhou S, Yang S, Li F, Hou J, Chang H. P-element Induced WImpy protein-like RNA-mediated gene silencing 2 regulates tumor cell progression, apoptosis, and metastasis in oral squamous cell carcinoma. J Int Med Res. 2021; 49:3000605211053158. doi: 10.1177/03000605211053158ZhouSYangSLiFHouJChangHP-element Induced WImpy protein-like RNA-mediated gene silencing 2 regulates tumor cell progression, apoptosis, and metastasis in oral squamous cell carcinoma2021493000605211053158.10.1177/03000605211053158857351834738477DOI öffnenSearch in Google Scholar
Xie K, Zhang K, Kong J, Wang C, Gu Y, Liang C, et al. Cancer-testis gene PIWIL1 promotes cell proliferation, migration, and invasion in lung adenocarcinoma. Cancer Med. 2018; 7:157–66.XieKZhangKKongJWangCGuYLiangCCancer-testis gene PIWIL1 promotes cell proliferation, migration, and invasion in lung adenocarcinoma201871576610.1002/cam4.1248577400229168346Search in Google Scholar
Yao J, Wang YW, Fang BB, Zhang SJ, Cheng BL. piR-651 and its function in 95-D lung cancer cells. Biomed Rep. 2016; 4:546–50.YaoJWangYWFangBBZhangSJChengBLpiR-651 and its function in 95-D lung cancer cells201645465010.3892/br.2016.628484078327123245Search in Google Scholar
Zhang S-J, Yao J, Shen B-Z, Li G-B, Kong S-S, Bi D-D, et al. Role of piwi-interacting RNA-651 in the carcinogenesis of non-small cell lung cancer. Oncol Lett. 2018; 15:940–6.ZhangS-JYaoJShenB-ZLiG-BKongS-SBiD-DRole of piwi-interacting RNA-651 in the carcinogenesis of non-small cell lung cancer201815940610.3892/ol.2017.7406577278829399156Search in Google Scholar
Li D, Luo Y, Gao Y, Yang Y, Wang Y, Xu Y, et al. piR-651 promotes tumor formation in non-small cell lung carcinoma through the upregulation of cyclin D1 and CDK4. Int J Mol Med. 2016; 38:927–36.LiDLuoYGaoYYangYWangYXuYpiR-651 promotes tumor formation in non-small cell lung carcinoma through the upregulation of cyclin D1 and CDK42016389273610.3892/ijmm.2016.267127431575Search in Google Scholar
Reeves ME, Firek M, Jliedi A, Amaar YG. Identification and characterization of RASSF1C piRNA target genes in lung cancer cells. Oncotarget. 2017; 8:34268–82.ReevesMEFirekMJliediAAmaarYGIdentification and characterization of RASSF1C piRNA target genes in lung cancer cells20178342688210.18632/oncotarget.15965547096628423657Search in Google Scholar
Chen S, Ben S, Xin J, Li S, Zheng R, Wang H, et al. The biogenesis and biological function of PIWI-interacting RNA in cancer. J Hematol Oncol. 2021; 14:93. doi: 10.1186/s13045-021-01104-3ChenSBenSXinJLiSZhengRWangHThe biogenesis and biological function of PIWI-interacting RNA in cancer2021149310.1186/s13045-021-01104-3819980834118972DOI öffnenSearch in Google Scholar
Rui, Y. piRNAs variants and lung cancer risk: a post-GWAS study [Masters Public Health thesis]. New Haven (CI): Yale Univ; 2016. Available from: https://elischolar.library.yale.edu/ysphtdl/1335RuiY.[Masters Public Health thesis]New Haven (CI)Yale Univ2016Available from: https://elischolar.library.yale.edu/ysphtdl/1335Search in Google Scholar
Liang D, Dong M, Hu L-J, Fang Z-H, Xu X, Shi E-H, Yang Y-J. Hiwi knockdown inhibits the growth of lung cancer in nude mice. Asian Pac J Cancer Prev. 2013; 14:1067–72.LiangDDongMHuL-JFangZ-HXuXShiE-HYangY-JHiwi knockdown inhibits the growth of lung cancer in nude mice20131410677210.7314/APJCP.2013.14.2.106723621188Search in Google Scholar
Reeves ME, Firek M, Chen ST, Amaar YG. Evidence that RASSF1C stimulation of lung cancer cell proliferation depends on IGFBP-5 and PIWIL1 expression levels. PloS One. 2014; 9:e101679. doi: 10.1371/journal.pone.0101679ReevesMEFirekMChenSTAmaarYGEvidence that RASSF1C stimulation of lung cancer cell proliferation depends on IGFBP-5 and PIWIL1 expression levels20149e10167910.1371/journal.pone.0101679409014825007054DOI öffnenSearch in Google Scholar
Wang Y, Gable T, Ma MZ, Clark D, Zhao J, Zhang Y, et al. A piRNA-like small RNA induces chemoresistance to cisplatin-based therapy by inhibiting apoptosis in lung squamous cell carcinoma. Mol Ther Nucleic Acids. 2017; 6:269–78.WangYGableTMaMZClarkDZhaoJZhangYA piRNA-like small RNA induces chemoresistance to cisplatin-based therapy by inhibiting apoptosis in lung squamous cell carcinoma201762697810.1016/j.omtn.2017.01.003536350928325293Search in Google Scholar
Brock M, Mei Y. Protein functional effector sncRNAs (pfeRNAs) in lung cancer. Cancer Lett. 2017; 403:138–43.BrockMMeiYProtein functional effector sncRNAs (pfeRNAs) in lung cancer20174031384310.1016/j.canlet.2017.06.01328642173Search in Google Scholar
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646–74.HanahanDWeinbergRAHallmarks of cancer: the next generation20111446467410.1016/j.cell.2011.02.01321376230Search in Google Scholar