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PIWI-interacting RNAs function as novel tumor suppressors in glioblastoma multiforme

ABSTRACT: PIWI-interacting RNAs (piRNAs) are small non-coding RNAs that partner with PIWI proteins to protect germline tissues from destabilizing transposon activity. While the aberrant expression of PIWI proteins has been linked with poor outcomes for many cancers, less is known about the expression or function of piRNAs in cancer. We performed array-based piRNA expression profiling in seven pairs of normal and glioblastoma multiforme (GBM) tissue specimens and identified expression of ~350 piRNAs in both tissues and a subset with dysregulated expression in GBM. Several down-regulated piRNAs inhibited proliferation when transfected into glioma cell lines while those equivalently expressed in tumor and normal tissues did not, consistent with piRNA-specific tumor-suppressive roles. Upregulation of the most underexpressed piRNA, piR-8041, was found to induce cell cycle arrest and apoptosis and to alter transcriptional levels of several genes involved in stress and cell survival pathways. Additionally, the volume of intracranial mouse xenograft tumors was significantly reduced for approximately ten days after pre-implantation transfection with piR-8041. Taken together, our study reveals a previously unidentified functional role for piRNAs as tumor suppressors in gliomagenesis, and suggests that restoration of piRNA levels may be a potential strategy for GBM therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79438 | GEO | 2016/06/04

SECONDARY ACCESSION(S): PRJNA315847

REPOSITORIES: GEO

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A piRNA like small RNA interacts with and modulates p-ERM proteins in human somatic cells

Project description:PIWI-interacting RNAs (piRNAs) are thought to silence transposon and gene expression during development. However, the roles of piRNAs in somatic tissues are largely unknown. Here we report the identification of 555 piRNAs in human lung bronchial epithelial (HBE) and non-small cell lung cancer (NSCLC) cell lines, including 295 that don’t exist in databases termed as piRNA-Like sncRNAs or piRNA-Ls. Distinctive piRNA/piRNA-L expression patterns are observed between HBE and NSCLC cells. piRNA-L-163 (piR-L-163), the top down-regulated piRNA-L in NSCLC cells, binds directly to phosphorylated ERM proteins (p-ERM), which is dependent on the central part of UUNNUUUNNUU motif in piR-L-163 and the RRRKPDT element in ERM, and. The piR-L-163/p-ERM interaction is critical for p-ERM’s binding capability to filamentous actin (F-actin) and ERM-binding phosphoprotein 50 (EBP50). Thus, piRNA/piRNA-L may play a regulatory role through direct interaction with proteins in physiological and pathophysiological conditions.

2015-09-03 | PXD002076 | Pride

PIWI-interacting RNAs in gliomagenesis: Evidence from post-GWAS and functional analyses

Project description:Background: PIWI-interacting RNAs (piRNAs), the largest class of noncoding RNAs in mammals, cooperate with PIWI proteins to safeguard the genome from insertional mutations during germline development. Although a growing number studies have linked the PIWI-piRNA pathway to carcinogenesis, the role of piRNAs in glioma has not been explored. Methods: Utilizing directly measured and imputed genotypes from the GliomaScan genome-wide association study (1,840 cases and 2,401 controls), genetic variants in 1,428 piRNAs were analyzed for association with glioma risk. In vitro assays were performed to interrogate the functional impact of a top identified piRNA and its variant allele. Results: Variants in five piRNAs were considered to be associations of interest and four of these showed narrow clusters of enhanced association signals surrounding the index variant. Functional analyses of one of these piRNAs, piR-598, revealed that transfection of the wild-type piRNA impacted expression of genes involved in cell death/survival, and reduced glioma cell viability and colony formation. However, upon delivery of piR-598 containing the variant allele at rs147061479 (OR=1.80; 95% CI: 1.33-2.46; P=1.69 x 10-4), cell proliferation was sharply increased. Conclusions: These findings suggest that variant rs147061479 in piR-598 increases glioma risk by abolishing the tumor-suppressive function of piR-598, instead conferring growth-promoting properties that may result from a shift in piRNA targets. Impact: This transdisciplinary study demonstrates a role of piRNAs in gliomagenesis by evidence from both post-GWAS and in vitro functional analyses, and supports expanded investigation into the link between the PIWI-piRNA pathway and cancer.

2016-06-04 | GSE78935 | GEO

PIWI-interacting RNAs are dysregulated in renal cell carcinoma and associated with tumor metastasis and cancer specific survival

Project description:Piwi-interacting RNAs (piRNAs) are a distinct group of small non-coding RNAs (sncRNAs) that silence transposable genetic elements to protect genome integrity. Due to their limited expression in gonads and sequence diversity, piRNAs remain the most mysterious class of small RNAs. Studies have shown piRNAs are present in somatic cells and dysregulated in gastric, breast and liver cancers. By deep sequencing 24 frozen benign kidney and clear cell renal cell carcinoma (ccRCC) specimens and using the publically available piRNA database, we found 26,991 piRNAs present in human kidney tissue. Among 920 piRNAs that at least had two copies in one specimen, 19 were differentially expressed in benign kidney and ccRCC tissues, and 46 were associated with metastasis. Among the metastasis-related piRNAs, we found 3 piRNAs, piR- 32051, piR-39894 and piR-43607, to be derived from the same piRNA cluster at chromosome 17. We confirmed the 3 selected piRNAs not to be miRNAs or miRNA-like sncRNAs. We further validated the aberrant expression of the 3 piRNAs in a 68-case formalin-fixed and paraffin-embedded (FFPE) ccRCC tissue cohort and showed the upregulation of the 3 piRNAs to be highly associated with ccRCC metastasis, late clinical stage and cancer-specific survival.

2015-07-31 | GSE69259 | GEO

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Project description:Clear cell renal cell carcinoma is one of the most common diagnostic tumor, with nearly one third patients diagnosed as metastatic ccRCC. Although increasing number of studies have revealed that piwi-interacting RNAs were aberrantly expressed in diverse type of cancers, few of them explored the detailed molecular mechanism of piRNAs in carcinogenesis, particular in ccRCC. In this study, differentially expressed piRNAs associated with ccRCC was selected by using piRNA-sequencing combined with analyzing TCGA data, from which piR-57125 was identified. PiR-57125 was found remarkably downregulated in ccRCC samples. Functionally, knockdown of piR-57125 promoted migration and invasion of ccRCC, while overexpression of piR-57125 suppressed ccRCC metastasis. In vivo lung metastasis model also confirmed the same results. CCL3 was identified as the direct target of piR-57125 which could reverse the inhibition effect of piR-57125 in ccRCC metastasis. Further studies revealed that piR-57125 modulated ccRCC metastasis through AKT/ERK pathway. Those data indicate that piR-57125 restrains ccRCC metastasis through directly targeting CCL3 and inhibiting AKT/ERK pathway, and could be a potential therapeutic target for ccRCC.

2021-09-08 | GSE183496 | GEO

piR-36249 and DHX36 together inhibit testicular cancer cell progression by upregulating OAS2

Project description:PIWI-interacting RNAs (piRNAs) have been identified in mammalian germline initially and later also found to be aberrantly expressed in various cancers. However, their functions in cancer is not very clear. Here, we studied the role of piR-36249, a member of the piRNA family, in testicular cancer. We show that piR-36249 is significantly downregulated in testicular cancer tissues comparing to tumor-adjacent tissues. Functional studies demonstrate that piR-36249 inhibits testicular cancer cell proliferation, migration and invasion. Mass Spectrometry (MS) analysis of piR-36249 pull-downed proteins reveals that piR-36249 interacts with ATP-dependent DNA/RNA helicase (DHX36). Dual-luciferase assays shows that piR-36249 binds to the 3'UTR of 2'-5'-oligoadenylate synthetase 2 (OAS2) mRNA. OAS2 has been shown in literature as a tumor suppressor modulating the occurrence and development of some tumors, such as colorectal cancer and breast cancer. In this study, OAS2 knockdown also promotes testicular cancer cell proliferation and migration. Furthermore, RNA immunoprecipitation assay reveals that DHX36 can also bind to OAS2 mRNA, and knockdown of DHX36 increases OAS2 mRNA yet downregulates its protein, indicating the enhancing OAS2 protein expression level effect of DHX36. All these data suggest that piR-36249, together with DHX36, functions in inhibiting testicular cancer cells proliferation, migration and invasion by upregulating OAS2 protein, and piR-36249 may serve as a potential predictor for the prognosis of testicular cancer.

2023-01-25 | GSE213411 | GEO

Vreteno, a gonad-specific protein, is essential for germline development and primary piRNA biogenesis in Drosophila

Project description:In Drosophila, Piwi proteins associate with Piwi-interacting RNAs (piRNAs) and protect the germline genome by silencing mobile genetic elements. This defense system acts in germline and gonadal somatic tissue to preserve germline development. Genetic control for these silencing pathways varies greatly between tissues of the gonad. Here, we identified Vreteno (Vret), a novel gonad-specific protein essential for germline development. Vret is required for piRNA-based transposon regulation in both germline and somatic gonadal tissues. We show that Vret, which contains Tudor domains, associates physically with Piwi and Aubergine (Aub), stabilizing these proteins via a gonad-specific mechanism, absent in other fly tissues. In the absence of vret, Piwi-bound piRNAs are lost without changes in piRNA precursor transcript production, supporting a role for Vret in primary piRNA biogenesis. In the germline, piRNAs can engage in an Aub/Argonaute 3 (AGO3)-dependent amplification in the absence of Vret, suggesting that Vret function can distinguish between primary piRNAs loaded into Piwi/Aub complexes and piRNAs engaged in the amplification cycle. We propose that Vret acts at an early step in primary piRNA processing where it plays an essential role in transposon regulation. These studies show that vreteno (vret) has a role in germline development and primary piRNA regulation in Drosophila. Transposable element expression profiles from Drosophila ovaries mutant for vreteno, piwi and aubergine were compared using genome-wide mRNA expression profiling by Affymetrix GeneChip arrays (Drosophila 2.0). Key targets were validated by qPCR experiments.

2011-09-28 | E-GEOD-30360 | biostudies-arrayexpress

Vreteno, a gonad-specific protein, is essential for germline development and primary piRNA biogenesis in Drosophila

2011-09-29 | GSE30360 | GEO

Cloning of 50-75 nt small RNAs associated with Armitage in OSCs

Project description:Armitage (Armi) is a component of Yb bodies and functions in the primary piRNA processing pathway. Armi interaction with Piwi does not require Yb expression; however, without Yb, the Armi-Piwi complex does not localize at Yb bodies and contains few piR-ILs (small RNAs associated with Armitage complex). These results suggest that only upon its localization at Yb bodies does the Armi-Piwi-Yb complex gain an opportunity to interact with piR-ILs. Currently, however, it remains unclear how piR-ILs are loaded onto the Piwi complex at Yb bodies and which protein(s) within the complex is directly bound to them. 1 sample examined: Ovarian somatic cell (OSC) line

2010-10-24 | E-GEOD-23931 | biostudies-arrayexpress

Cloning of 50-75 nt small RNAs associated with Armitage in OSCs

2010-10-25 | GSE23931 | GEO

Vreteno, a gonad-specific protein, is essential for germline development and primary piRNA biogenesis in Drosophila.

Project description:Here, we analyzed small RNA libraries derived from ovarian tissues heterozygous or mutant for the Tudor gene, Vreteno. In the absence of vret, Piwi-bound piRNAs are lost without changes in piRNA precursor transcript production, supporting a role for Vret in primary piRNA biogenesis. In the germline, piRNAs can engage in an Aub/Argonaute 3 (AGO3)-dependent amplification in the absence of Vret, suggesting that Vret function can distinguish between primary piRNAs loaded into Piwi/Aub complexes and piRNAs engaged in the amplification cycle. We propose that Vret acts at an early step in primary piRNA processing where it plays an essential role in transposon regulation. Keyword : Epigenetics

2011-08-15 | GSE30088 | GEO

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