PIWI-Interacting RNAs in Gliomagenesis: Evidence from Post-GWAS and Functional Analyses

Abstract

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 of 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

The Updated World Health Organization Glioma Classification: Cellular and Molecular Origins of Adult Infiltrating Gliomas

“…111,112 Inherited Factors Genome-wide association studies have identified several genetic loci associated with increased risk of glioma, including TERT, CDKN2A/2B, RTEL1, PHLDB1, EGFR, TP53, TERC, DDX6, and PIWI-interacting RNAs. [113][114][115] Of these genes, TERT, CDKN2A/2B, EGFR, and TP53 are wellcharacterized recurrently altered genes in sporadic IGs. In addition to well-known inherited tumor syndromes, such as Li Fraumeni, the study of familial cases of IG remains an important avenue toward identifying genetic candidates that drive glioma formation.…”

PIWI Proteins and PIWI-Interacting RNA: Emerging Roles in Cancer

“…In addition, piRNA-823 abrogation in MM cells reduced vascular endothelial growth factor secretion, accompanied by decreased proangiogenic activity, suggesting an oncogenic role of piRNA-823 in the biology of MM [77]. Jacobs et al [78] utilized directly measured and imputed genotypes from the GliomaScan genome-wide association study (GWAS) to analyze piRNAs associated with glioma risk and the results revealed that piR-598 impacted cell survival and reduced glioma cell viability and colony formation, which sharply promoted cell proliferation. Recently, piR-55490 was found to be silenced in lung carcinoma specimens and cell lines, compared with normal lung tissues and cells, and piR-55490 suppression led to the gain in the proliferation rate.…”

Part 2: Deregulated Expressions of PIWI Proteins and piRNAs as New Candidate Biomarkers and Potential Therapeutic Tools in Cancer

“…In glioma, PIWIL4 upregulated cyclin D1 expression and repressed the inhibitor of cyclin D1/CDK4 p16. PIWIL4 also promoted cyclin D1 expression through activation of STAT3, Bcl2, and Bcl-xL, and its expression was modulated by miR384 [46]. In cervical cancer, PIWIL4 promoted survival of cancer cells by inhibiting expression of p14-ARF and p53 and prevented apoptosis by inactivating the p14-ARF/p53 axis.…”

“…PiRNA-823 repression promoted deregulation of cell cycle regulators and apoptosis-related proteins and inhibited pro-angiogenic activity [44]. In glioblastoma, piR-598 promoted cancer cells survival and proliferation [46]. In lung carcinoma, piR-55490 underexpression was associated with increased proliferation through reduction of piRNAinduced 3'UTR mTOR mRNA binding and degradation.…”