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HMGA1P7-pseudogene regulates H19 and Igf2 expression by a competitive endogenous RNA mechanism.

ABSTRACT: Recent studies have revealed that pseudogene transcripts can function as competing endogenous RNAs, and thereby can also contribute to cancer when dysregulated. We have recently identified two pseudogenes, HMGA1P6 and HMGA1P7 for the HMGA1 gene whose overexpression has a critical role in cancer progression. These pseudogenes work as competitive endogenous RNA decoys for HMGA1 and other cancer related genes suggesting their role in carcinogenesis. Looking for new HMGA1 pseudogene ceRNAs, we performed RNA sequencing technology on mouse embryonic fibroblasts deriving from transgenic mice overexpressing HMGA1P7. Here, we report that HMGA1P7 mRNA sustains the H19 and Igf2 overexpression by acting as miRNA decoy. Lastly, the expression of HMGA1P7 was significantly correlated with H19 and IGF2 levels in human breast cancer thereby suggesting a role for HMGA1P7 deregulation in this neoplasia.

SUBMITTER: De Martino M

PROVIDER: S-EPMC5118720 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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HMGA1P7-pseudogene regulates H19 and Igf2 expression by a competitive endogenous RNA mechanism.

De Martino Marco M Forzati Floriana F Marfella Marianna M Pellecchia Simona S Arra Claudio C Terracciano Luigi L Fusco Alfredo A Esposito Francesco F

Scientific reports 20161122

Recent studies have revealed that pseudogene transcripts can function as competing endogenous RNAs, and thereby can also contribute to cancer when dysregulated. We have recently identified two pseudogenes, HMGA1P6 and HMGA1P7 for the HMGA1 gene whose overexpression has a critical role in cancer progression. These pseudogenes work as competitive endogenous RNA decoys for HMGA1 and other cancer related genes suggesting their role in carcinogenesis. Looking for new HMGA1 pseudogene ceRNAs, we perfo ...[more]

PMID: 27874091

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Project description:Introduction: Acute myeloid leukemia (AML) is a malignant proliferative disease affecting the bone marrow hematopoietic system and has a poor long-term outcome. Exploring genes that affect the malignant proliferation of AML cells can facilitate the accurate diagnosis and treatment of AML. Studies have confirmed that circular RNA (circRNA) is positively correlated with its linear gene expression. Therefore, by exploring the effect of SH3BGRL3 on the malignant proliferation of leukemia, we further studied the role of circRNA produced by its exon cyclization in the occurrence and development of tumors. Methods: Genes with protein-coding function obtained from the TCGA database. we detected the expression of SH3BGRL3 and circRNA_0010984 by real-time quantitative polymerase chain reaction (qRT-PCR). We synthesized plasmid vectors and carried out cell experiments, including cell proliferation, cell cycle and cell differentiation by cell transfection. We also studied the transfection plasmid vector (PLVX-SHRNA2-PURO) combined with a drug (daunorubicin) to observe the therapeutic effect. The miR-375 binding site of circRNA_0010984 was queried using the circinteractome databases, and the relationship was validated by RNA immunoprecipitation and Dual-luciferase reporter assay. Finally, a protein-protein interaction network was constructed with a STRING database. GO and KEGG functional enrichment identified mRNA-related functions and signaling pathways regulated by miR-375. Results: We identified the related gene SH3BGRL3 in AML and explored the circRNA_0010984 produced by its cyclization. It has a certain effect on the disease progression. In addition, we verified the function of circRNA_0010984. We found that circSH3BGRL3 knockdown specifically inhibited the proliferation of AML cell lines and blocked the cell cycle. We then discussed the related molecular biological mechanisms. CircSH3BGRL3 acts as an endogenous sponge for miR-375 to isolate miR-375 and inhibits its activity, increases the expression of its target YAP1, and ultimately activates the Hippo signaling pathway involved in malignant tumor proliferation. Discussion: We found that SH3BGRL3 and circRNA_0010984 are important to AML. circRNA_0010984 was significantly up-regulated in AML and promoted cell proliferation by regulating miR-375 through molecular sponge action.

Project description:BackgroundType 1 diabetes mellitus (T1DM), an autoimmune disease with a genetic tendency, has an increasing prevalence. Long non-coding RNA (lncRNA) and circular RNA (circRNA) are receiving increasing attention in disease pathogenesis. However, their roles in T1DM are poorly understood. The present study aimed at identifying signature lncRNAs and circRNAs and investigating their roles in T1DM using the competing endogenous RNA (ceRNA) network analysis.MethodsThe T1DM expression profile was downloaded from Gene Expression Omnibus (GEO) database to identify the differentially expressed circRNAs, lncRNAs, and mRNAs. The biological functions of these differentially expressed circRNAs, lncRNAs, and mRNAs were analyzed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Targeting relationships of circRNA-miRNA, lncRNA-miRNA, and miRNA-mRNA were predicted, and the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network was established. Finally, qRT-PCR was applied to identify the effect of hsa_circ_0002202 inhibition on the IFN-I induced macrophage inflammation.ResultsA total of 178 circRNAs, 404 lncRNAs, and 73 mRNAs were identified to be abnormally expressed in T1DM samples. Functional enrichment analysis results indicated that the differentially expressed genes were mainly enriched in extracellular matrix components and macrophage activation. CeRNA regulatory network showed that circRNAs and lncRNAs regulate mRNAs through integrate multiple miRNAs. In addition, in vitro experiments showed that hsa_circ_0002202 inhibition suppressed the type I interferon (IFN-I)-induced macrophage inflammation.ConclusionIn the present study, the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network in T1DM was established for the first time. We also found that hsa_circ_0002202 inhibition suppressed the IFN-I-induced macrophage inflammation. Our study may lay a foundation for future studies on the ceRNA regulatory network in T1DM.

Dataset Information

HMGA1P7-pseudogene regulates H19 and Igf2 expression by a competitive endogenous RNA mechanism.

Publications

HMGA1P7-pseudogene regulates H19 and Igf2 expression by a competitive endogenous RNA mechanism.

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