RESUMO
The present study demonstrated for the first time that SNORA70E, which belongs to box H/ACA small nucleolar noncoding RNAs (snoRNAs) who could bind and induce pseudouridylation of RNAs, was significantly elevated in ovarian cancer tissues and was an unfavourable prognostic factor of ovarian cancer. The over-expression of SNORA70E showed increased cell proliferation, invasion and migration in vitro and induced tumour growth in vivo. Further research found that SNORA70E regulates RAS-Related Protein 1B (RAP1B) mRNA through pseudouracil modification by combing with the pyrimidine synthase Dyskerin Pseudouridine Synthase 1 (DKC1) and increase RAP1B protein level. What's more, the silencing of DKC1/RAP1B in SNORA70E overexpression cells both inhibited cell proliferation, migration and invasion through reducing ß-catenin, PI3K, AKT1, mTOR, and MMP9 protein levels. Besides, RNA-Seq results revealed that SNORA70E regulates the alternative splicing of PARP-1 binding protein (PARPBP), leading to the 4th exon-skipping in PARPBP-88, forming a new transcript PARPBP-15, which promoted cell invasion, migration and proliferation. Finally, ASO-mediated silencing of SNORA70E could inhibit ovarian cancer cell proliferation, invasion, migration ability in vitro and inhibit tumorigenicity in vivo. In conclusion, SNORA70E promotes the occurrence and development of ovarian cancer through pseudouridylation modification of RAP1B and alternative splicing of PARPBP. Our results demonstrated that SNORA70E may be a new diagnostic and therapeutic target for ovarian cancer.
Assuntos
Proteínas de Ligação a DNA , Neoplasias Ovarianas , RNA Nucleolar Pequeno , Proteínas rap de Ligação ao GTP , Processamento Alternativo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Metaloproteinase 9 da Matriz/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/genética , Inibidores de Poli(ADP-Ribose) Polimerases , RNA Mensageiro , RNA Nucleolar Pequeno/genética , Serina-Treonina Quinases TOR/genética , beta Catenina/genética , Proteínas rap de Ligação ao GTP/genéticaRESUMO
Piwi-interacting RNAs (piRNAs) are mainly expressed in mammalian germ cells, playing an important role in maintaining germ line DNA integrity, inhibiting transposon transcription and translation, participating in heterochromatin formation, epigenetic regulation, and germ cell genesis. They combine with P-element induced wimpy testis (PIWI) proteins to form effector complexes known as piRNA-induced silencing complexes (pi-RISC) to regulate the gene silencing pathway. Recent evidence suggests that numerous piRNAs, with tumor-promoting and tumor-suppressing functions in cancer development, are dysregulated in tumor tissues, and are related to clinical prognosis. In the present review, we summarize the current state of knowledge on the function and regulatory mechanisms of piRNAs in the tumorigenesis and progression of cancer, providing evidence for the potential use of piRNAs in the diagnosis and clinical treatment of cancer.
