RESUMO
Lung cancer is the primary cause of cancer-related death worldwide, and its global incidence and mortality rates remain high. The differential expression of circular RNAs (circRNAs) can affect the development of cancer, but the mechanisms by which circRNAs regulate lung cancer progression remain unclear. In this study, we identified circSORBS1, a circRNA that has not been previously described in lung cancer and is significantly underexpressed in lung cancer tissues, blood and cell lines, and the low expression of circSORBS1 correlated with tumour grade and prognosis. In vitro and in vivo functional experiments revealed that circSORBS1 overexpression inhibited cell proliferation and migration while enhancing apoptosis. Mechanistically, circSORBS1 acts as a sponge for miR-6779-5p, indirectly inhibiting RUFY3 mRNA degradation. Simultaneously, it binds to RUFY3 mRNA to enhance its stability. This dual regulatory mechanism leads to an increase in RUFY3 protein levels, which ultimately activates the YWHAE/BAD/BCL2 apoptotic signalling pathway and suppresses lung cancer progression. Our findings not only increase the knowledge about the regulatory pattern of circRNA expression but also provide new insights into the mechanisms by which circRNAs regulate lung cancer development.
Assuntos
Apoptose , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , MicroRNAs , RNA Circular , RNA Mensageiro , Animais , Feminino , Humanos , Masculino , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Estabilidade de RNA/genética , RNA Circular/genética , RNA Circular/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/genéticaRESUMO
The N7-methylguanosine (m7G) modification and circular RNAs (circRNAs) have been shown to play important roles in the development of lung cancer. However, the m7G modification of circRNAs has not been fully elucidated. This study revealed the presence of the m7G modification in circFAM126A. We propose the novel hypothesis that the methyltransferase TRMT10C mediates the m7G modification of circFAM126A and that the stability of m7G-modified circFAM126A is reduced. circFAM126A is downregulated in lung cancer and significantly inhibits lung cancer growth both in vitro and in vivo. The expression of circFAM126A correlates with the stage of lung cancer and with the tumour diameter, and circFAM126A can be used as a potential molecular target for lung cancer. The molecular mechanism by which circFAM126A increases HSP90 ubiquitination and suppresses AKT1 expression to regulate cellular glycolysis, ultimately inhibiting the progression of lung cancer, is elucidated. This study not only broadens the knowledge regarding the expression and regulatory mode of circRNAs but also provides new insights into the molecular mechanisms that regulate tumour cell metabolism and affect tumour cell fate from an epigenetic perspective. These findings will facilitate the development of new strategies for lung cancer prevention and treatment.
Assuntos
Proliferação de Células , Glicólise , Neoplasias Pulmonares , Metiltransferases , RNA Circular , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Glicólise/genética , Metiltransferases/metabolismo , Metiltransferases/genética , Animais , Proliferação de Células/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/genética , Células A549 , Guanosina/análogos & derivados , Guanosina/metabolismo , Masculino , Feminino , Camundongos Endogâmicos BALB C , UbiquitinaçãoRESUMO
As a highly important methylation modification, the 5-methyladenosine (m5C) modification can profoundly affect RNAs by regulating their transcription, structure and stability. With the continuous development of high-throughput technology, differentially expressed circular RNAs (circRNAs) have been increasingly discovered, and circRNAs play unique roles in tumorigenesis and development. However, the regulatory mechanism of the m5C modification of circRNAs has not yet been revealed. In this study, circERI3, which is highly expressed in lung cancer tissue and significantly correlated with the clinical progression of lung cancer, was initially identified through differential expression profiling of circRNAs. A combined m5C microarray analysis revealed that circERI3 contains the m5C modification and that the NSUN4-mediated m5C modification of circERI3 can increase its nuclear export. The important function of circERI3 in promoting lung cancer progression in vitro and in vivo was clarified. Moreover, we elucidated the novel mechanism by which circERI3 targets DNA binding protein 1 (DDB1), regulates its ubiquitination, enhances its stability, and in turn promotes the transcription of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) through DDB1 to affect mitochondrial function and energy metabolism, which ultimately promotes the development of lung cancer. This study not only revealed the reasons for the abnormal distribution of circERI3 in lung cancer tissues from the perspective of methylation and clarified the important role of circERI3 in lung cancer progression but also described a novel mechanism by which circERI3 promotes lung cancer development through mitochondrial energy metabolism, providing new insights for the study of circRNAs in lung cancer.