RESUMO
Long noncoding RNAs (lncRNAs) have drawn growing attention due to their regulatory roles in various diseases, including tumors. Recently, lncRNA FOXD3 antisense RNA 1 (FOXD3-AS1) was shown to be overexpressed in colon adenocarcinoma and glioma, exerting oncogenic functions. However, its expression and effects in cervical cancer (CC) remained unknown. In this research, our group first reported that the levels of FOXD3-AS1 were distinctly elevated in CC samples and cell lines. The distinct upregulation of FOXD3-AS1 was associated with lymphatic invasion, distant metastasis, and International Federation of Gynecology and Obstetrics stage, and also predicted poor clinical results of CC patients. Next, transcription factor SP1 was demonstrated to resulting in the upregulation of FOXD3-AS1 in CC. Functional assays indicated that knockdown of FOXD3-AS1 distinctly suppressed CC progression via affecting cell proliferation, cell apoptosis, and metastasis. Moreover, mechanistic studies suggested that FOXD3-AS1 acted as an endogenous sponge by directly binding miR-296-5p, resulting in the suppression of miR-296-5p. In addition, we also reported that high mobility group A, a direct target of miR-296-5p, could mediate the tumor-promotive effects that FOXD3-AS1 displayed. Overall, our present study might help to lead a better understanding of the pathogenesis of CC, provide a novel possible tumor biomarker, and probe the feasibility of lncRNA-directed treatments for CC.
Assuntos
Proteína HMGA1a/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , Fator de Transcrição Sp1/metabolismo , Neoplasias do Colo do Útero/metabolismo , Apoptose/genética , Apoptose/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteína HMGA1a/genética , Humanos , MicroRNAs/genética , Fator de Transcrição Sp1/genética , Neoplasias do Colo do Útero/genéticaRESUMO
OBJECTIVE: Berberine improves insulin sensitivity and ovulation function in PCOS patients. However, the mechanism by which berberine initiates glucose metabolism-related signaling pathways in ovarian cells remains unknown. This study unveiled a new mechanism by which berberine promotes ovarian cell glucose uptake, and demonstrated that SIRT3 ubiquitination is involved in the insulin sensitizing effect of berberine. METHODS: Berberine was used at different concentrations to treat cultured KGN cells. Then, cell viability, cell apoptosis, intracellular ROS levels, mitochondrial depolarization and activation of related signaling pathways were evaluated. RESULTS: Berberine administration led to mitochondrial depolarization and AMP accumulation by promoting SIRT3 ubiquitination. We confirmed that AMP accumulation activated AMPK signaling and further promoted glucose uptake. Meanwhile, berberine reduced the activity of mitochondrial complex I in a dose-depended manner, but not that of mitochondrial complex II. Furthermore, intracellular ROS levels and the expression of mitochondrial apoptosis pathway related factors increased with berberine concentration. Berberine caused significant SIRT3 ubiquitination and degradation by activating the AMPK pathway and increasing intracellular ROS levels. Interestingly, berberine induced ubiquitination paralleled the increased FOXO3a phosphorylation and FOXO3a/Parkin pathway activation. CONCLUSIONS: Berberine promotes glucose uptake and inhibits mitochondrial function by promoting SIRT3 ubiquitination, and is likely to regulate autophagy related function in ovarian cells by activating the AMPK pathway. These findings may provide novel insights into the development of drugs for the treatment of abnormal reproductive functions of the ovary.