RESUMEN
TP53 mutation is considerably common in advanced high-grade serous ovarian cancer (HGSOC) and significantly associated with a poor prognosis. In this study, we investigated the role of Cyclin G1 (CCNG1), a target gene of wild-type TP53 (P53wt), in HGSOC and the possible regulatory mechanism between TP53 mutant (P53mt) and CCNG1 in the progression of HGSOC. High expression level of CCNG1 was found in 61.3% of HGSOC tissues and only 18.2% in fimbriae of fallopian tubes. Additionally, overexpression of CCNG1 was significantly associated with a shorter overall survival (P < 0.0001) and progression-free survival (P < 0.0004) in HGSOC patients. In vitro, CCNG1 promoted both tumor cell motility by inducing epithelial-mesenchymal transition (EMT) and resistance to cisplatin (CDDP). In vivo, knockdown expression of CCNG1 inhibited cancer metastasis. Furthermore, P53mt increased the expression of CCNG1 by regulating Notch3 expression, and a positive correlation between CCNG1 and Notch3 protein expression was observed by Immunohistochemistry (IHC) (r = 0.39, P: 0.01528). In conclusion, the activation of P53mt-Notch3-CCNG1 pathway was responsible for tumor progression to advanced disease with correlation with worse prognosis in patients with HGSOC. These data suggest a possible molecular mechanism of disease and highlights CCNG1's potential role as a therapeutic target in HGSOC.
Asunto(s)
Ciclina G1/genética , Neoplasias Ováricas/genética , Receptor Notch3/genética , Proteína p53 Supresora de Tumor/genética , Antineoplásicos/uso terapéutico , Carcinogénesis , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular , Cisplatino/uso terapéutico , Ciclina G1/metabolismo , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/patología , Pronóstico , Receptor Notch3/metabolismoRESUMEN
High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecologic malignancies. Currently, anti-angiogenesis therapy is the most promising strategy for the successful treatment of HGSOC. In this study, we found Neferine could inhibit the angiogenesis of ovarian cancer cells both in vitro and in vivo. Further analysis revealed that its suppressive effect on human umbilical vein endothelial cell (HUVEC) proliferation correlated with promoting cell cycle arrest and autophagy. The cell cycle genes were dose-dependently reduced and the level of LC3II/LC3I (microtubule associated protein 1 light chain 3) was increased. Using a specific marker for macrophages (CD206 and Mrc1), we indicated that Neferine could inhibit M2-macrophage in vivo. Finally, CD206 was stained in 150 HGSOC samples and its high expression predicted inferior overall survival. Our current study is the first to demonstrate the anti-angiogenesis mechanism of Neferine by inducing autophagy via mTOR/p70S6K pathway inhibition and suppressing M2-macrophage polarization. Our findings suggest that Neferine is an attractive reagent with great potential in HGSOC therapy, especially in standard-therapy resistant cases.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Autofagia , Bencilisoquinolinas/farmacología , Cistadenocarcinoma Seroso/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Neovascularización Patológica/prevención & control , Neoplasias Ováricas/tratamiento farmacológico , Animales , Apoptosis , Ciclo Celular , Movimiento Celular , Proliferación Celular , Cistadenocarcinoma Seroso/irrigación sanguínea , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Femenino , Humanos , Macrófagos/patología , Ratones , Clasificación del Tumor , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Ováricas/irrigación sanguínea , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The activation of Notch3 is associated with potential progression of ovarian cancer, tumor invasion, metastasis and chemoresistance, which account for poor prognosis of high grade serous ovarian cancer (HGSOC). However, the underlying mechanisms of Notch3 are not yet very clear. Here we show that SUSD2 is one of Notch3-regulating genes and the elevated protein expression of SUSD2 in HGSOC. We also found that its high expression level was significantly correlated with worse overall survival, early recurrence and lymph nodes metastasis. Moreover, overexpression of SUSD2 in ovarian cancer cells promoted epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing SUSD2 in aggressive ovarian cancer cells inhibited these processes both in vitro and in vivo. Mechanistically, we found SUSD2 promoted EMT through regulating the expression of EpCAM and EpCAM silencing reversed SUSD2-induced E-cadherin reduction and cells migration. Further experiments indicated a role of SUSD2 in conferring cisplatin resistance in ovarian cancer probably through enhancing autophagy in vitro. Collectively, these findings shed a new insight into the role of Notch3 downstream gene SUSD2 and provided a new therapeutic target for HGSOC.