CCNG1 (Cyclin G1) regulation by mutant‐P53 via induction of Notch3 expression promotes high‐grade serous ovarian cancer (HGSOC) tumorigenesis and progression

Abstract

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.

Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

“…Notably, the proliferation rates of the two cell lines derived from the same patient (13363 and 15233 cells) were significantly different ( Figure S1). This difference between sensitive and resistant cells was also observed by Xu et al [35], who reported a higher migration and invasion of platinum-resistant ovarian cancer cells as compared with platinum-sensitive ones, explaining, at least partly, why patients diagnosed with platinum-resistant HGSOC often face faster tumor progression and worse prognosis of the disease.…”

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

“…The role of micro-RNAs in ovarian cancer and their influence on chemoresistance has been reviewed in several recent papers [124,125,126]. Micro-RNAs can regulate EMT and chemotherapy resistance by interacting with different transcripts, leading to their degradation and consequently preventing their translation.…”

Gain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis

“…[100,112,114,121,137,140,145,[148][149][150][151][152][153][154][155][156][157] Funding: Research in the laboratory of Varda Rotter is supported by a Center of Excellence Grant from the Israel Science Foundation (ISF) and a Center of Excellence Grant from the Flight Attendant Medical Research Institute (FAMRI). Varda Rotter is the incumbent of the Norman and Helen Asher Professorial Chair for Cancer Research at the Weizmann Institute.…”