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Research Paper|Volume 15, Issue 18|pp 9743—9758

NOTCH2 gene mutation and gamma-secretase inhibitor in mediating the malignancy of ovarian cancer

Wenjing Wang1,3, Ruiqian Liu2, Wei Liao3, Landie Ji1,3, Jie Mei3,4, Dan Su3,4
  • 1School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, China
  • 2Deyang People’s Hospital, Deyang 618099, Sichuan, China
  • 3Department of Gynecology and Obstetrics, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, China
  • 4Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610054, Sichuan, China
* Equal contribution
Received: April 10, 2023Accepted: August 25, 2023Published: September 19, 2023
https://doi.org/10.18632/aging.205045

Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The carcinogenic mechanisms by which serous ovarian cancer (OC) occurs remain to be explored. Currently, we have conducted whole-exome sequencing (WES) and targeted deep sequencing to validate new molecular markers, including NOTCH2, that impede the progression of cell malignancy in ovarian cancer (OC). Following NOTCH2 P2113S mutation and NOTCH signaling pathway inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) treatment, the cell proliferation, migration, and invasion of A2780 and SKOV3 OC cells were examined in vitro. WES identified the P2113S point mutation in NOTCH2. The NOTCH2 mutation rate was 26.67 % among the 75 OC cases. The NOTCH2 P2113S mutation and DAPT treatment downregulated Notch-2 protein levels in the two OC cells. Functionally, interfering with NOTCH2 expression promoted the migrative, proliferative, and invasive capacities of OC cells. Western blotting further confirmed that NOTCH2-mediated tumorigenesis lies in reducing apoptosis through dysregulation of Bax/Bcl2, affecting repair of DNA damage through reducing DNA-PK and blocking the transcription factor Hes1 along with increasing immune regulator p65. Furthermore, the NOTCH2-mediated tumorigenesis was mostly reversed after NF-κB inhibitor Bay11-7082 treatment. These findings identified the NOTCH2 P2113S mutation in ovarian carcinogenesis, and NOTCH2 P2113S is a potential target in treating OC.