Affiliation:
1. State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100021, P.R. China
Abstract
Background:
Ovarian cancer (OVCA) has unique epigenetic alterations and defects in
homologous recombination (HR). Despite initial sensitivity to platinum-based chemotherapy, HR
dysfunctional tumors eventually acquire drug resistance. Fanconi anemia (FA) is characterized by
bone marrow failure (BMF) and a reduced ability to eradicate DNA interstrand cross-links (ICL).
However, the mechanism of chemoresistance mediated by FANCI was unclear in OVCA.
Objective:
We explore to identify whether FANCI was involved in chemoresistance in OVCA.
Methods:
FANCI expression and epigenetic alterations were analyzed, respectively, using TIMER
and cBioPortal. The correlation between FANCI expression and the survival of OVCA patients was
analyzed using Kaplan-Meier Plotter, GSE63885, and TCGA-OVCA dataset. FANCI expression in
OVCA was detected by immunohistochemistry. Cell proliferation, migration, and invasion in FANCI
inhibiting cells were assessed by CCK-8 and Transwell. Apoptosis and DNA damage were examined
by flow cytometry and immunofluorescence. Meanwhile, the activity of caspase 3/7 was detected by
Caspase-Glo® 3/7 kit. In addition, the expression of FANCI, γH2AX, and apoptosis effectors was
examined by Western blot.
Results:
FANCI has copy number variations (CNVs) in OVCA. The high expression of FANCI in
OVCA patients was associated with poor survival. Moreover, FANCI expression was correlated with
the response to chemotherapy in OVCA. FANCI expression in OVCA cells was induced by carboplatin
in a time-dependent manner. Silencing of FANCI had no effect on cell proliferation, but
hindered OVCA cell migration and invasion. Mechanically, knockdown of FANCI enhanced DNA
damage-induced apoptosis through the CHK1/2-P53-P21 pathway.
Conclusion:
FANCI may be a potential therapeutic target for OVCA patients.
Funder
National Natural Science Foundation of China
Publisher
Bentham Science Publishers Ltd.
Subject
Cancer Research,Drug Discovery,Pharmacology,Oncology
Cited by
4 articles.
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