ABSTRACT
Cisplatin-based chemotherapy is the standard treatment for metastatic ovarian cancer (OC). However, chemoresistance continues to pose significant clinical challenges. Recent research has highlighted the baculoviral inhibitor of the apoptosis protein repeat-containing 5 (BIRC5) as a member of the inhibitor of the apoptosis protein (IAP) family. Notably, BIRC5, which has robust anti-apoptotic capabilities, is overexpressed in numerous cancers. Its dysfunction has been linked to challenges in cancer treatment. Yet, the role of BIRC5 in the chemoresistance of OC remains elusive. In our present study, we observed an upregulation of BIRC5 in cisplatin-resistant cell lines. This upregulation was associated with enhanced chemoresistance, which was diminished when the expression of BIRC5 was silenced. Intriguingly, BIRC5 exhibited a high number of N6-methyladenosine (m6 A) binding sites. The modification of m6 A was found to enhance the expression of BIRC5 by recognizing and binding to the 3'-UTR of mRNA. Additionally, the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) was shown to stabilize BIRC5 mRNA, synergizing with METTL3 and intensifying chemoresistance. Supporting these in vitro findings, our in vivo experiments revealed that tumors were significantly smaller in size and volume when BIRC5 was silenced. This reduction was notably counteracted by co-silencing BIRC5 and overexpressing IGF2BP1. Our results underscored the pivotal role of BIRC5 in chemoresistance. The regulation of its expression and the stability of its mRNA were influenced by m6 A modifications involving both METTL3 and IGF2BP1. These insights presented BIRC5 as a promising potential therapeutic target for addressing cisplatin resistance in OC.
ABSTRACT
BACKGROUND: Cytochrome P450 (CYP) 2C19 is a very important drug metabolizing enzyme. Although the single nucleotide polymorphisms (SNPs) of CYP2C19 G681A and G636A have been suggested that they may increase the incidence of cardiovascular events, the relationship between SNPs in CYP2C19 and cerebral ischemic stroke (CIS) are unclear. The aim of this study was to investigate the correlation between the distribution of G681A and G636A polymorphisms in CYP2C19 gene and the risk of CIS in Chinese. METHODS: The peripheral blood DNA was extracted from 299 patients with CIS and 295 healthy controls. The genotyping was conducted using the polymerase chain reaction-restriction fragment length polymorphism. The sampled sequencing was applied to verify the correctness of genotyping results. Both the genotype and allele distributions were compared in patients with CIS and healthy controls. RESULTS: The frequencies of CYP2C19 681AA (11.7% vs. 2.7%; P = 0.000), 636AA (4.0% vs. 0.7%; P = 0.007), 636AG (7.0% vs. 2.2%; P = 0.038) genotype, CYP2C19 681A (30.9% vs. 20.8%; P = 0.000) and 636A (13.0% vs. 5.8%; P = 0.000) allele in the CIS group are significantly higher than those in the controls. The frequencies of CYP2C19 681AA (16.7% vs. 8.6%; P = 0.036), CYP2C19 636AA (7.0% vs. 2.2%; P = 0.038) genotype, CYP2C19 681A (36.4% vs. 27.6%; P = 0.023) and CYP2C19 636A (17.5% vs.10.3%; P = 0.010) allele in the recurrent stroke group are significantly higher than those in the first onset group. Multivariate logistic regression analysis of risk factors for cerebral ischemic stroke and recurrent stroke respectively suggests that the CYP2C19 681AA genotype may be an independent risk factor for CIS (OR = 6.179, 95% CI: 2.285 ~ 16.708; P = 0.000) and recurrent stroke (OR = 2.305, 95% CI: 1.121 ~ 4.743; P = 0.023). CONCLUSIONS: The AA genotype and A allele of CYP2C19 G681A may be related to the occurrence and recurrence of cerebral ischemic stroke.
