Hepatocyte nuclear factor-1 beta protects endometriotic cells against apoptotic cell death by up-regulating the expression of antiapoptotic genes†

Abstract

The overexpression of hepatocyte nuclear factor-1 beta (HNF1β) in endometriotic lesion has been demonstrated. However, the role of HNF1β in endometriosis remains largely unknown. Human endometriotic 12Z cells showed higher level of HNF1β when compared with normal endometrial HES cells. In human endometriotic 12Z cells, HNF1β knockdown increased susceptibility to apoptotic cell death by oxidative stress, while HNF1β overexpression suppressed apoptosis. In addition, HNF1β knockdown and overexpression significantly decreased and increased, respectively, the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent antiapoptotic genes. Knockdown of the antiapoptotic genes significantly reduced the HNF1β-induced resistance against oxidative stress in 12Z cells. Furthermore, HNF1β regulated the transcriptional activity of NF-κB, and an NF-κB inhibitor suppressed the HNF1β-enhanced NF-κB-dependent antiapoptotic gene expression and the resistance of the 12Z cells against cell death. Taken together, these data suggest that HNF1β overexpression may protect endometriotic cells against oxidative damage by augmenting antiapoptotic gene expression.

An Update on the Multifaceted Role of NF-kappaB in Endometriosis

“…Notably, most NF-κB-related endometriosis studies chose normal/ectopic endometrial stromal cells for subsequent experiments. However, several studies also revealed that the role of NF-κB in endometrial epithelial cells shares several similarities with its role in endometrial stromal cells, such as the regulation by TNFα, estrogen signaling, and ncRNAs [24,31,61]; the promotion of cell proliferation, migration, invasion, and adhesion [56,73,74]; and the contribution to the resistance of ROS stress-induced cell apoptosis [56]. In addition, several drugs exert anti-endometriotic effects by downregulating NF-κB expression in endometrial epithelial cells [67,93,[117][118][119].…”

“…Iron overload activates IKKβ and stimulates NF-κB signaling, conferring pro-endometriotic behaviors on endometrial stromal cells 27 . Hepatocyte nuclear factor-1 beta (HNF1β) is a homeobox transcription factor that is overexpressed in endometriotic cells 56 . It functions as a coactivator for NF-κB, and its activation can enhance the survivability of endometriotic cells in oxidative cellular environments 56 .…”

“…Hepatocyte nuclear factor-1 beta (HNF1β) is a homeobox transcription factor that is overexpressed in endometriotic cells 56 . It functions as a coactivator for NF-κB, and its activation can enhance the survivability of endometriotic cells in oxidative cellular environments 56 .…”

“…NF-κB signaling affects endometriosis progression by regulating the activities of endometriotic cells. The abnormal survivability of endometriotic cells is correlated with NF-κB-mediated activities, such as secretion of the proinflammatory cytokine IL8 and activation of the antiapoptotic molecules XIAP, Bcl-2, and Bcl-xL 18 , 56 , 66 , 67 . In a Macaca fascicularis model of endometriosis, p65 knockdown by short hairpin RNA considerably reduced the expression of proliferating cell nuclear antigen (PCNA) and the microvessel density of ectopic lesions, indicating that NF-κB can be a therapeutic target for preventing the growth and angiogenesis of endometriotic lesions 68 .…”

Bioinformatics strategy for the screening of key genes to differentiate adenomyosis from endometriosis (Review)

“…We found that the survival and apoptosis-related genes were upregulated or downregulated in the previous studies cited. Thus, the proliferation-and growth-related genes, including IGF1 (16)(17)(18)(19), IGF2 (19), vascular endothelial growth factor (VEGF) (40)(41)(42), hepatocyte growth factor (HGF) (43)(44)(45), nerve growth factor (NGF) (46)(47)(48), platelet-derived growth factor (PDGF) (16,49), epidermal growth factor receptor (EGFR) (16,17,49,50), fibroblast growth factor 2 (FGF2) (49,51,52) and mechanistic target of rapamycin kinase (mTOR) (53,54), were upregulated in both the ectopic and eutopic endometria from subjects with adenomyosis compared with the eutopic endometria from women without adenomyosis, while the anti-apoptotic or autophagy-related genes, such as BCL2 apoptosis regulator (BCL2) (38,(55)(56)(57), beclin 1 (BECN1) (58,59) and programmed cell death 4 (PDCD4) (60,61), were much higher in the ectopic and eutopic endometria than in the control endometria. Furthermore, the decreased expression of BCL2 associated X, apoptosis regulator (BAX) has been observed in adenomyosis, suggesting that the downregulation of apoptotic cell death machinery is a hallmark of adenomyosis (39).…”