Interferon-γ(IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason...Interferon-γ(IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells(BMECs) in vitro. In this study, we investigated the mechanisms underlying pthe malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ(10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4(CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene(c-Abl) and histone deacetylase 2(HDAC2). The HDAC2 inhibitor, valproate(VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.展开更多
Steroid resistance represents a major clinical problem in the treatment of severe asthma,and therefore a better understanding of its pathogenesis is warranted.Recent studies indicated that histone deacetylase 2(HDAC2)...Steroid resistance represents a major clinical problem in the treatment of severe asthma,and therefore a better understanding of its pathogenesis is warranted.Recent studies indicated that histone deacetylase 2(HDAC2)and interleukin 17A(IL-17A)play important roles in severe asthma.HDAC2 activity is reduced in patients with severe asthma and smoking-induced asthma,perhaps accounting for the amplified expression of inflammatory genes,which is associated with increased acetylation of glucocorticoid receptors.Neutrophilic inflammation contributes to severe asthma and may be related to T helper(Th)17 rather than Th2 cytokines.IL-17A levels are elevated in severe asthma and correlate with the presence of neutrophils.Restoring the activity of HDAC2 or targeting the Th17 signaling pathway is a potential therapeutic approach to reverse steroid insensitivity.展开更多
基金Project supported by the National Natural Science Foundation of China(No.31772715)
文摘Interferon-γ(IFN-γ) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells(BMECs) in vitro. In this study, we investigated the mechanisms underlying pthe malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ(10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4(CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene(c-Abl) and histone deacetylase 2(HDAC2). The HDAC2 inhibitor, valproate(VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.
基金This work was supported by the Guangdong Basic and Applied Ba-sic Research Foundation(No.2020B1515020004)the National Natural Science Foundation of China(No.81873404)+1 种基金Project of Young Inno-vative Talents in Colleges and Universities in Guangdong Province(No.2018KQNCX095)Affiliated Hospital of Guangdong Medical University Clinical Research Program(Nos.LCYJ2018C001,LCYJ2019B011).
文摘Steroid resistance represents a major clinical problem in the treatment of severe asthma,and therefore a better understanding of its pathogenesis is warranted.Recent studies indicated that histone deacetylase 2(HDAC2)and interleukin 17A(IL-17A)play important roles in severe asthma.HDAC2 activity is reduced in patients with severe asthma and smoking-induced asthma,perhaps accounting for the amplified expression of inflammatory genes,which is associated with increased acetylation of glucocorticoid receptors.Neutrophilic inflammation contributes to severe asthma and may be related to T helper(Th)17 rather than Th2 cytokines.IL-17A levels are elevated in severe asthma and correlate with the presence of neutrophils.Restoring the activity of HDAC2 or targeting the Th17 signaling pathway is a potential therapeutic approach to reverse steroid insensitivity.
基金supported by grants from the National Key Research and Development Program of China (No.2018YFC1003701, 2018YFC1003801)the National Natural Science Foundation of China (No.31872792)Institution of Higher Education Projects of Building First-class Discipline Construction in Ningxia Region (Biology),China (No.NXYLXK2017B05)。
