Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells

γ干扰素通过c-Abl/HDAC2信号通路调节乳腺上皮细胞恶性生长（英文）

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.

目的:在之前的研究中我们发现γ干扰素(IFN-γ)通过营养感受器GCN2诱导牛乳腺上皮细胞(BMEC)的恶性转化。在恶性转化的表型中,包括细胞周期缩短、细胞增殖增加、细胞迁移和侵袭的发生,而细胞生长的异常调节是细胞恶性转化的第一步。因此,本研究旨在探讨IFN-γ诱导细胞恶性生长的分子机制。创新点:实验对象γ-BMEC能够更好的用于乳腺癌发生的基础研究,是一种新的研究工具。我们选择恶性细胞生长来详细研究IFN-γ的作用机制,为IFN-γ、恶性细胞生长甚至乳腺癌之间的密切关系提供直接证据。方法:通过MTT实验检测IFN-γ长期刺激下细胞的增殖能力;蛋白质印迹(Westernblot)检测cyclin D1/CDK4、p21、HDAC2、c-Abl蛋白的表达;免疫荧光观察c-Abl入核。结论:IFN-γ通过c-Abl/HDAC2信号通路促进恶性BMEC的生长。