Abstract
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 the 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.
概要
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(Western blot)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。
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Project supported by the National Natural Science Foundation of China (No. 31772715)
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Ren, Wb., Xia, Xj., Huang, J. et al. Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells. J. Zhejiang Univ. Sci. B 20, 39–48 (2019). https://doi.org/10.1631/jzus.B1800211
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DOI: https://doi.org/10.1631/jzus.B1800211