College of Veterinary Medicine, Jilin University, Changchun 130062, China.
The First Hospital, Jilin University, Changchun 130021, China.
J Zhejiang Univ Sci B. 2019;20(1):39-48. doi: 10.1631/jzus.B1800211.
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.
干扰素-γ（IFN-γ）已被用于临床治疗癌症。然而，越来越多的报告表明，在某些情况下，长期治疗后效果会下降，原因尚不清楚。我们之前曾报道过长时间的 IFN-γ 治疗会诱导体外健康泌乳牛乳腺上皮细胞（BMEC）恶性转化。在这项研究中，我们研究了 IFN-γ 处理下 BMEC 恶性增殖的机制。本研究中使用的原代 BMEC 长期受到 IFN-γ（10ng/mL）刺激以促进恶性转化。我们观察到 IFN-γ 可促进恶性细胞增殖，增加细胞周期蛋白 D1/细胞周期蛋白依赖性激酶 4（CDK4）的表达，降低 p21 的表达，并上调细胞癌基因（c-Abl）和组蛋白去乙酰化酶 2（HDAC2）的表达。HDAC2 抑制剂丙戊酸钠（VPA）和 c-Abl 抑制剂伊马替尼降低了 cyclin D1/CDK4 的表达水平，增加了 p21 的表达水平，从而对 IFN-γ 诱导的恶性细胞生长具有抑制作用。当 c-Abl 下调时，HDAC2 水平也通过促进蛋白酶体降解而降低。这些数据表明，IFN-γ 通过 c-Abl/HDAC2 信号通路促进恶性 BMEC 的生长。我们的研究结果表明，长期应用 IFN-γ 可能与促进细胞生长甚至乳腺癌的发生密切相关。
