Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells.
- Author:
Wen-Bo REN
1
;
Xiao-Jing XIA
2
;
Jing HUANG
3
;
Wen-Fei GUO
3
;
Yan-Yi CHE
1
;
Ting-Hao HUANG
1
;
Lian-Cheng LEI
1
Author Information
- Publication Type:Journal Article
- Keywords: Interferon-γ (IFN-γ); Cellular-abelsongene (c-Abl); Histone deacetylase 2 (HDAC2); Malignant cell growth
- MeSH: Animals; Carcinogenesis/pathology*; Cattle; Cell Cycle Proteins/metabolism*; Cell Proliferation/drug effects*; Cell Transformation, Neoplastic/pathology*; Cells, Cultured; Epithelial Cells/pathology*; Female; Histone Deacetylase 2/metabolism*; Imatinib Mesylate/pharmacology*; Interferon-gamma/pharmacology*; Mammary Glands, Animal/pathology*; Mammary Neoplasms, Experimental/pathology*; Proto-Oncogene Proteins c-abl/metabolism*; Signal Transduction; Valproic Acid/pharmacology*
- From: Journal of Zhejiang University. Science. B 2019;20(1):39-48
- CountryChina
- Language:English
- 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.
