LAP3 contributes to IFN-γ-induced arginine depletion and malignant transformation of bovine mammary epithelial cells

作者：Li Li, Fengyang Li, Xiuhong Hu, Zengshuai Wu, Wenbo Ren, Tingting Wang, Zhengchao Ji, Na Li, Jingmin Gu, Changjiang Sun, Xin Feng, Wenyu Han, Jing Huang, Liancheng Lei · 发表于：BMC Cancer · 年份：2022 · DOI：10.1186/s12885-022-09963-w · 被引用次数：35 · 研究领域：Cancer Research and Treatments、Ferroptosis and cancer prognosis、Immune cells in cancer

BACKGROUND: IFN-γ has been traditionally recognized as an inflammatory cytokine that involves in inflammation and autoimmune diseases. Previously we have shown that sustained IFN-γ induced malignant transformation of bovine mammary epithelial cells (BMECs) via arginine depletion. However, the molecular mechanism underlying this is still unknown. METHODS: In this study, the amino acids contents in BMECs were quantified by a targeted metabolomics method. The acquisition of differentially expressed genes was mined from RNA-seq dataset and analyzed bioinformatically. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), western blotting, and immunohistochemistry (IHC) assay were performed to detect gene mRNA and protein expression levels. CCK-8 and would healing assays were used to detect cell proliferation and migration abilities, respectively. Cell cycle phase alternations were analyzed by flow cytometry. RESULTS: The targeted metabolomics analysis specifically discovered IFN-γ induced arginine depletion through accelerating arginine catabolism and inhibiting arginine anabolism in BMECs. Transcriptome analysis identified leucine aminopeptidase 3 (LAP3), which was regulated by p38 and ERK MAPKs, to downregulate arginine level through interfering with argininosuccinate synthetase (ASS1) as IFN-γ stimulated. Moreover, LAP3 also contributed to IFN-γ-induced malignant transformation of BMECs by upregulation of HDAC2 (histo...