ArticleBMC cancer2022
LAP3 contributes to IFN-γ-induced arginine depletion and malignant transformation of bovine mammary epithelial cells.
Article in BMC cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 34 citations in OpenAlex.
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- Ubenimex synergizes with the PD-L1 blockade in gastric cancer by competitively binding LAP3 with UBE3A.Cell death & disease · 2026Article
- Lactylation-driven molecular taxonomy of melanoma: linking epigenetic modifications to immune evasion and clinical outcomes.American journal of cancer research · 2025Article
- TheFrontiers in cellular and infection microbiology · 2025Article
- Study of Plasma Biochemistry and Plasma Metabolomics Differences in Montbéliard and Holstein Backcross and Holstein Heifers.Animals : an open access journal from MDPI · 2024Article
- Mitochondrial-related hub genes in dermatomyositis: muscle and skin datasets-based identification andFrontiers in genetics · 2024Article
- Untargeted metabolomics reveals alternations in metabolism of bovine mammary epithelial cells upon IFN-γ treatment.BMC veterinary research · 2023Article
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundIFN-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.
methodsIn 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.
resultsThe 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 (histone deacetylase 2) expression and promotion of cell cycle proteins cyclin A1 and D1 expressions. Arginine supplementation did not affect LAP3 and HDAC2 expressions, but slowed down cell cycle process of malignant BMECs. In clinical samples of patients with breast cancer, LAP3 was confirmed to be upregulated, while ASS1 was downregulated compared with healthy control.
conclusionsThese results demonstrated that LAP3 mediated IFN-γ-induced arginine depletion to malignant transformation of BMECs. Our findings provide a potential therapeutic target for breast cancer both in humans and dairy cows.
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