Continuous TNF-α exposure in mammary epithelial cells promotes cancer phenotype acquisition via EGFR/TNFR2 activation

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2024-05-11 DOI:10.1007/s12272-024-01497-y
Jin-Hee Lee, Steffanus Pranoto Hallis, Mi-Kyoung Kwak
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Abstract

Tumor necrosis factor alpha (TNF-α), an abundant inflammatory cytokine in the tumor microenvironment (TME), is linked to breast cancer growth and metastasis. In this study, we established MCF10A cell lines incubated with TNF-α to investigate the effects of continuous TNF-α exposure on the phenotypic change of normal mammary epithelial cells. The established MCF10A-LE cell line, through long-term exposure to TNF-α, displayed cancer-like features, including increased proliferation, migration, and sustained survival signaling even in the absence of TNF-α stimulation. Unlike the short-term exposed cell line MCF10A-SE, MCF10A-LE exhibited elevated levels of epidermal growth factor receptor (EGFR) and subsequent TNF receptor 2 (TNFR2), and silencing of EGFR or TNFR2 suppressed the cancer-like phenotype of MCF10A-LE. Notably, we demonstrated that the elevated levels of NAD(P)H oxidase 4 (NOX4) and the resulting increase in reactive oxygen species (ROS) were associated with EGFR/TNFR2 elevation in MCF10A-LE. Furthermore, mammosphere-forming capacity and the expression of cancer stem cell (CSC) markers increased in MCF10A-LE. Silencing of EGFR reversed these effects, indicating the acquisition of CSC-like properties via EGFR signaling. In conclusion, our results reveal that continuous TNF-α exposure activates the EGFR/TNFR2 signaling pathway via the NOX4/ROS axis, promoting neoplastic changes in mammary epithelial cells within the inflammatory TME.

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乳腺上皮细胞持续暴露于 TNF-α 可通过表皮生长因子受体/表皮生长因子受体 2 的激活促进癌症表型的获得。
肿瘤坏死因子α(TNF-α)是肿瘤微环境(TME)中一种丰富的炎症细胞因子,与乳腺癌的生长和转移有关。在本研究中,我们建立了与 TNF-α 培养的 MCF10A 细胞系,以研究持续暴露于 TNF-α 对正常乳腺上皮细胞表型变化的影响。已建立的MCF10A-LE细胞系通过长期暴露于TNF-α,显示出癌症样特征,包括增殖、迁移和持续存活信号,即使在没有TNF-α刺激的情况下也是如此。与短期暴露的细胞系MCF10A-SE不同,MCF10A-LE表现出表皮生长因子受体(EGFR)和随后的TNF受体2(TNFR2)水平的升高,而EGFR或TNFR2的沉默抑制了MCF10A-LE的癌样表型。值得注意的是,我们证明了NAD(P)H氧化酶4(NOX4)水平的升高以及由此导致的活性氧(ROS)的增加与MCF10A-LE中表皮生长因子受体/TNFR2的升高有关。此外,在MCF10A-LE中,乳腺泡形成能力和癌症干细胞(CSC)标记物的表达增加。抑制表皮生长因子受体可逆转这些影响,表明通过表皮生长因子受体信号转导获得了类似 CSC 的特性。总之,我们的研究结果表明,持续暴露于TNF-α可通过NOX4/ROS轴激活表皮生长因子受体/表皮生长因子受体2信号通路,促进炎性TME内乳腺上皮细胞的肿瘤性变化。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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