Oxidative stress promotes oral carcinogenesis via Thbs1-mediated M1-like tumor-associated macrophages polarization

IF 10.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Redox Biology Pub Date : 2024-09-05 DOI:10.1016/j.redox.2024.103335
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Abstract

Although oxidative stress is closely associated with tumor invasion and metastasis, its’ exact role and mechanism in the initial stage of oral cancer remain ambiguous. Glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) participates in glutathione synthesis to resolve oxidative stress. Currently, we firstly found that ASCT2 deletion caused oxidative stress in oral mucosa and promoted oral carcinogenesis induced by 4-Nitroquinoline-1-oxide (4-NQO) using transgenic mice of ASCT2 knockout in oral epithelium. Subsequently, we identified an upregulated gene Thbs1 linked to macrophage infiltration by mRNA sequencing and immunohistochemistry. Importantly, multiplex immunohistochemistry showed M1-like tumor-associated macrophages (TAMs) were enriched in cancerous area. Mechanically, targeted ASCT2 effectively curbed glutamine uptake and caused intracellular reactive oxygen species (ROS) accumulation, which upregulated Thbs1 in oral keratinocytes and then activated p38, Akt and SAPK/JNK signaling to polarize M1-like TAMs via exosome-transferred pathway. Moreover, we demonstrated M1-like TAMs promoted malignant progression of oral squamous cell carcinoma (OSCC) both in vitro and in vivo by a DOK transformed cell line induced by 4-NQO. All these results establish that oxidative stress triggered by ASCT2 deletion promotes oral carcinogenesis through Thbs1-mediated M1 polarization, and indicate that restore redox homeostasis is a new approach to prevent malignant progression of oral potentially malignant disorders.

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氧化应激通过 Thbs1 介导的 M1 类肿瘤相关巨噬细胞极化促进口腔癌发生
虽然氧化应激与肿瘤的侵袭和转移密切相关,但其在口腔癌初期的确切作用和机制仍不明确。由丙氨酸-丝氨酸-半胱氨酸转运体 2(ASCT2)介导的谷氨酰胺摄取参与了谷胱甘肽的合成,以解决氧化应激问题。目前,我们首先发现 ASCT2 基因缺失会导致口腔黏膜氧化应激,并通过转基因小鼠在口腔上皮细胞中敲除 ASCT2 基因,促进 4-硝基喹啉-1-氧化物(4-NQO)诱导的口腔癌发生。随后,我们通过 mRNA 测序和免疫组化发现了与巨噬细胞浸润相关的上调基因 Thbs1。重要的是,多重免疫组化显示,M1样肿瘤相关巨噬细胞(TAMs)在癌区富集。从机理上讲,靶向 ASCT2 能有效抑制谷氨酰胺的摄取,并导致细胞内活性氧(ROS)积累,从而上调口腔角朊细胞中的 Thbs1,进而激活 p38、Akt 和 SAPK/JNK 信号,通过外泌体转移途径使 M1 样 TAMs 极化。此外,我们还通过 4-NQO 诱导的 DOK 转化细胞系证明,M1 样 TAMs 在体外和体内都促进了口腔鳞状细胞癌(OSCC)的恶性进展。所有这些结果证实,ASCT2缺失引发的氧化应激通过Thbs1介导的M1极化促进口腔癌的发生,并表明恢复氧化还原平衡是防止口腔潜在恶性疾病恶性进展的一种新方法。
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来源期刊
Redox Biology
Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
19.90
自引率
3.50%
发文量
318
审稿时长
25 days
期刊介绍: Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.
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