Areca nut-induced metabolic reprogramming and M2 differentiation promote OPMD malignant transformation.

IF 11.4 1区 医学 Q1 ONCOLOGY
Shyng-Shiou F Yuan, Leong-Perng Chan, Hieu D H Nguyen, Chang-Wei Su, Yuk-Kwan Chen, Jeff Yi-Fu Chen, Shigetaka Shimodaira, Stephen Chu-Sung Hu, Steven Lo, Yen-Yun Wang
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引用次数: 0

Abstract

Background: Betel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive.

Methods: Immunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE.

Results: We reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters.

Conclusion: Our study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.

亚麻仁诱导的代谢重编程和M2分化促进了OPMD的恶性转化。
背景:国际癌症研究机构(IARC)认为,槟榔及其主要成分槟榔是导致口腔癌的主要危险因素。接触阿月浑子提取物(ANE)与口腔微小病变(OPMD)的发展和恶性转化为口腔癌(OSCC)有关。然而,ANE作用于口腔微环境中其他细胞类型以促进口腔癌发生的详细机制仍未确定:方法:通过免疫组织化学和免疫荧光染色对与 OPMD 和 OSCC 相关的巨噬细胞进行免疫分析。方法:通过免疫组织化学和免疫荧光染色对与OPMD和OSCC相关的巨噬细胞进行免疫分析,并进行磷酸激酶和细胞因子阵列分析和免疫印迹,以确定其潜在机制。采用 Transwell 试验评估 ANE 的迁移促进作用。最后应用仓鼠模型证实了 ANE 的体内效应:结果:我们发现M2巨噬细胞与口腔癌的进展呈正相关。ANE诱导M2巨噬细胞分化、CREB磷酸化和VCAM-1分泌,并增加线粒体代谢。经ANE处理的巨噬细胞的培养基和VCAM-1可促进口腔癌前病变细胞的迁移和间质表型。体内研究表明,ANE 增强了仓鼠口腔颊组织中的 M2 极化和相关信号通路:我们的研究为山苍子诱导口腔癌的发生提供了新的机制,证明山苍子能促进 M2 巨噬细胞分化并分泌致癌细胞因子,从而关键性地激活口腔癌前病变细胞的恶性转化。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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