Objectives: Integrins, the coordinator of extracellular and intracellular signaling, are often found to be aberrant in tumors and can reshape the tumor microenvironment. Although previous studies showed that integrin beta 2 (ITGB2) is important for host defense, its expression profile and role in tumors, especially in cancer associated fibroblasts (CAFs) are still unknown./nMethods: Immunofluorescence stain and fluorescence activated cell sorting were used to analyze the ITGB2 expression profile in oral squamous cell carcinoma (OSCC). RT-PCR and western blot were used to compare ITGB2 expression in normal fibroblasts (NFs) and cancer associated fibroblasts (CAFs). Clinical data and function-based experiments were used to investigate the promoting tumor growth ability of ITGB2 expressing CAFs. Enhanced glycolysis activity was identified by using bioinformatics analyses and GC/MS assays. MCT1 knockdown OSCC cell lines were constructed to explore the pro-proliferative mechanisms of ITGB2 expressing CAFs in multiple in vitro and in vivo assays./nResults: We found that CAFs exhibited significantly higher ITGB2 expression than the matched NFs. In addition, higher ITGB2 expression in CAFs was correlated with higher TNM stages and more Ki67+ tumor cells, indicating its ability to promote OSCC proliferation. Further, co-culture assay demonstrated that ITGB2-mediated lactate release in CAFs promoted OSCC cell proliferation. Mechanically, ITGB2 regulated PI3K/AKT/mTOR pathways to enhance glycolysis activity in CAFs. Accordingly, lactate derived from ITGB2-expressing CAFs was absorbed and metabolized in OSCC to generate NADH, which was then oxidized in the mitochondrial oxidative phosphorylation system (OXPHOS) to produce ATP. Notably, inhibiting the OXPHOS system with metformin delayed the proliferative capacity of OSCC cells cultured in the ITGB2-expressing CAFs medium./nConclusions: Our study uncovered the ITGB2^high pro-tumoral CAFs that activated the PI3K/AKT/mTOR axis to promote tumor proliferation in OSCC by NADH oxidation in the mitochondrial oxidative phosphorylation system.

中文翻译：

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CAGB中ITGB2介导的代谢转换通过线粒体氧化磷酸化系统中NADH的氧化促进OSCC增殖

目的：整联蛋白是细胞外和细胞内信号转导的协调者，通常在肿瘤中异常，可以重塑肿瘤的微环境。尽管以前的研究表明，整合素2（ITGB2）是宿主防御，它的表达谱和作用于肿瘤的重要，尤其是在癌症相关成纤维细胞（CAF中）仍unknown./n方法：免疫荧光染色和荧光激活细胞分选用于分析口腔鳞状细胞癌（OSCC）中ITGB2的表达谱。RT-PCR和蛋白质印迹用于比较ITGB2在正常成纤维细胞（NFs）和癌症相关成纤维细胞（CAFs）中的表达。临床数据和基于功能的实验用于研究表达ITGB2的CAF促进肿瘤生长的能力。通过使用生物信息学分析和GC / MS分析鉴定出增强的糖酵解活性。MCT1击倒OSCC细胞系构建探索ITGB2表达在多种的CAF亲增殖机制在体外和体内assays./n结果：我们发现，CAF比匹配的NFs表现出更高的ITGB2表达。此外，CAF中较高的ITGB2表达与较高的TNM分期和更多的Ki67 +肿瘤细胞相关，表明其具有促进OSCC增殖的能力。此外，共培养测定表明，CAF中ITGB2介导的乳酸释放促进了OSCC细胞增殖。从机械上讲，ITGB2调节PI3K / AKT / mTOR途径，以增强CAF中的糖酵解活性。因此，源自表达ITGB2的CAF的乳酸盐在OSCC中吸收并代谢以生成NADH，然后在线粒体氧化磷酸化系统（OXPHOS）中将其氧化以生成ATP。值得注意的是，用二甲双胍抑制OXPHOS系统会延迟在表达ITGB2的CAFs培养基中培养的OSCC细胞的增殖能力。结论：我们的研究发现了ITGB2^高肿瘤前CAF，其通过线粒体氧化磷酸化系统中的NADH氧化激活了PI3K / AKT / mTOR轴以促进OSCC中的肿瘤增殖。