Glycometabolic reprogramming-mediated proangiogenic phenotype enhancement of cancer-associated fibroblasts in oral squamous cell carcinoma: role of PGC-1α/PFKFB3 axis
Glycometabolic reprogramming-mediated proangiogenic phenotype enhancement of cancer-associated fibroblasts in oral squamous cell carcinoma: role of PGC-1α/PFKFB3 axis
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糖代谢重编程介导的口腔鳞癌癌相关成纤维细胞促血管生成表型增强：PGC-1α/PFKFB 3轴的作用
DOI：
10.1038/s41416-022-01818-2
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发表时间：
2022-04
影响因子：
8.8
通讯作者：
Xia Li;E. Jiang;Hui Zhao;Yang Chen;Yuming Xu;Chang-Xue Feng;Ji Li;Z. Shang
中科院分区：
文献类型：
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作者：
Xia Li;E. Jiang;Hui Zhao;Yang Chen;Yuming Xu;Chang-Xue Feng;Ji Li;Z. Shang
背景血管生成是肿瘤进展过程中关键的限速步骤。癌症相关成纤维细胞 (CAF) 是 OSCC 基质中最丰富的成分，在促血管生成中发挥着重要作用。最近，基质“反向Warburg效应”被提出，PFKFB3作为调节糖代谢的代谢酶而受到关注。然而，糖代谢重编程是否参与促进CAFs的血管生成仍不清楚。方法从OSCC和癌旁组织中分离CAFs和癌旁成纤维细胞(PFs)。我们检测了三对成纤维细胞的促血管生成和糖代谢表型。通过靶向阻断PFKFB3或激活PGC-1α信号，在体外和体内研究糖酵解对CAFs血管生成的调节作用。结果与PFs相比，CAFs表现出代谢重编程和增强的促血管生成表型。抑制 PFKFB3 依赖性糖酵解会损害 CAF 中促血管生成因子（VEGF-A、PDGF-C 和 MMP9）的表达。此外，CAF 的促血管生成表型通过 PGC-1α/PFKFB3 轴受到糖代谢的调节。一致地，在异种移植模型中，CAF 中 PGC-1α 过表达或 PFKFB3 敲低通过减少肿瘤血管生成来减缓肿瘤发展。结论 OSCC 的 CAF 具有糖代谢重编程和增强的促血管生成表型的特征。我们的研究结果表明，激活 PGC-1α 信号传导可通过阻断 PFKFB3 驱动的糖酵解来损害 CAF 的促血管生成表型。
BackgroundAngiogenesis is a key rate-limiting step in the process of tumour progression. Cancer-associated fibroblasts (CAFs), the most abundant component OSCC stroma, play important roles in pro-angiogenesis. Recently, the stroma “reverse Warburg effect” was proposed, and PFKFB3 has been brought to the forefront as a metabolic enzyme regulating glycometabolism. However, it remains unclear whether glycometabolism reprogramming is involved in promoting the angiogenesis of CAFs.MethodsCAFs and paracancerous fibroblasts (PFs) were isolated from OSCC and adjacent tissues. We detected the pro-angiogenesis and glycometabolism phenotype of three pairs of fibroblasts. Targeted blockage of PFKFB3 or activation of PGC-1α signal was used to investigate the effect of glycolysis on regulating angiogenesis of CAFs in vitro and vivo.ResultsCAFs exhibited metabolic reprogramming and enhanced proangiogenic phenotype compared with PFs. Inhibition of PFKFB3-dependent glycolysis impaired proangiogenic factors (VEGF-A, PDGF-C and MMP9) expression in CAFs. Furthermore, CAFs proangiogenic phenotype was regulated by glycometabolism through the PGC-1α/PFKFB3 axis. Consistently, PGC-1α overexpression or PFKFB3 knockdown in CAFs slowed down tumour development by reducing tumour angiogenesis in the xenograft model.ConclusionCAFs of OSCC are characterised with glycometabolic reprogramming and enhanced proangiogenic phenotypes. Our findings suggest that activating PGC-1α signalling impairs proangiogenic phenotype of CAFs by blocking PFKFB3-driven glycolysis.