有氧糖酵解是指将葡萄糖加工成乳酸,是癌细胞中葡萄糖代谢的一般特征。有氧糖酵解增加了生物合成,抑制细胞凋亡并产生信号代谢物。在肿瘤中,缺氧使肿瘤细胞经历糖酵解,而有氧糖酵解也可在某些没有缺氧区域被诱导。缺氧诱导因子-1(hypoxia inducing factor,HIF-1)是氧传感转录因子,决定了葡萄糖是通过氧化方式还是糖酵解方式被消耗。肿瘤微环境中的多种因素,如缺氧、活性氧、一氧化氮和某些代谢产物,可以调节PHD2的羟化酶活性,防止HIF-1α降解,导致HIF-1α蛋白水平增加,并增强肿瘤细胞有氧糖酵解。
在癌症环境中,肿瘤相关巨噬细胞(tumour-associated macrophages,TAMs)是最丰富的炎症细胞,并与多种类型癌症的患者预后不良相关。然而,人们对TAMs是否以及如何调节肿瘤细胞糖酵解尚不清楚。近日,来自中山大学的研究人员在Nature Cell Biology杂志在线发文,揭示了TAMs通过外泌体包裹的lncRNA,调控肿瘤细胞的代谢重编程。该研究证明TAMs通过包含lncRNA,内含HIF-1α稳定长非编码RNA(HIF-1α-stabilizing long noncoding RNA,HISLA)的细胞外囊泡(extracellular vesicle,EVs)传递增强乳腺癌细胞的有氧糖酵解和细胞抗凋亡能力。在作用机制上,HISLA阻断PHD2和HIF-1α的相互作用以抑制HIF-1α的羟基化和降解。相反,从糖酵解肿瘤细胞释放的乳酸会上调巨噬细胞中的HISLA,构成TAMs和肿瘤细胞之间的前馈环,阻断EVs传播的HISLA会抑制体内乳腺癌的糖酵解和化学抗性。
这项研究强调了外泌体lncRNAs作为信号传导物的潜力,靶向TAMs特异性lncRNA或能抑制肿瘤细胞的糖酵解和细胞抗凋亡能力,提示外泌体lncRNA或为肿瘤治疗提供潜在靶点。
推荐阅读原文:
Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells.
Metabolic reprogramming is a hallmark of cancer. Here, we demonstrate that tumour-associated macrophages (TAMs) enhance the aerobic glycolysis and apoptotic resistance of breast cancer cells via the extracellular vesicle (EV) transmission of a myeloid-specific lncRNA, HIF-1α-stabilizing long noncoding RNA (HISLA). Mechanistically, HISLA blocks the interaction of PHD2 and HIF-1α to inhibit the hydroxylation and degradation of HIF-1α. Reciprocally, lactate released from glycolytic tumour cells upregulates HISLA in macrophages, constituting a feed-forward loop between TAMs and tumour cells. Blocking EV-transmitted HISLA inhibits the glycolysis and chemoresistance of breast cancer in vivo. Clinically, HISLA expression in TAMs is associated with glycolysis, poor chemotherapeutic response and shorter survival of patients with breast cancer. Our study highlights the potential of lncRNAs as signal transducers that are transmitted between immune and tumour cells via EVs to promote cancer aerobic glycolysis.
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