Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Nat Cell Biol. 2019 Apr;21(4):498-510. doi: 10.1038/s41556-019-0299-0. Epub 2019 Apr 1.
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.
代谢重编程是癌症的一个标志。在这里，我们证明肿瘤相关巨噬细胞（TAMs）通过髓样特异性长非编码 RNA（HIF-1α 稳定的长非编码 RNA，HISLA）的细胞外囊泡（EV）传递，增强乳腺癌细胞的有氧糖酵解和抗凋亡能力。从机制上讲，HISLA 阻止了 PHD2 和 HIF-1α 的相互作用，从而抑制了 HIF-1α 的羟化和降解。反过来，来自糖酵解肿瘤细胞的乳酸会在上皮细胞中上调 HISLA，构成 TAMs 和肿瘤细胞之间的正反馈循环。阻断 EV 传递的 HISLA 可抑制体内乳腺癌的糖酵解和化学抗性。临床上，TAMs 中的 HISLA 表达与糖酵解、化疗反应不良和乳腺癌患者生存时间较短有关。我们的研究强调了长非编码 RNA 作为信号转导物的潜力，它们通过 EV 在免疫细胞和肿瘤细胞之间传递，以促进癌症的有氧糖酵解。
