Liu Yanfang, Song Junjiao, Shi Qili, Chen Bing, Qiu Wenying, Liu Yizhe, Huang Shenglin, He Xianghuo
Department of Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
Clin Transl Med. 2024 Dec;14(12):e70122. doi: 10.1002/ctm2.70122.
Metabolic reprogramming provides the necessary energy for the development of malignant tumours and is emerging as a novel tumour treatment strategy. However, the widespread expression of metabolic enzymes in diverse cell types makes the development of specific drugs that target cancer cells without affecting normal cellular functions challenging. Accumulating evidence has demonstrated the essential roles of long non-coding RNAs (lncRNAs) in the regulatory network associated with glucose metabolism in tumour cells. The mechanism and therapeutic potential of cancer-specific lncRNAs in modulating tumour glucose metabolism warrant in-depth exploration. Here we revealed that glucose-induced LINC01419 promoted the growth and metastasis of HCC cells by driving metabolic reprogramming. Mechanistically, LINC01419 directly interacted with Y-box binding protein 1 (YBX1) in the cytoplasm and facilitated its binding to PDK1 mRNA, thus enhancing PDK1 mRNA stability and increasing lactate production. Furthermore, YY1 contributed to the transcriptional activation of LINC01419 in HCC under high-glucose conditions. Notably, administration of an N-acetylgalactosamine (GalNAc)-conjugated siRNA specifically targeting LINC01419 markedly retarded the growth of orthotopic xenograft tumours. These findings provide evidence for an unprecedented regulatory mechanism of LINC01419 involving metabolic reprogramming in human cancer. The newly identified LINC01419/YBX1-PDK1 axis may represent a promising therapeutic target for HCC. Moreover, GalNAc-siLINC01419 holds significant potential for clinical application. KEY POINTS: This study highlights the considerable regulatory role of LINC01419 in the metabolism of HCC. The newly identified LINC01419/YBX1-PDK1 axis constitutes a valuable target. Hepatic-specific delivery of GalNAc-siLINC01419 presents a promising therapeutic strategy for HCC.
代谢重编程为恶性肿瘤的发展提供了必要的能量，并且正成为一种新的肿瘤治疗策略。然而，代谢酶在多种细胞类型中的广泛表达使得开发在不影响正常细胞功能的情况下靶向癌细胞的特异性药物具有挑战性。越来越多的证据表明长链非编码RNA（lncRNA）在肿瘤细胞中与葡萄糖代谢相关的调控网络中发挥着重要作用。癌症特异性lncRNA在调节肿瘤葡萄糖代谢中的机制和治疗潜力值得深入探索。在这里，我们揭示了葡萄糖诱导的LINC01419通过驱动代谢重编程促进肝癌细胞的生长和转移。机制上，LINC01419在细胞质中直接与Y盒结合蛋白1（YBX1）相互作用，并促进其与PDK1 mRNA的结合，从而增强PDK1 mRNA的稳定性并增加乳酸生成。此外，YY1在高糖条件下促进肝癌中LINC01419的转录激活。值得注意的是，给予特异性靶向LINC01419的N-乙酰半乳糖胺（GalNAc）偶联的siRNA显著抑制了原位异种移植肿瘤的生长。这些发现为LINC01419在人类癌症中涉及代谢重编程的前所未有的调控机制提供了证据。新发现的LINC01419/YBX1-PDK1轴可能是肝癌的一个有前景的治疗靶点。此外，GalNAc-siLINC01419具有显著的临床应用潜力。要点：本研究突出了LINC01419在肝癌代谢中的重要调控作用。新发现的LINC01419/YBX1-PDK1轴构成了一个有价值的靶点。肝脏特异性递送GalNAc-siLINC01419为肝癌提供了一种有前景的治疗策略。
