Targeting uridine-cytidine kinase 2 induced cell cycle arrest through dual mechanism and could improve the immune response of hepatocellular carcinoma.
Targeting uridine-cytidine kinase 2 induced cell cycle arrest through dual mechanism and could improve the immune response of hepatocellular carcinoma.
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DOI：
10.1186/s11658-022-00403-y
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发表时间：
2022-11-26
影响因子：
8.3
通讯作者：
中科院分区：
文献类型：
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嘧啶代谢对肿瘤进展至关重要。尿苷-胞苷激酶2（UCK 2）是嘧啶代谢的关键调节因子，在肝细胞癌（HCC）发展过程中升高，并表现出致癌作用。然而，UCK 2促进HCC的关键机制和UCK 2的治疗价值仍不清楚。本研究的目的是探讨UCK 2作为肝癌治疗靶点的潜力。基因表达矩阵从公共数据库获得。采用RNA-seq、免疫共沉淀和RNA结合蛋白免疫共沉淀等方法研究UCK 2促进HCC的机制。评估免疫细胞浸润水平和免疫相关功能评分，以评估肿瘤微环境与UCK 2之间的联系。在HCC中，TGFβ1刺激部分上调UCK 2的表达。UCK 2通过抑制mTOR蛋白降解和维持PDPK 1 mRNA的稳定性，促进肝癌细胞周期进程。我们还鉴定了UCK 2作为一种新的RNA结合蛋白。下调UCK 2可诱导细胞周期阻滞并激活TNFα/NFκB信号通路相关的衰老相关分泌表型，从而改变肿瘤微环境。此外，UCK 2是免疫抑制微环境的生物标志物。下调UCK 2诱导分泌表型，这可以改善微环境，并且降低UCK 2重塑代谢可以降低肿瘤细胞对T细胞介导的杀伤的抗性。靶向UCK 2可抑制HCC进展，并可改善HCC患者对免疫治疗的反应。我们的研究表明UCK 2可能是HCC的理想靶点。在线版本包含补充材料，可通过10.1186/s11658-022-00403-y获得。
Pyrimidine metabolism is critical for tumour progression. Uridine–cytidine kinase 2 (UCK2), a key regulator of pyrimidine metabolism, is elevated during hepatocellular carcinoma (HCC) development and exhibits carcinogenic effects. However, the key mechanism of UCK2 promoting HCC and the therapeutic value of UCK2 are still undefined. The aim of this study is to investigate the potential of UCK2 as a therapeutic target for HCC. Gene expression matrices were obtained from public databases. RNA-seq, co-immunoprecipitation and RNA-binding protein immunoprecipitation were used to determine the mechanism of UCK2 promoting HCC. Immune cell infiltration level and immune-related functional scores were evaluated to assess the link between tumour microenvironment and UCK2. In HCC, the expression of UCK2 was upregulated in part by TGFβ1 stimulation. UCK2 promoted cell cycle progression of HCC by preventing the degradation of mTOR protein and maintaining the stability of PDPK1 mRNA. We also identified UCK2 as a novel RNA-binding protein. Downregulation of UCK2 induced cell cycle arrest and activated the TNFα/NFκB signalling pathway-related senescence-associated secretory phenotype to modify the tumour microenvironment. Additionally, UCK2 was a biomarker of the immunosuppressive microenvironment. Downregulated UCK2 induced a secretory phenotype, which could improve the microenvironment, and decreased UCK2 remodelling metabolism could lower the resistance of tumour cells to T-cell-mediated killing. Targeting UCK2 inhibits HCC progression and could improve the response to immunotherapy in patients with HCC. Our study suggests that UCK2 could be an ideal target for HCC. The online version contains supplementary material available at 10.1186/s11658-022-00403-y.
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