Uridine Inhibits Hepatocellular Carcinoma Cell Development by Inducing Ferroptosis.
Uridine Inhibits Hepatocellular Carcinoma Cell Development by Inducing Ferroptosis.
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尿苷通过诱导肝吞噬作用抑制肝细胞癌细胞的发育。
DOI：
10.3390/jcm12103552
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发表时间：
2023-05-18
影响因子：
3.9
通讯作者：
Zhao, Qingyan
中科院分区：
文献类型：
--
作者：
Zi, Liuliu;Ma, Wangbin;Zhang, Lilong;Qiao, Boyang;Qiu, Zhendong;Xu, Junhui;Zhang, Jiacheng;Ye, Yahong;Yang, Yueyuan;Dong, Keshuai;Chen, Chen;Wang, Weixing;Zhao, Qingyan
尿苷是一种关键的代谢物，作为DNA、RNA和葡萄糖生成的底物，主要在肝脏中合成。目前尚不清楚肝细胞癌（HCC）患者肿瘤微环境中尿苷水平是否发生改变，以及尿苷是否可以作为肿瘤治疗的靶点。本研究通过组织芯片检测肝癌组织中尿苷新生合成、氨甲酰磷酸合成酶2、天冬氨酸转甲氨基酰基酶、二氢羟化酶（CAD） （n = 115）、二氢羟化脱氢酶（DHODH） （n = 115）相关基因，发现CAD和DHODH在肿瘤中的表达高于副肿瘤组织。接下来，我们收集手术切除的HCC患者的肿瘤组织和相应的邻近非肿瘤组织（n = 46）进行LC-MS /MS分析。结果表明，非肿瘤组织和肿瘤组织中尿苷含量的中位数和四分位数范围分别为640.36（504.45-807.43）和484.22 (311.91-626.73)nmol/g。这些结果提示肝细胞癌患者尿苷代谢紊乱。为了进一步研究尿苷是否可以作为肿瘤治疗靶点，我们在体外和体内将一系列高浓度尿苷与HCC细胞孵育。我们观察到尿苷通过激活铁下垂通路，呈剂量依赖性地抑制HCC细胞的增殖、侵袭和迁移。总之，这些结果首次揭示了人类HCC组织中尿苷含量的范围，并提示尿苷可能是HCC治疗的新靶点。
Uridine is a key metabolite used as a substrate for the production of DNA, RNA, and glucose, and it is mainly synthesized in the liver. Currently, it is not known whether uridine levels are altered in the tumor microenvironment of patients with hepatocellular carcinoma (HCC) and whether uridine can be a target for tumor therapy. In this study, the detection of genes associated with de novo uridine synthesis, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) (n = 115), and dihydroorotate dehydrogenase (DHODH) (n = 115) in HCC tissues through tissue microarrays revealed that the expression of CAD and DHODH was higher in tumor compared with paraneoplastic tissues. Next, we collected tumor tissues from surgically resected HCC patients and the corresponding adjacent non-tumor tissues (n = 46) for LC–MS/MS assays. The results showed that the median and interquartile ranges of uridine content in non-tumor and tumor tissues were 640.36 (504.45–807.43) and 484.22 (311.91–626.73) nmol/g, respectively. These results suggest that uridine metabolism is disturbed in HCC patients. To further investigate whether uridine can be used as a tumor-therapeutic target, a series of high concentrations of uridine were incubated with HCC cells in vitro and in vivo. It was observed that uridine dose-dependently inhibited the proliferation, invasion, and migration of HCC cells by activating the ferroptosis pathway. Overall, these results reveal for the first time the range of uridine content in human HCC tissues and suggest that uridine may be a new target for HCC therapy.
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影响因子：
50.5
作者：
VANGROENINGEN, CJ;PETERS, GJ;PINEDO, HM
通讯作者：
PINEDO, HM
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M
影响因子：
64.8
作者：
Jiang, Le;Kon, Ning;Li, Tongyuan;Wang, Shang-Jui;Su, Tao;Hibshoosh, Hanina;Baer, Richard;Gu, Wei
通讯作者：
Gu, Wei
影响因子：
28.2
作者：
Mathur D;Stratikopoulos E;Ozturk S;Steinbach N;Pegno S;Schoenfeld S;Yong R;Murty VV;Asara JM;Cantley LC;Parsons R
通讯作者：
Parsons R
影响因子：
64.8
作者：
Mao C;Liu X;Zhang Y;Lei G;Yan Y;Lee H;Koppula P;Wu S;Zhuang L;Fang B;Poyurovsky MV;Olszewski K;Gan B
通讯作者：
Gan B