CCL3 secreted by hepatocytes promotes the metastasis of intrahepatic cholangiocarcinoma by VIRMA-mediated N6-methyladenosine (m(6)A) modification.
CCL3 secreted by hepatocytes promotes the metastasis of intrahepatic cholangiocarcinoma by VIRMA-mediated N6-methyladenosine (m(6)A) modification.
复制标题
肝细胞分泌的CCL3通过VIRMA介导的N6-甲基腺苷（m6A）修饰促进肝内胆管癌的转移
DOI：
10.1186/s12967-023-03897-y
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发表时间：
2023-01-23
影响因子：
7.4
通讯作者：
Li, Yaqing
中科院分区：
文献类型：
--
作者：
Zhou, Shurui;Yang, Kege;Chen, Shaojie;Lian, Guoda;Huang, Yuzhou;Yao, Hanming;Zhao, Yue;Huang, Kaihong;Yin, Dong;Lin, Haoming;Li, Yaqing
关键词：
肝内胆管细胞癌(ICC)是一种起病隐蔽、进展快、复发率高、死亡率高的恶性疾病。然而，关于肿瘤微环境(TME)如何在转录水平调节ICC转移的数据仍不清楚。本研究旨在探讨肝细胞与ICC细胞相互作用的机制。我们通过细胞因子抗体阵列分析了ICC与肝脏微环境的相互作用。然后，我们在体外、体内实验和临床标本中研究了N6-甲基腺苷(M6A)修饰及其下游靶点的作用。我们的研究表明，肝细胞分泌的细胞因子CCL3通过病毒样的M6A甲基转移酶相关蛋白(Virma)调节ICC细胞中M6A的修饰，从而促进肿瘤转移。此外，免疫组织化学分析显示，在ICC患者中，Virma与不良预后相关。最后，我们在体外和体内证实，CCL3可以激活Virma及其关键的下游靶标SIRT1，从而促进ICC的肿瘤转移。综上所述，我们的研究结果加深了我们对肝细胞与ICC细胞之间相互作用的理解，并揭示了CCL3/Virma/SIRT1途径通过m6A介导的调控ICC转移的分子机制。这些研究强调了ICC的诊断、治疗和预后的潜在靶点。网上版载有补充材料，可在10.1186/s12967-023-03897-y查阅。
Intrahepatic cholangiocarcinoma (ICC) is a malignant disease characterized by onset occult, rapid progression, high relapse rate, and high mortality. However, data on how the tumor microenvironment (TME) regulates ICC metastasis at the transcriptomic level remains unclear. This study aimed to explore the mechanisms and interactions between hepatocytes and ICC cells. We analyzed the interplay between ICC and liver microenvironment through cytokine antibody array analysis. Then we investigated the role of N6-methyladenosine (m6A) modification and the downstream target in vitro, in vivo experiments, and in clinical specimens. Our study demonstrated that cytokine CCL3, which is secreted by hepatocytes, promotes tumor metastasis by regulating m6A modification via vir-like m6A methyltransferase associated (VIRMA) in ICC cells. Moreover, immunohistochemical analyses showed that VIRMA correlated with poor outcomes in ICC patients. Finally, we confirmed both in vitro and in vivo that CCL3 could activate VIRMA and its critical downstream target SIRT1, which fuels tumor metastasis in ICC. In conclusion, our results enhanced our understanding of the interaction between hepatocytes and ICC cells, and revealed the molecular mechanism of the CCL3/VIRMA/SIRT1 pathway via m6A-mediated regulation in ICC metastasis. These studies highlight potential targets for the diagnosis, treatment, and prognosis of ICC. The online version contains supplementary material available at 10.1186/s12967-023-03897-y.
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影响因子：
37.3
作者：
Chen, Xiaoxiang;Xu, Mu;Wang, Shukui
通讯作者：
Wang, Shukui
影响因子：
29.4
作者：
Chen, Huarong;Gao, Shanshan;Yu, Jun
通讯作者：
Yu, Jun
DOI：
10.1186/s13046-021-02072-9
发表时间：
2021-08-25
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Miranda-Gonçalves V;Lobo J;Guimarães-Teixeira C;Barros-Silva D;Guimarães R;Cantante M;Braga I;Maurício J;Oing C;Honecker F;Nettersheim D;Looijenga LHJ;Henrique R;Jerónimo C
通讯作者：
Jerónimo C
影响因子：
23.9
作者：
Matsumoto, Tomonori;Wakefield, Leslie;Grompe, Markus
通讯作者：
Grompe, Markus
DOI：
10.1002/hep.31410
发表时间：
2021-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Fabris L;Sato K;Alpini G;Strazzabosco M
通讯作者：
Strazzabosco M