Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, metastasis and sorafenib resistance through STAT3 activation.
Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, metastasis and sorafenib resistance through STAT3 activation.
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纤维化肝脏的炎症微环境通过STAT3激活促进肝细胞癌生长、转移和索拉非尼耐药
DOI：
10.1111/jcmm.16256
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发表时间：
2021-03
影响因子：
5.3
通讯作者：
Hong J
中科院分区：
文献类型：
--
作者：
Jiang Y;Chen P;Hu K;Dai G;Li J;Zheng D;Yuan H;He L;Xie P;Tu M;Peng S;Qu C;Lin W;Chung RT;Hong J
促炎症和促纤维化的肝脏微环境促进了肝癌的发生。然而，肝纤维炎症微环境调节肝内肝细胞癌（HCC）进展及其对系统治疗反应的作用和机制在很大程度上仍未被探索。我们建立了CCl4灌胃致一系列持续性肝损伤的同源原位肝癌小鼠模型，模拟肝脏病理微环境对肝内肝癌生长和转移的动态影响。非侵入性生物发光成像用于随时间跟踪肿瘤进展。研究了肝损伤后肝脏微环境对索拉非尼耐药的影响。我们发现持续的肝损伤促进了HCC的生长和转移，这与肝脏炎症程度呈正相关，而与肝纤维化程度呈正相关。肝损伤后肝组织中炎性细胞因子明显升高。两种指示的细胞因子，肿瘤坏死因子α （TNF‐α）和白细胞介素- 6 (IL‐6)，都通过STAT3激活促进肝内HCC的进展。此外，肝脏炎症微环境通过STAT3介导的抗凋亡蛋白促进索拉非尼耐药，STAT3抑制剂sgi‐201显著改善索拉非尼因肝脏炎症受损的疗效。在临床上，肝组织炎症的增加伴随着STAT3激活的上调。综上所述，我们认为肝脏炎症微环境通过激活STAT3促进肝内HCC的生长、转移和索拉非尼耐药。
The pro‐inflammatory and pro‐fibrotic liver microenvironment facilitates hepatocarcinogenesis. However, the effects and mechanisms by which the hepatic fibroinflammatory microenvironment modulates intrahepatic hepatocellular carcinoma (HCC) progression and its response to systematic therapy remain largely unexplored. We established a syngeneic orthotopic HCC mouse model with a series of persistent liver injury induced by CCl4 gavage, which mimic the dynamic effect of hepatic pathology microenvironment on intrahepatic HCC growth and metastasis. Non‐invasive bioluminescence imaging was applied to follow tumour progression over time. The effect of the liver microenvironment modulated by hepatic injury on sorafenib resistance was investigated in vivo and in vitro. We found that the persistent liver injury facilitated HCC growth and metastasis, which was positively correlated with the degree of liver inflammation rather than the extent of liver fibrosis. The inflammatory cytokines in liver tissue were clearly increased after liver injury. The two indicated cytokines, tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), both promoted intrahepatic HCC progression via STAT3 activation. In addition, the hepatic inflammatory microenvironment contributed to sorafenib resistance through the anti‐apoptotic protein mediated by STAT3, and STAT3 inhibitor S3I‐201 significantly improved sorafenib efficacy impaired by liver inflammation. Clinically, the increased inflammation of liver tissues was accompanied with the up‐regulated STAT3 activation in HCC. Above all, we concluded that the hepatic inflammatory microenvironment promotes intrahepatic HCC growth, metastasis and sorafenib resistance through activation of STAT3.
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DOI：
10.1007/978-3-0348-0837-8_16
发表时间：
2014-01-01
期刊：
INFLAMMATION AND CANCER
影响因子：
--
作者：
Bishayee, Anupam
通讯作者：
Bishayee, Anupam
影响因子：
11.5
作者：
Chen, Kuen-Feng;Tai, Wei-Tien;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii
影响因子：
5
作者：
Duan, Xu-Hua;Li, Hao;Kuang, Dong-Lin
通讯作者：
Kuang, Dong-Lin
影响因子：
7.6
作者：
Pinter M;Peck-Radosavljevic M
通讯作者：
Peck-Radosavljevic M
影响因子：
12.4
作者：
Guerra AD;Yeung OWH;Qi X;Kao WJ;Man K
通讯作者：
Man K