Lect2 Controls Inflammatory Monocytes to Constrain the Growth and Progression of Hepatocellular Carcinoma
Lect2 Controls Inflammatory Monocytes to Constrain the Growth and Progression of Hepatocellular Carcinoma
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DOI：
10.1002/hep.30140
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发表时间：
2019-01-01
期刊：
影响因子：
13.5
通讯作者：
Couty, Jean-Pierre
中科院分区：
文献类型：
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作者：
L'Hermitte, Antoine;Pham, Sandrine;Couty, Jean-Pierre
白细胞源趋化因子2（LECT 2）最初被鉴定为肝细胞分泌的趋化因子样因子和β-连环蛋白信号传导的阳性靶点。在这里，我们解剖了LECT 2调节肝细胞癌（HCC）的发展机制，使用HCC小鼠模型和人HCC样本。我们已经证明LECT 2具有双重能力，因为它对肿瘤表型本身和免疫微环境具有深远的影响。它的缺乏赋予Ctnnb-1突变的肿瘤肝细胞更强的能力，经历上皮间质转化，并促进具有免疫抑制特性和强肿瘤促进潜力的贬义炎症单核细胞的积累。与我们的HCC小鼠模型一致，人HCC中低水平的LECT 2与高肿瘤分级和炎性浸润的存在密切相关，强调了LECT 2在人肝脏肿瘤发生中的临床价值。结论：我们的研究结果表明，LECT 2是肝脏肿瘤发生的关键因素，因为它的缺失重塑了肿瘤微环境和肿瘤表型，揭示了LECT 2作为HCC的一种有前途的免疫选择。
Leukocyte cell-derived chemotaxin-2 (LECT2) was originally identified as a hepatocyte-secreted chemokine-like factor and a positive target of beta-catenin signaling. Here, we dissected out the mechanisms by which LECT2 modulates hepatocellular carcinoma (HCC) development using both HCC mouse models and human HCC samples. We have demonstrated that LECT2 exhibits dual abilities as it has profound repercussions on the tumor phenotype itself and the immune microenvironment. Its absence confers Ctnnb-1-mutated tumor hepatocytes a stronger ability to undergo epithelial to mesenchymal transition and fosters the accumulation of pejorative inflammatory monocytes harboring immunosuppressive properties and strong tumor-promoting potential. Consistent with our HCC mouse model, a low level of LECT2 in human HCC is strongly associated with high tumor grade and the presence of inflammatory infiltrates, emphasizing the clinical value of LECT2 in human liver tumorigenesis. Conclusion: Our findings have demonstrated that LECT2 is a key player in liver tumorigenesis because its absence reshapes the tumor microenvironment and the tumor phenotype, revealing LECT2 as a promising immunotherapeutic option for HCC.