LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours.
LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours.
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DOI：
10.1136/gutjnl-2014-308810
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发表时间：
2016-10
期刊：
影响因子：
24.5
通讯作者：
Wiltrout RH
中科院分区：
文献类型：
--
作者：
Scarzello AJ;Jiang Q;Back T;Dang H;Hodge D;Hanson C;Subleski J;Weiss JM;Stauffer JK;Chaisaingmongkol J;Rabibhadana S;Ruchirawat M;Ortaldo J;Wang XW;Norris PS;Ware CF;Wiltrout RH
炎症信号和相继致癌基因失调在肝癌发病机制中的相对作用尚不完全清楚。淋巴毒素-β受体(LTβR)信号通路在肝炎和肝肿瘤发生中起重要作用。因此，我们探索了炎性淋巴毒素信号和特定的致癌途径在肝癌进展过程中的相互依赖关系。将致癌基因V-Akt小鼠胸腺瘤病毒同源基因Akt/β-catenin或Akt/Notch表达载体进行流体动力转染，可诱导不同病理类型的小鼠肝肿瘤形成。为探讨LTβR信号转导途径与特定致癌途径的关系，癌基因转染后给予LTβR拮抗剂(LTβR-Fc)或激动剂(抗LTβR)。对启动的肝脏/肿瘤的癌基因表达、肿瘤增殖、进展、潜伏期和病理变化进行调查。此外，通过对肝内胆管细胞癌患者样本的转录分析，在人肝癌细胞系中研究了特异性LTβR介导的分子事件。AKT/β-catenin基因转染组大鼠肝组织中LTβ和LTβR的表达增加，LTβR信号转导通路的拮抗作用可延缓肿瘤进展，提高存活率。相反，AKT/β-连环蛋白启动的肿瘤的强制LTβR激活以AKT依赖的方式诱导肝肿瘤表型的增殖和进展的强劲增加。LTβR的激活也加速了AKT/Notch启动的ICC进展，但不是Notch单独启动的。此外，LTβR的加速发育与Notch、Hes1、c-myc、paKt和β-catenin的增加相一致。我们进一步证明在人肝癌细胞系中LTβR信号是Notch、pAKTser473和β-连环蛋白的调节因子。转录组分析来自具有国际刑事法院链接的患者的样本增加了LTβR网络的表达，患者的存活率较低，Notch1的表达增加，Notch1和AKT/PI3K信号转导增加。我们的发现将LT、βR和致癌的AKT信号在肝细胞癌的发生发展中联系起来。
The relative contributions of inflammatory signalling and sequential oncogenic dysregulation driving liver cancer pathogenesis remain incompletely understood. Lymphotoxin-β receptor (LTβR) signalling is critically involved in hepatitis and liver tumorigenesis. Therefore, we explored the interdependence of inflammatory lymphotoxin signalling and specific oncogenic pathways in the progression of hepatic cancer. Pathologically distinct liver tumours were initiated by hydrodynamic transfection of oncogenic V-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT)/β-catenin or AKT/Notch expressing plasmids. To investigate the relationship of LTβR signalling and specific oncogenic pathways, LTβR antagonist (LTβR-Fc) or agonist (anti-LTβR) were administered post oncogene transfection. Initiated livers/tumours were investigated for changes in oncogene expression, tumour proliferation, progression, latency and pathology. Moreover, specific LTβR-mediated molecular events were investigated in human liver cancer cell lines and through transcriptional analyses of samples from patients with intrahepatic cholangiocarcinoma (ICC). AKT/β-catenin-transfected livers displayed increased expression of LTβ and LTβR, with antagonism of LTβR signalling reducing tumour progression and enhancing survival. Conversely, enforced LTβR-activation of AKT/β-catenin-initiated tumours induced robust increases in proliferation and progression of hepatic tumour phenotypes in an AKT-dependent manner. LTβR-activation also rapidly accelerated ICC progression initiated by AKT/Notch, but not Notch alone. Moreover, LTβR-accelerated development coincides with increases of Notch, Hes1, c-MYC, pAKT and β-catenin. We further demonstrate LTβR signalling in human liver cancer cell lines to be a regulator of Notch, pAKTser473 and β-catenin. Transcriptome analysis of samples from patients with ICC links increased LTβR network expression with poor patient survival, increased Notch1 expression and Notch and AKT/PI3K signalling. Our findings link LTβR and oncogenic AKT signalling in the development of ICC.
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影响因子：
6.4
作者：
Bai, Dong;Ueno, Lynn;Vogt, Peter K.
通讯作者：
Vogt, Peter K.
影响因子：
56.9
作者：
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8
作者：
Cadoret, A;Ovejero, C;Perret, C
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Perret, C
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50.3
作者：
Haybaeck J;Zeller N;Wolf MJ;Weber A;Wagner U;Kurrer MO;Bremer J;Iezzi G;Graf R;Clavien PA;Thimme R;Blum H;Nedospasov SA;Zatloukal K;Ramzan M;Ciesek S;Pietschmann T;Marche PN;Karin M;Kopf M;Browning JL;Aguzzi A;Heikenwalder M
通讯作者：
Heikenwalder M
影响因子：
5
作者：
Andersen JB;Thorgeirsson SS
通讯作者：
Thorgeirsson SS