Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease.
Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease.
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DOI：
10.3390/cancers14010078
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发表时间：
2021-12-24
期刊：
影响因子：
5.2
通讯作者：
Cubero FJ
中科院分区：
文献类型：
--
作者：
Chen C;Wu H;Ye H;Tortajada A;Rodríguez-Perales S;Torres-Ruiz R;Vidal A;Peligros MI;Reissing J;Bruns T;Mohamed MR;Zheng K;Lujambio A;Iraburu MJ;Colyn L;Latasa MU;Arechederra M;Fernández-Barrena MG;Berasain C;Vaquero J;Bañares R;Nelson LJ;Trautwein C;Davis RJ;Martinez-Naves E;Nevzorova YA;Villanueva A;Avila MA;Cubero FJ
多囊肝病（PLD）是一组罕见的疾病，其起因于肝脏中胆管树发育的结构变化。在目前的工作中，我们研究了可能导致这些病理的分子机制和信号通路的改变。我们发现，未折叠蛋白反应的激活，一个响应于内质网腔中未折叠或错误折叠蛋白的积累而发生的过程，以及肝组织的瘢痕形成，有助于PLD的发病机制和癌症的发展。作为临床前动物模型，我们使用了特定信号传导途径的突变小鼠，c-Jun N-末端激酶1/2（JNK 1/2）。这些小鼠类似于研究PLD和早期癌症发展的完美模型。纤维多囊性肝病的特征是胆管上皮细胞过度增殖和多个扩张囊肿的形成，这是一个与未折叠蛋白反应（UPR）相关的过程。在本研究中，我们的目的是了解肝细胞c-Jun N-末端激酶1/2（JNK 1/2）基因敲除小鼠的囊肿形成和UPR激活的机制。在肝脏疾病进展期间的不同时间点处死Floxed JNK 1/2（Jnkf/f）和JNk Hepa动物。标本的组织学检查证明存在胶原纤维沉积、α-平滑肌肌动蛋白（αSMA）增加、CD 45、CD 11b和F4/80细胞和促炎细胞因子（Tnf、Tgfβ1）的浸润以及肝损伤（例如，ALT、凋亡和Ki 67阳性细胞）与32周龄的Jnkf/f肝脏进行比较。这与UPR效应子的激活有关，包括BiP/GRP 78、CHOP和剪接的XBP 1。衣霉素（TM）的挑战强烈诱导ER应激和纤维化的JNK hepa动物相比，JNKF/F同窝仔。最后，硫代乙酰胺（TAA）管理JNK肝癌小鼠诱导UPR激活，胆管周围纤维化，肝损伤和标志物的胆管增生和胆管癌（CCA）。DEN/CCl 4处理的JNK Hepa肝组织的同种异体移植物引发恶性CCA。总之，这些结果表明，激活的UPR与纤维化可能触发肝囊肿和CCA的早期阶段。
Polycystic liver disease (PLD) is a group of rare disorders that result from structural changes in the biliary tree development in the liver. In the present work, we studied alterations in molecular mechanisms and signaling pathways that might be responsible for these pathologies. We found that activation of the unfolded protein response, a process that occurs in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum, as well as the scarring of the liver tissue, contribute to the pathogenesis of PLD and the development of cancer. As a preclinical animal model we have used mutant mice of a specific signaling pathway, the c-Jun N-terminal kinase 1/2 (Jnk1/2). These mice resemble a perfect model for the study of PLD and early cancer development. Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.
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影响因子：
29.4
作者：
Cubero FJ;Zoubek ME;Hu W;Peng J;Zhao G;Nevzorova YA;Al Masaoudi M;Bechmann LP;Boekschoten MV;Muller M;Preisinger C;Gassler N;Canbay AE;Luedde T;Davis RJ;Liedtke C;Trautwein C
通讯作者：
Trautwein C
DOI：
10.1073/pnas.2002672117
发表时间：
2020-07-14
影响因子：
11.1
作者：
Manieri, Elisa;Folgueira, Cintia;Sabio, Guadalupe
通讯作者：
Sabio, Guadalupe
影响因子：
11.2
作者：
Ambrogio, Chiara;Carmona, Francisco J.;Villanueva, Alberto
通讯作者：
Villanueva, Alberto
影响因子：
16.6
作者：
Lee DH;Park JO;Kim TS;Kim SK;Kim TH;Kim MC;Park GS;Kim JH;Kuninaka S;Olson EN;Saya H;Kim SY;Lee H;Lim DS
通讯作者：
Lim DS
影响因子：
13.5
作者：
Colyn, Leticia;Barcena-Varela, Marina;Avila, Matias A.
通讯作者：
Avila, Matias A.