Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma.
Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma.
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LKB1肿瘤抑制因子的低表达与Wnt信号增强和人肝内胆管癌的恶性特征相关
DOI：
10.18632/oncotarget.4305
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发表时间：
2015-08-07
期刊：
影响因子：
--
通讯作者：
Yen Y
中科院分区：
文献类型：
--
作者：
Wang J;Zhang K;Wang J;Wu X;Liu X;Li B;Zhu Y;Yu Y;Cheng Q;Hu Z;Guo C;Hu S;Mu B;Tsai CH;Li J;Smith L;Yang L;Liu Q;Chu P;Chang V;Zhang B;Wu M;Jiang X;Yen Y
肝内胆管细胞癌(ICC)是一种罕见且高度侵袭性的恶性肿瘤。在本研究中，我们发现肝细胞癌组织中存在导致肝细胞癌抑癌基因LKB1失活或低表达的基因缺失和错义突变，并排除了肝细胞癌组织中LKB1基因高甲基化的参与。免疫组织化学分析显示，与癌旁正常组织相比，LKB1在326例ICC组织中低表达。经统计学分析，LKB1在ICC组织中的低表达与ICC患者的生存不良和恶性疾病特征显着相关。此外，我们还发现，LKB1基因的敲除显著促进了三种LKB1活性的ICC细胞系的生长、迁移和侵袭。全球转录谱分析发现，HIF-1、α、CD24、Talin1、vinculin、WNT5等多种促癌基因以及Hedgehog、Wnt/β-catenin和细胞黏附等信号通路是LKB1在国际胆管癌细胞中低表达的新靶点。此外，在肝细胞癌中，LKB1基因的表达下调显著增强了Wnt/β-catenin信号转导，而在肝细胞癌组织中，Lkb1基因的表达与核β-catenin的表达呈负相关。我们的发现提示了一种新的癌变机制，在这种机制中，LKB1的低表达增强了包括Wnt/β-catenin在内的多个信号通路，从而促进了疾病的进展。
Intrahepatic cholangiocarcinoma (ICC) is a rare and highly aggressive malignancy. In this study, we identified the presence of gene deletion and missense mutation leading to inactivation or underexpression of liver kinase B1 (LKB1) tumor suppressor and excluded the involvement of LKB1 gene hypermethylation in ICC tissues. Immunohistochemical analysis showed that LKB1 was underexpressed in a portion of 326 ICC tissues compared to their adjacent normal tissues. By statistical analysis underexpression of LKB1 in ICC tissues significantly correlated with poor survival and malignant disease characteristics in ICC patients. Moreover, we showed that knockdown of LKB1 significantly enhanced growth, migration, and invasion of three LKB1-competent ICC cell lines. Global transcriptional profiling analysis identified multiple malignancy-promoting genes, such as HIF-1α, CD24, Talin1, Vinculin, Wnt5, and signaling pathways including Hedgehog, Wnt/β-catenin, and cell adhesion as novel targets of LKB1 underexpression in ICC cells. Furthermore, knockdown of LKB1 gene expression dramatically enhanced Wnt/β-catenin signaling in ICC cells, while an inverse correlation between LKB1 and nuclear β-catenin was observed in ICC tissues. Our findings suggest a novel mechanism for ICC carcinogenesis in which LKB1 underexpression enhances multiple signaling pathways including Wnt/β-catenin to promote disease progression.
影响因子：
3.7
作者：
Wang J;Li L;Zhang K;Yu Y;Li B;Li J;Yan Z;Hu Z;Yen Y;Wu M;Jiang X;Qian Q
通讯作者：
Qian Q