Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma

Jinghan Wang, Keqiang Zhang, Jinhui Wang, Xiwei Wu, Xiyong Liu, Bin Li, Yan Zhu, Yong Yu, Qingbao Cheng, Zhenli Hu, Chao Guo, Shuya Hu, Bing Mu, Chun Hao Tsai, Jie Li, Lynne Smith, Lu Yang, Qi Liu, Peiguo Chu, Vincent ChangBaihe Zhang, Mengchao Wu, Xiaoqing Jiang, Yun Yen

研究成果: 雜誌貢獻文章

22 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)18905-18920
頁數16
期刊Oncotarget
6
發行號22
出版狀態已發佈 - 2015

指紋

Cholangiocarcinoma
Phosphotransferases
Liver
Catenins
Neoplasms
Vinculin
Wnt Signaling Pathway
Sequence Deletion
Gene Deletion
Missense Mutation
Cell Adhesion
Genes
Disease Progression
Carcinogenesis
Gene Expression
Cell Line
Survival

ASJC Scopus subject areas

  • Oncology

引用此文

Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma. / Wang, Jinghan; Zhang, Keqiang; Wang, Jinhui; Wu, Xiwei; Liu, Xiyong; Li, Bin; Zhu, Yan; Yu, Yong; Cheng, Qingbao; Hu, Zhenli; Guo, Chao; Hu, Shuya; Mu, Bing; Tsai, Chun Hao; Li, Jie; Smith, Lynne; Yang, Lu; Liu, Qi; Chu, Peiguo; Chang, Vincent; Zhang, Baihe; Wu, Mengchao; Jiang, Xiaoqing; Yen, Yun.

於: Oncotarget, 卷 6, 編號 22, 2015, p. 18905-18920.

研究成果: 雜誌貢獻文章

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 2015, 'Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma', Oncotarget, 卷 6, 編號 22, 頁 18905-18920.
Wang, Jinghan ; Zhang, Keqiang ; Wang, Jinhui ; Wu, Xiwei ; Liu, Xiyong ; Li, Bin ; Zhu, Yan ; Yu, Yong ; Cheng, Qingbao ; Hu, Zhenli ; Guo, Chao ; Hu, Shuya ; Mu, Bing ; Tsai, Chun Hao ; Li, Jie ; Smith, Lynne ; Yang, Lu ; Liu, Qi ; Chu, Peiguo ; Chang, Vincent ; Zhang, Baihe ; Wu, Mengchao ; Jiang, Xiaoqing ; Yen, Yun. / Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma. 於: Oncotarget. 2015 ; 卷 6, 編號 22. 頁 18905-18920.
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title = "Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma",
abstract = "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.",
keywords = "Global transcriptional profiling, Intrahepatic cholangiocarcinoma (ICC), Liver kinase B1 (LKB1), Recurrence and metastasis, Wnt/β-catenin",
author = "Jinghan Wang and Keqiang Zhang and Jinhui Wang and Xiwei Wu and Xiyong Liu and Bin Li and Yan Zhu and Yong Yu and Qingbao Cheng and Zhenli Hu and Chao Guo and Shuya Hu and Bing Mu and Tsai, {Chun Hao} and Jie Li and Lynne Smith and Lu Yang and Qi Liu and Peiguo Chu and Vincent Chang and Baihe Zhang and Mengchao Wu and Xiaoqing Jiang and Yun Yen",
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T1 - Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma

AU - Wang, Jinghan

AU - Zhang, Keqiang

AU - Wang, Jinhui

AU - Wu, Xiwei

AU - Liu, Xiyong

AU - Li, Bin

AU - Zhu, Yan

AU - Yu, Yong

AU - Cheng, Qingbao

AU - Hu, Zhenli

AU - Guo, Chao

AU - Hu, Shuya

AU - Mu, Bing

AU - Tsai, Chun Hao

AU - Li, Jie

AU - Smith, Lynne

AU - Yang, Lu

AU - Liu, Qi

AU - Chu, Peiguo

AU - Chang, Vincent

AU - Zhang, Baihe

AU - Wu, Mengchao

AU - Jiang, Xiaoqing

AU - Yen, Yun

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Global transcriptional profiling

KW - Intrahepatic cholangiocarcinoma (ICC)

KW - Liver kinase B1 (LKB1)

KW - Recurrence and metastasis

KW - Wnt/β-catenin

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M3 - Article

C2 - 26056085

AN - SCOPUS:84938870050

VL - 6

SP - 18905

EP - 18920

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 22

ER -