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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.
Affiliation
  • Wang J; The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
  • Zhang K; Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
  • Wang J; Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
  • Wu X; The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
  • Liu X; The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
  • Li B; Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
  • Zhu Y; The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
  • Yu Y; Changhai Hospital, The Second Military Medical University, Shanghai, China.
  • Cheng Q; The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
  • Hu Z; The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
  • Guo C; Changhai Hospital, The Second Military Medical University, Shanghai, China.
  • Hu S; The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
  • Mu B; Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
  • Tsai CH; The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
  • Li J; Department of Orthopedic Surgery, School of Medicine, China Medical University, Taichung, Taiwan.
  • Smith L; Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
  • Yang L; Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
  • Liu Q; The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
  • Chu P; Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
  • Chang V; Department of Pathology, City of Hope National Medical Center; Duarte, California, USA.
  • Zhang B; Program for Translation Medicine, Taipei Medical University, Taipei, Taiwan.
  • Wu M; The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
  • Jiang X; The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
  • Yen Y; The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
Oncotarget ; 6(22): 18905-20, 2015 Aug 07.
Article in En | MEDLINE | ID: mdl-26056085
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/ß-catenin, and cell adhesion as novel targets of LKB1 underexpression in ICC cells. Furthermore, knockdown of LKB1 gene expression dramatically enhanced Wnt/ß-catenin signaling in ICC cells, while an inverse correlation between LKB1 and nuclear ß-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/ß-catenin to promote disease progression.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Bile Duct Neoplasms / Protein Serine-Threonine Kinases / Cholangiocarcinoma / Wnt Signaling Pathway Type of study: Prognostic_studies / Risk_factors_studies Limits: Female / Humans / Male / Middle aged Language: En Journal: Oncotarget Year: 2015 Document type: Article Affiliation country: China Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Bile Duct Neoplasms / Protein Serine-Threonine Kinases / Cholangiocarcinoma / Wnt Signaling Pathway Type of study: Prognostic_studies / Risk_factors_studies Limits: Female / Humans / Male / Middle aged Language: En Journal: Oncotarget Year: 2015 Document type: Article Affiliation country: China Country of publication: United States