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.
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.|Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Jinghan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Zhang
authors.affiliation: The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Changhai Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Qingbao
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Changhai Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Zhenli
authors.initials: Z
authors.lastname: Hu
authors.affiliation: The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Shuya
authors.initials: S
authors.lastname: Hu
authors.affiliation: The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Mu
authors.affiliation: Department of Orthopedic Surgery, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Smith
authors.affiliation: The Integrative Genomics Core lab of Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, City of Hope National Medical Center; Duarte, California, USA.
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.affiliation: Program for Translation Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chang
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Baihe
authors.initials: B
authors.lastname: Zhang
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.affiliation: The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center, Duarte, California, USA.|PhD Program of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases
keywords: Wnt/β-catenin; global transcriptional profiling; intrahepatic cholangiocarcinoma (ICC); liver kinase B1 (LKB1); recurrence and metastasis