title: Hypoxia activates Wnt/β-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma.
abstract: The Wnt/β-catenin signaling is abnormally activated in the progression of hepatocellular carcinoma (HCC). BCL9 is an essential co-activator in the Wnt/β-catenin signaling. Importantly, BCL9 is absent from tumors originating from normal cellular counterparts and overexpressed in many cancers including HCC. But the mechanism for BCL9 overexpression remains unknown. Ample evidence indicates that hypoxia inducible factors (HIFs) play a role in the development of HCC. It was found in our study that BCL9 was overexpressed in both primary HCC and bone metastasis specimens; loss of BCL9 inhibited the proliferation, migration and angiogenesis of HCC; and that that hypoxia mechanically induced the expression of BCL9. BCL9 induction under the hypoxic condition was predominantly mediated by HIF-1α but not HIF2α. In vitro evidence from xenograft models indicated that BCL9 promoter/gene knockout inhibited HCC tumor growth and angiogenesis. Notably, we found that BCL9 and HIF-1α were coordinately regulated in human HCC specimen. The above findings suggest that hypoxia may promote the expression of BCL9 and associate with the development of HCC. Specific regulation of BCL9 expression by HIF-1α may prove to be an underlying crosstalk between Wnt/β-catenin signaling and hypoxia signaling pathways.
authors.affiliation: Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.
authors.forename: Mo
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.|Department of Anatomy, Xuzhou Medical University, NO. 209, Tongshan Road, Xuzhou, 221004, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anatomy, Xuzhou Medical University, NO. 209, Tongshan Road, Xuzhou, 221004, China.
authors.forename: Zhian
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.
authors.forename: Shaohui
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, NO. 225, Changhai Road, Shanghai, 200438, China.
authors.forename: Xiangji
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Bone and soft tissue tumors, Fudan Cancer Center, Fudan University, NO. 270, Dong'an Road, Shanghai, 200000, China.
authors.forename: Wending
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.
authors.forename: Tianrui
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.|Department of Bone and soft tissue tumors, Fudan Cancer Center, Fudan University, NO. 270, Dong'an Road, Shanghai, 200000, China.
authors.forename: Wangjun
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001859:Bone Neoplasms / Q000556:secondary; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D015687:Cell Hypoxia; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005818:Genetic Engineering; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D000069896:Transcription Activator-Like Effector Nucleases; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000235:genetics; D060449:Wnt Signaling Pathway; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D000069896:Transcription Activator-Like Effector Nucleases; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C111180:BCL9 protein, human