title: Elevated expression of Erbin destabilizes ERα protein and promotes tumorigenesis in hepatocellular carcinoma.
abstract: Aberrant estrogen receptor-α (ERα) expression and signaling are implicated in the development of hepatocellular carcinoma (HCC), but its regulation in HCC remains enigmatic. Herein, we aimed to identify a new mechanism by which ERα signaling is regulated in HCC, which may lead to a potential new strategy for HCC therapy.
  
  
  
  Expression levels of Erbin and ERα in human HCC samples were evaluated by immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of Erbin and ERα signaling on HCC cell growth. Crosstalk between Erbin and ERα signaling was analyzed by molecular methods. Animal models of diethylnitrosamine (DEN) or DEN/CCl4-induced HCC in wild-type Erbin+/+and mutant ErbinΔC/ΔCmice were observed. The regulatory effects of Erbin on tamoxifen treatment of HCC were evaluated in vitro and in vivo.
  
  
  
  Erbin inactivated ERα signaling to drive tumorigenesis of HCC, acting to enhance binding of Chip to ERα via its interaction with ERα and thereby promoting ubiquitination and degradation of ERα. Deletion of the PDZ domain of Erbin in ErbinΔC/ΔCmice, disrupted the interaction of Chip and ERα, increased the stability of ERα protein, and thus inhibited tumorigenesis of HCC. Silencing of Erbin effectively sensitized the response of HCC after tamoxifen treatment in vitro and in vivo.
  
  
  
  Our data uncovered an important role of Erbin in regulating HCC tumorigenesis through inactivating ERα-mediated tumor-suppressive signaling, suggesting a new strategy for tamoxifen therapy in HCC by targeting Erbin/ERα signaling axis.
  
  
  
  Erbin expression is significantly elevated in human hepatocellular carcinoma (HCC) tissue. This elevated expression of Erbin contributes to tumorigenesis of HCC by negatively regulating ERα signaling. However, restoring ERα signaling by inhibiting Erbin expression enhances the sensitivity of HCC cells to tamoxifen treatment, providing a new approach for tamoxifen treatment in HCC.
authors.affiliation: Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Pathology, Soochow University, Suzhou 215123, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
authors.forename: Su
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Pathology, Soochow University, Suzhou 215123, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Soochow University, Suzhou 215123, China.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Department of Pathology, Soochow University, Suzhou 215123, China.
authors.forename: Peng-Da
authors.initials: PD
authors.lastname: Guo
authors.affiliation: Department of Pathology, Soochow University, Suzhou 215123, China.
authors.forename: Xiu-Ming
authors.initials: XM
authors.lastname: Li
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Gan
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.affiliation: State Key Laboratory of Organ Failure Research, Key Laboratory of Psychiatric Disorders of Guangdong Province, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: tgao@fimmu.com.
authors.forename: Tian-Ming
authors.initials: TM
authors.lastname: Gao
authors.affiliation: Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Pathology, Soochow University, Suzhou 215123, China; Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: jianmingli@suda.edu.cn.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011379:Prognosis; D055550:Protein Stability; D012737:Sex Factors; D013629:Tamoxifen / Q000627:therapeutic use; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; D002352:Carrier Proteins; C413364:ERBIN protein, human; C506487:ESR1 protein, human; C498804:Erbb2ip protein, mouse; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; D013629:Tamoxifen; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: ERα signaling; Hepatocellular carcinoma; Mouse model; Tamoxifen therapy; Tumorigenesis