Hua Wu1, Su Yao2, Shen Zhang3, Jing-Ru Wang3, Peng-Da Guo3, Xiu-Ming Li3, Wen-Juan Gan4, Lin Mei5, Tian-Ming Gao6, Jian-Ming Li7. 1. Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Pathology, Soochow University, Suzhou 215123, China. 2. 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. 3. Department of Pathology, Soochow University, Suzhou 215123, China. 4. Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China. 5. Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA. 6. 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. 7. 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.
Abstract
BACKGROUND & AIMS: 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. METHODS: 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/ΔC mice were observed. The regulatory effects of Erbin on tamoxifen treatment of HCC were evaluated in vitro and in vivo. RESULTS: 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/ΔC mice, 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. CONCLUSIONS: 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. LAY SUMMARY: 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.
BACKGROUND & AIMS: 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. METHODS: 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/ΔC mice were observed. The regulatory effects of Erbin on tamoxifen treatment of HCC were evaluated in vitro and in vivo. RESULTS: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/ΔC mice, 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. CONCLUSIONS: 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. LAY SUMMARY:Erbin expression is significantly elevated in humanhepatocellular 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.