Elevated expression of Erbin destabilizes ERα protein and promotes tumorigenesis in hepatocellular carcinoma

Hua Wu, Su Yao, Shen Zhang, Jing Ru Wang, Peng Da Guo, Xiu Ming Li, Wen Juan Gan, Lin Mei, Tian Ming Gao, Jian Ming Li

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1193-1204
Number of pages12
JournalJournal of Hepatology
Volume66
Issue number6
DOIs
StatePublished - Jun 2017

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Hepatocellular Carcinoma
Carcinogenesis
Estrogen Receptors
Tamoxifen
Diethylnitrosamine
estrophilin
Therapeutics
PDZ Domains
Ubiquitination
Animal Models
Immunohistochemistry

Keywords

  • ERα signaling
  • Hepatocellular carcinoma
  • Mouse model
  • Tamoxifen therapy
  • Tumorigenesis

ASJC Scopus subject areas

  • Hepatology

Cite this

Elevated expression of Erbin destabilizes ERα protein and promotes tumorigenesis in hepatocellular carcinoma. / Wu, Hua; Yao, Su; Zhang, Shen; Wang, Jing Ru; Guo, Peng Da; Li, Xiu Ming; Gan, Wen Juan; Mei, Lin; Gao, Tian Ming; Li, Jian Ming.

In: Journal of Hepatology, Vol. 66, No. 6, 06.2017, p. 1193-1204.

Research output: Contribution to journalArticle

Wu, H, Yao, S, Zhang, S, Wang, JR, Guo, PD, Li, XM, Gan, WJ, Mei, L, Gao, TM & Li, JM 2017, 'Elevated expression of Erbin destabilizes ERα protein and promotes tumorigenesis in hepatocellular carcinoma', Journal of Hepatology, vol. 66, no. 6, pp. 1193-1204. https://doi.org/10.1016/j.jhep.2017.01.030
Wu, Hua ; Yao, Su ; Zhang, Shen ; Wang, Jing Ru ; Guo, Peng Da ; Li, Xiu Ming ; Gan, Wen Juan ; Mei, Lin ; Gao, Tian Ming ; Li, Jian Ming. / Elevated expression of Erbin destabilizes ERα protein and promotes tumorigenesis in hepatocellular carcinoma. In: Journal of Hepatology. 2017 ; Vol. 66, No. 6. pp. 1193-1204.
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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.",
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author = "Hua Wu and Su Yao and Shen Zhang and Wang, {Jing Ru} and Guo, {Peng Da} and Li, {Xiu Ming} and Gan, {Wen Juan} and Lin Mei and Gao, {Tian Ming} and Li, {Jian Ming}",
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T1 - Elevated expression of Erbin destabilizes ERα protein and promotes tumorigenesis in hepatocellular carcinoma

AU - Wu, Hua

AU - Yao, Su

AU - Zhang, Shen

AU - Wang, Jing Ru

AU - Guo, Peng Da

AU - Li, Xiu Ming

AU - Gan, Wen Juan

AU - Mei, Lin

AU - Gao, Tian Ming

AU - Li, Jian Ming

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N2 - 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.

AB - 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.

KW - ERα signaling

KW - Hepatocellular carcinoma

KW - Mouse model

KW - Tamoxifen therapy

KW - Tumorigenesis

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