Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

Shan Wan; Anne Sophie Meyer; Sofia Maria Elisabeth Weiler; Christian Rupp; Marcell Tóth; Carsten Sticht; Stephan Singer; Stefan Thomann; Stephanie Roessler; Marina Schorpp-Kistner; Jennifer Schmitt; Norbert Gretz; Peter Angel; Darjus Felix Tschaharganeh; Jens Marquardt; Peter Schirmacher; Federico Pinna; Kai Breuhahn

doi:10.1002/hep.29669

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

Shan Wan, Anne Sophie Meyer, Sofia Maria Elisabeth Weiler, Christian Rupp, Marcell Tóth, Carsten Sticht, Stephan Singer, Stefan Thomann, Stephanie Roessler, Marina Schorpp-Kistner, Jennifer Schmitt, Norbert Gretz, Peter Angel, Darjus Felix Tschaharganeh, Jens Marquardt, Peter Schirmacher, Federico Pinna, Kai Breuhahn^*

^*Corresponding author for this work

Clinic of Internal Medicine I

51 Citations (Scopus)

Abstract

The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the basolateral cell polarity complex protein scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison with HCC cells stably expressing wild-type Scrib (Scrib^WT), mutated Scrib with enforced cytoplasmic enrichment (Scrib^P305L) induced AKT signaling through the destabilization of phosphatase and tensin homolog (PTEN) and PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). Cytoplasmic Scrib^P305L stimulated a gene signature and a phenotype characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. Scrib^P305L-dependent invasion was mediated by the activator protein 1 (AP-1) constituents ATF2 and JunB through induction of paracrine-acting secreted protein acidic and cysteine-rich (SPARC). Coexpression of Scrib^P305L and the oncogene c-MYC through hydrodynamic gene delivery in mouse livers promoted tumor formation and increased abundance of pAKT, pATF2, and SPARC in comparison with controls. Finally, cytoplasmic Scrib localization correlated with AKT and ATF2 phosphorylation in human HCC tissues, and the Scrib^P305L-dependent gene signature was enriched in cancer patients with poor prognosis. Conclusion: Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination through specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patients with higher risk for the development of metastasis. (Hepatology 2018;67:1842-1856).

Original language	English
Journal	Hepatology
Volume	67
Issue number	5
Pages (from-to)	1842-1856
Number of pages	15
ISSN	0270-9139
DOIs	https://doi.org/10.1002/hep.29669
Publication status	Published - 05.2018

Funding

The Gateway pDONR 201 and pEGFP vectors were provided by Stefan Pusch (Heidelberg, Germany). Tissue samples were provided by the tissue bank of the National Center of Tumor Diseases (Heidelberg, Germany) in accordance with the regulations of the tissue bank and the approval of the Ethics Committee of Heidelberg University. We thank the Center of Model System and Comparative Pathology (Felix Lasitschka and Tanja Poth) and Heike Conrad for their support. This study was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe/Dr. Mildred Scheel Stiftung, DKH 111524 [to K.B.]), the SFB/TR 209 “Liver Cancer” (to K.B., S.S., S.R., P.A., D.F.T., P.S.), and the China Scholarship (to S.W.). J.U.M. is supported by a grant from the Volkswagenfoundation (Lichtenberg Program). P.S. and S.R. are supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667273 (HEP-CAR). *These authors share co-senior authorship. Transcriptome data are available in the Gene Expression Omnibus public database (accession number GSE93742).

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1002/hep.29669

Cite this

Wan, S., Meyer, A. S., Weiler, S. M. E., Rupp, C., Tóth, M., Sticht, C., Singer, S., Thomann, S., Roessler, S., Schorpp-Kistner, M., Schmitt, J., Gretz, N., Angel, P., Tschaharganeh, D. F., Marquardt, J., Schirmacher, P., Pinna, F., & Breuhahn, K. (2018). Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness. Hepatology, 67(5), 1842-1856. https://doi.org/10.1002/hep.29669

@article{2bf710bb8acf4daab7c7ad110c22e56f,

title = "Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness",

abstract = "The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the basolateral cell polarity complex protein scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison with HCC cells stably expressing wild-type Scrib (ScribWT), mutated Scrib with enforced cytoplasmic enrichment (ScribP305L) induced AKT signaling through the destabilization of phosphatase and tensin homolog (PTEN) and PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). Cytoplasmic ScribP305L stimulated a gene signature and a phenotype characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. ScribP305L-dependent invasion was mediated by the activator protein 1 (AP-1) constituents ATF2 and JunB through induction of paracrine-acting secreted protein acidic and cysteine-rich (SPARC). Coexpression of ScribP305L and the oncogene c-MYC through hydrodynamic gene delivery in mouse livers promoted tumor formation and increased abundance of pAKT, pATF2, and SPARC in comparison with controls. Finally, cytoplasmic Scrib localization correlated with AKT and ATF2 phosphorylation in human HCC tissues, and the ScribP305L-dependent gene signature was enriched in cancer patients with poor prognosis. Conclusion: Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination through specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patients with higher risk for the development of metastasis. (Hepatology 2018;67:1842-1856).",

author = "Shan Wan and Meyer, \{Anne Sophie\} and Weiler, \{Sofia Maria Elisabeth\} and Christian Rupp and Marcell T{\'o}th and Carsten Sticht and Stephan Singer and Stefan Thomann and Stephanie Roessler and Marina Schorpp-Kistner and Jennifer Schmitt and Norbert Gretz and Peter Angel and Tschaharganeh, \{Darjus Felix\} and Jens Marquardt and Peter Schirmacher and Federico Pinna and Kai Breuhahn",

note = "Publisher Copyright: {\textcopyright} 2017 by the American Association for the Study of Liver Diseases.",

year = "2018",

month = may,

doi = "10.1002/hep.29669",

language = "English",

volume = "67",

pages = "1842--1856",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Lippincott Williams and Wilkins",

number = "5",

}

Wan, S, Meyer, AS, Weiler, SME, Rupp, C, Tóth, M, Sticht, C, Singer, S, Thomann, S, Roessler, S, Schorpp-Kistner, M, Schmitt, J, Gretz, N, Angel, P, Tschaharganeh, DF, Marquardt, J, Schirmacher, P, Pinna, F & Breuhahn, K 2018, 'Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness', Hepatology, vol. 67, no. 5, pp. 1842-1856. https://doi.org/10.1002/hep.29669

TY - JOUR

T1 - Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

AU - Wan, Shan

AU - Meyer, Anne Sophie

AU - Weiler, Sofia Maria Elisabeth

AU - Rupp, Christian

AU - Tóth, Marcell

AU - Sticht, Carsten

AU - Singer, Stephan

AU - Thomann, Stefan

AU - Roessler, Stephanie

AU - Schorpp-Kistner, Marina

AU - Schmitt, Jennifer

AU - Gretz, Norbert

AU - Angel, Peter

AU - Tschaharganeh, Darjus Felix

AU - Marquardt, Jens

AU - Schirmacher, Peter

AU - Pinna, Federico

AU - Breuhahn, Kai

PY - 2018/5

Y1 - 2018/5

N2 - The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the basolateral cell polarity complex protein scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison with HCC cells stably expressing wild-type Scrib (ScribWT), mutated Scrib with enforced cytoplasmic enrichment (ScribP305L) induced AKT signaling through the destabilization of phosphatase and tensin homolog (PTEN) and PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). Cytoplasmic ScribP305L stimulated a gene signature and a phenotype characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. ScribP305L-dependent invasion was mediated by the activator protein 1 (AP-1) constituents ATF2 and JunB through induction of paracrine-acting secreted protein acidic and cysteine-rich (SPARC). Coexpression of ScribP305L and the oncogene c-MYC through hydrodynamic gene delivery in mouse livers promoted tumor formation and increased abundance of pAKT, pATF2, and SPARC in comparison with controls. Finally, cytoplasmic Scrib localization correlated with AKT and ATF2 phosphorylation in human HCC tissues, and the ScribP305L-dependent gene signature was enriched in cancer patients with poor prognosis. Conclusion: Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination through specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patients with higher risk for the development of metastasis. (Hepatology 2018;67:1842-1856).

AB - The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the basolateral cell polarity complex protein scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison with HCC cells stably expressing wild-type Scrib (ScribWT), mutated Scrib with enforced cytoplasmic enrichment (ScribP305L) induced AKT signaling through the destabilization of phosphatase and tensin homolog (PTEN) and PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). Cytoplasmic ScribP305L stimulated a gene signature and a phenotype characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. ScribP305L-dependent invasion was mediated by the activator protein 1 (AP-1) constituents ATF2 and JunB through induction of paracrine-acting secreted protein acidic and cysteine-rich (SPARC). Coexpression of ScribP305L and the oncogene c-MYC through hydrodynamic gene delivery in mouse livers promoted tumor formation and increased abundance of pAKT, pATF2, and SPARC in comparison with controls. Finally, cytoplasmic Scrib localization correlated with AKT and ATF2 phosphorylation in human HCC tissues, and the ScribP305L-dependent gene signature was enriched in cancer patients with poor prognosis. Conclusion: Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination through specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patients with higher risk for the development of metastasis. (Hepatology 2018;67:1842-1856).

UR - https://www.scopus.com/pages/publications/85041383608

U2 - 10.1002/hep.29669

DO - 10.1002/hep.29669

M3 - Journal articles

C2 - 29152770

AN - SCOPUS:85041383608

SN - 0270-9139

VL - 67

SP - 1842

EP - 1856

JO - Hepatology

JF - Hepatology

IS - 5

ER -

Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness

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