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 baso-lateral cell polarity complex protein Scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison to HCC cells stably expressing wildtype 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, which were characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. Scrib^P305L-dependent invasion was mediated by the AP-1 constituents ATF2 and JunB via induction of paracrine-acting secreted protein acidic and cysteine rich (SPARC). Co-expression of Scrib^P305L and the oncogene c-MYC via hydrodynamic gene delivery in mouse livers promoted tumor formation and increased pAKT, pATF2, and SPARC abundance in comparison to controls. Lastly, 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 via specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patient groups with higher risk for the development of metastasis. This article is protected by copyright. All rights reserved.

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