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).

中文翻译：

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细胞极性因子 Scribble 的细胞质定位支持肝肿瘤形成和肿瘤细胞侵袭

上皮细胞极性的丧失在肝癌的发生发展中起重要作用。然而，支持肿瘤发生和进展的具体分子机制知之甚少。在这项研究中，来自肝细胞癌 (HCC) 患者的组织样本的转录组数据和免疫荧光染色显示，与基底外侧细胞极性复合蛋白涂鸦 (Scrib) 的细胞质定位相关的过度表达与 HCC 患者的不良预后相关。与稳定表达野生型 Scrib (ScribWT) 的 HCC 细胞相比，具有强制细胞质富集的突变 Scrib (ScribP305L) 通过磷酸酶和张力蛋白同源物 (PTEN) 和 PH 结构域和富含亮氨酸重复蛋白磷酸酶 1 的不稳定来诱导 AKT 信号传导（ PHLPP1)。细胞质 ScribP305L 刺激了上皮间质转化 (EMT) 和 HCC 细胞侵袭性的基因特征和表型特征。ScribP305L 依赖性侵袭由激活蛋白 1 (AP-1) 成分 ATF2 和 JunB 通过诱导旁分泌作用的分泌蛋白酸性和富含半胱氨酸 (SPARC) 介导。与对照组相比，ScribP305L 和致癌基因 c-MYC 通过流体动力学基因传递在小鼠肝脏中的共表达促进了肿瘤形成并增加了 pAKT、pATF2 和 SPARC 的丰度。最后，细胞质 Scrib 定位与人 HCC 组织中的 AKT 和 ATF2 磷酸化相关，并且 ScribP305L 依赖性基因特征在预后不良的癌症患者中富集。结论：由于 Scrib 的过度表达和细胞质富集，肝细胞极性的扰动通过特定的分子机制支持肿瘤起始和 HCC 细胞传播。本研究中鉴定的生物标志物特征可用于鉴定发生转移风险较高的 HCC 患者。（肝病学 2018；67：1842-1856）。