肝癌是世界上第六种最常见的癌症类型，也是第五个导致癌症死亡的主要原因。Scribble在大多数肿瘤中被证明具有肿瘤抑制基因的作用。我们先前的研究报告中指出，Scribble的下调或错位足以引发乳腺肿瘤发生和非小细胞肺 癌（NSCLC）。最近的报道显示，Scribble在肝细胞癌（HCC）中的表达水平较高。我们的目标是研究Scribble是如何被上调并在HCC中具有矛盾的作用的。利用四氯化碳（CCl4）诱导的肝纤维化小鼠模型系统，我们展示了Scribble的过度表达，并可能保护小鼠免受肝纤维化的影响。令人意外的是，在肝细胞癌小鼠模型的晚期（DEN与CCl4诱导的）中，我们发现Scribble有成为肿瘤驱动基因的潜力。此外，我们观察到，在HCC肿瘤中，Scribble的表达水平更高，且存在着上调的野生型p53。最重要的是，核转位的Scribble可以与p53相互作用，导致p53的稳定性和转录活性增强。从机制上讲，我们的数据表明，Scribble可能通过促进p53通过p53上调的凋亡调节子（PUMA）介导的华尔堡（Warburg）效应来推动HCC的进展。我们的数据揭示了肝纤维化特异性基因极性基因Scribble表达的分子基础。有趣的是，在从纤维化向肝硬化再到肝癌的过程中，它的核转位促进了野生型p53介导的癌症代谢转换和肿瘤进展。总之，我们证明了Scribble在肝纤维化中被上调并起到保护作用，同时在基于纤维化的肝癌发生中似乎充当了肿瘤驱动基因的角色。版权所有© 2023 Elsevier B.V. 发布。

Liver cancer is the sixth most common type of cancer and the fifth leading cause of cancer mortality worldwide. Scribble has been shown to function as a neoplastic tumor suppressor gene in most tumors. Our previous studies reported that down-regulation or mislocalization of Scribble was sufficient to initiate mammary tumorigenesis and NSCLC. Recently, it was reported that Scribble was highly expressed in hepatocellular carcinoma (HCC). We aim to study how it was up-regulated and the contradictory role of Scribble in HCC.Using a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis system, we showed that Scribble was over-expressed and which may protect the mice against hepatic fibrosis. Unexpectedly, we found out the potential for Scribble to act as a tumor driver at the advanced stage of N-nitrosodiethylamine (DEN) plus CCl4 induced HCC mice model in vivo. In addition, we observed even higher expression of Scribble in HCC tumors harboring elevated levels of wild-type p53. Most importantly, nuclear translocated Scribble could interact with p53, which lead to enhanced stability and transcriptional activity of p53. Mechanistically, our data suggested that Scribble might drive HCC progression by promoting metabolic regulation of p53 through p53-upregulated modulator of apoptosis (PUMA)-mediated Warburg effect.Our data identified the molecular basis of hepatic fibrosis-specific gene expression of polarity gene, such as Scribble. Interestingly, with the progression from fibrosis to cirrhosis to HCC, its nuclear translocation promoted a wild-type p53-mediated cancer metabolic switch and tumor progression in HCC. Taken together, we demonstrated that Scribble was up-regulated and served a protective role in liver fibrosis, while also apparently acting as a tumor driver in fibrosis-dependent hepatocarcinogenesis.Copyright © 2023. Published by Elsevier B.V.