Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Guangdong Province Key laboratory of Malignant Tumour Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Theranostics. 2020 Aug 18;10(22):10345-10359. doi: 10.7150/thno.42069. eCollection 2020.
In addition to protein tyrosine kinases, accumulating evidence has shown that protein tyrosine phosphatases (PTPs) are suitable therapeutic targets in cancer. PRL-3 is a PTP member that has been well studied in many malignant tumours. The goal of the present study was to elucidate the role of PRL-3 in hepatocellular carcinoma (HCC), which remains largely unknown. Bioinformatic and immunohistochemical analyses were performed to analyse PRL-3 expression in HCC tissue samples and determine its clinical relevance. PRL-3 gene copy number variations were evaluated by bioinformatic analysis and quantitative-genomic polymerase chain reaction. The biological functions of PRL-3 were investigated and vitro. Gene microarray assays, RT-qPCR, western blotting and luciferase experiments were performed to identify the downstream effectors of PRL-3 that mediate its functions in HCC. PRL-3 expression was upregulated in HCC samples from public databases and in cohort samples from our centre. High PRL-3 expression was associated with poor prognosis. Copy number gains and amplification of chromosome 8q24.3 in HCC were determined to be positively correlated with the PRL-3 overexpression. PRL-3 overexpression promoted HCC cell proliferation, migration and adhesion, while its loss had the opposite effects. Further study showed that focal adhesion kinase (FAK) was co-amplified and co-expressed with PRL-3 in HCC. Interestingly, PRL-3 also promoted the phosphorylation of FAK, which subsequently mediated the oncogenic functions of PRL-3 in HCC cells. Moreover, TGFB1 was identified as a downstream molecule of PRL-3. TGF-β signalling was shown to mediate the PRL-3-induced activation of FAK. Furthermore, the p38 and PI3K/AKT pathways were observed to mediate the PRL-3-induced expression of TGFB1 and the subsequent activation of FAK, while the activation of FAK in turn stimulated activation of the p38 and PI3K/AKT pathways, forming a PRL-3-triggered AKT/p38/TGFB1/FAK positive feedback loop. Collectively, our findings indicate that the PTP PRL-3 plays a crucial role in the progression of HCC and provides an example of how co-amplified genes work together in HCC.
除了蛋白酪氨酸激酶外，越来越多的证据表明，蛋白酪氨酸磷酸酶（PTPs）是癌症治疗的合适靶点。PRL-3 是一种 PTP 成员，在许多恶性肿瘤中得到了很好的研究。本研究的目的是阐明 PRL-3 在肝细胞癌（HCC）中的作用，目前对此知之甚少。通过生物信息学和免疫组织化学分析，分析 HCC 组织样本中 PRL-3 的表达情况，并确定其临床相关性。通过生物信息学分析和定量基因组聚合酶链反应评估 PRL-3 基因拷贝数的变化。在体研究了 PRL-3 的生物学功能。进行基因微阵列分析、RT-qPCR、western blot 和荧光素酶实验，以鉴定 PRL-3 在 HCC 中发挥功能的下游效应物。PRL-3 的表达在公共数据库中的 HCC 样本和我们中心的队列样本中上调。高 PRL-3 表达与预后不良相关。在 HCC 中，8q24.3 染色体的拷贝数增加和扩增与 PRL-3 的过表达呈正相关。PRL-3 的过表达促进 HCC 细胞的增殖、迁移和黏附，而其缺失则产生相反的效果。进一步的研究表明，粘着斑激酶（FAK）在 HCC 中与 PRL-3 共扩增和共表达。有趣的是，PRL-3 还促进了 FAK 的磷酸化，随后介导了 PRL-3 在 HCC 细胞中的致癌功能。此外，TGFB1 被鉴定为 PRL-3 的下游分子。TGF-β 信号介导了 PRL-3 诱导的 FAK 激活。此外，还观察到 p38 和 PI3K/AKT 途径介导 PRL-3 诱导的 TGFB1 表达和随后的 FAK 激活，而 FAK 的激活反过来又刺激了 p38 和 PI3K/AKT 途径的激活，形成了 PRL-3 触发的 AKT/p38/TGFB1/FAK 正反馈回路。综上所述，我们的研究结果表明，PTP PRL-3 在 HCC 的进展中起着关键作用，并提供了一个例证，说明共扩增基因如何在 HCC 中协同作用。
