Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France; Functional Genomics of Solid Tumors Laboratory, équipe Labellisée Ligue Nationale Contre le Cancer, Paris, France.
Service d'Anatomopathologie, Hôpital Henri Mondor, APHP, Institut Mondor de Recherche Biomédicale, Créteil, France.
J Hepatol. 2023 Sep;79(3):704-716. doi: 10.1016/j.jhep.2023.05.004. Epub 2023 May 16.
BACKGROUND & AIMS: Recurrent somatic mutations of the RPS6KA3 gene encoding for the serine/threonine kinase RSK2 were identified in hepatocellular carcinomas (HCCs), suggesting its tumour-suppressive function. Our goal was to demonstrate the tumour suppressor role of RSK2 in the liver and investigate the functional consequences of its inactivation.
We analysed a series of 1,151 human HCCs for RSK2 mutations and 20 other driver genetic alterations. We then modelled RSK2 inactivation in mice in various mutational contexts recapitulating or not those naturally found in human HCC, using transgenic mice and liver-specific carcinogens. These models were monitored for liver tumour appearance and subjected to phenotypic and transcriptomic analyses. Functional consequences of RSK2 rescue were also investigated in a human RSK2-deficient HCC cell line.
RSK2-inactivating mutations are specific to human HCC and frequently co-occur with AXIN1-inactivating or β-catenin-activating mutations. Modelling of these co-occurrences in mice showed a cooperative effect in promoting liver tumours with transcriptomic profiles recapitulating those of human HCCs. By contrast, there was no cooperation in liver tumour induction between RSK2 loss and BRAF-activating mutations chemically induced by diethylnitrosamine. In human liver cancer cells, we also showed that RSK2 inactivation confers some dependency to the activation of RAS/MAPK signalling that can be targeted by MEK inhibitors.
Our study demonstrates the tumour suppressor role of RSK2 and its specific synergistic effect in hepatocarcinogenesis when its loss of function is specifically combined with AXIN1 inactivation or β-catenin activation. Furthermore, we identified the RAS/MAPK pathway as a potential therapeutic target for RSK2-inactivated liver tumours.
This study demonstrated the tumour suppressor role of RSK2 in the liver and showed that its inactivation specifically synergises with AXIN1 inactivation or β-catenin activation to promote the development of HCC with similar transcriptomic profiles as found in humans. Furthermore, this study highlights that activation of the RAS/MAPK pathway is one of the key signalling pathways mediating the oncogenic effect of RSK2 inactivation that can be targeted with already available anti-MEK therapies.
在肝细胞癌（HCC）中发现编码丝氨酸/苏氨酸激酶 RSK2 的 RPS6KA3 基因的反复体细胞突变，提示其具有肿瘤抑制功能。我们的目标是证明 RSK2 在肝脏中的肿瘤抑制作用，并研究其失活的功能后果。
我们分析了一系列 1151 例人类 HCC 中 RSK2 突变和 20 种其他驱动基因突变。然后，我们在各种突变背景下，使用转基因小鼠和肝特异性致癌物，在模拟或不模拟人类 HCC 中自然发生的突变的情况下，对 RSK2 失活进行了建模。监测这些模型的肝肿瘤出现情况，并进行表型和转录组分析。我们还在一个人 RSK2 缺陷 HCC 细胞系中研究了 RSK2 恢复的功能后果。
RSK2 失活突变是人类 HCC 的特异性，并且经常与 AXIN1 失活或 β-catenin 激活突变同时发生。在小鼠中模拟这些同时发生的情况表明，在转录组谱上与人类 HCC 相吻合的情况下，协同促进肝肿瘤的发生。相比之下，在由二乙基亚硝胺化学诱导的 RSK2 缺失与 BRAF 激活突变之间，在肝肿瘤诱导中没有协同作用。在人类肝癌细胞中，我们还表明 RSK2 失活赋予了对 RAS/MAPK 信号通路的激活的一些依赖性，该依赖性可以被 MEK 抑制剂靶向。
我们的研究证明了 RSK2 的肿瘤抑制作用及其在肝癌发生中的特定协同作用，当 RSK2 功能丧失与 AXIN1 失活或 β-catenin 激活特异性结合时。此外，我们确定了 RAS/MAPK 通路作为 RSK2 失活肝肿瘤的潜在治疗靶点。
这项研究证明了 RSK2 在肝脏中的肿瘤抑制作用，并表明其失活与 AXIN1 失活或 β-catenin 激活特异性协同作用，促进了与人类相似的转录组谱的 HCC 的发展。此外，这项研究强调了 RAS/MAPK 通路的激活是介导 RSK2 失活的致癌作用的关键信号通路之一，可以用现有的抗 MEK 治疗来靶向。
