Linking chronic inflammation with tumor suppressor gene inactivation in liver cancer

将慢性炎症与肝癌中的肿瘤抑制基因失活联系起来

• 批准号: 493697503
• 负责人: Professorin Dr. Stephanie Rössler
• 金额: --
• 依托单位: Pathologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/493697503?language=en
• 关键词: Linking; chronic; inflammation; tumor; suppressor

In previous work using an integrative genomic and transcriptomic approach, we showed that in HCC loss of chromosome 8p is observed in 45% of tumors and associated with poor patient outcome. In addition, we identified SORBS3 and SH2D4A as two novel tumor suppressor genes on chromosome 8p, which are associated with expression patterns characteristic of reduced interleukin-6 (IL-6) signaling. IL-6 signaling is critically involved in inflammation, and especially in tumorigenesis and metastasis of HCC suggesting that SORBS3 and SH2D4A may modulate the immune cell induced IL-6/STAT3 signaling in liver cancer cells. Recently, we demonstrated that SH2D4A and SORBS3 functionally cooperate to inhibit IL-6/STAT3 signaling and HCC cell growth. In addition, we demonstrated that SH2D4A directly interacts with the mitochondrial protein prohibitin 1 (PHB1) and SH2D4A knockdown alters basal mitochondrial respiration and mitochondrial ATP production. The usage of the selective PHB inhibitor FL3 led to a repression of these effects suggesting that SH2D4A may be involved in mitochondrial function and inhibition by FL3 may rescue the effects of SH2D4A loss in tumor cells. Thus, we were able to functionally characterize and molecularly dissect the role of the chromosome 8p tumor suppressor gene SH2D4A. In the next stage of the project, we aim to broaden the project by identification of genes essential in chromosome 8p deleted HCCs which are associated with tumor progression and response to the tumor microenvironment. To this end, we have identified FOXM1 to be essential in HCC cells with wildtype chromosome 8p, whereas PARD3/PARD6B were essential in HCC cells with chromosome 8p deletion. In the here proposed project, we aim to dissect essential genes in HCC with or without chromosome 8p deletion in regard to inflammatory IL-6 signaling. Thus, we will functionally dissect the role of FOXM1 (Aim 1) and of PARD3/PARD6B (Aim 2) in HCCs with or without chromosome 8p deletion. Furthermore, we will identify chromosome 8p associated essential genes using our engineered chromosome 8p deleted and corresponding wildtype cells with or without IL-6 exposure (Aim 3) and functionally dissect candidate genes essential in HCC with chromosome 8p deletion and STAT3 activation.

在之前使用整合基因组和转录组方法的工作中，我们发现在 HCC 中，45% 的肿瘤中观察到 8p 染色体缺失，并且与患者预后不良相关。此外，我们还发现 SORBS3 和 SH2D4A 是 8p 染色体上的两个新型肿瘤抑制基因，它们与白细胞介素 6 (IL-6) 信号传导减少的表达模式特征相关。 IL-6 信号传导与炎症密切相关，尤其是 HCC 的肿瘤发生和转移，表明 SORBS3 和 SH2D4A 可能调节肝癌细胞中免疫细胞诱导的 IL-6/STAT3 信号传导。最近，我们证明 SH2D4A 和 SORBS3 在功能上协同抑制 IL-6/STAT3 信号传导和 HCC 细胞生长。此外，我们证明 SH2D4A 直接与线粒体蛋白抑制蛋白 1 (PHB1) 相互作用，并且 SH2D4A 敲低会改变基础线粒体呼吸和线粒体 ATP 产生。选择性 PHB 抑制剂 FL3 的使用导致这些效应受到抑制，表明 SH2D4A 可能参与线粒体功能，并且 FL3 的抑制可能会挽救肿瘤细胞中 SH2D4A 缺失的影响。因此，我们能够对 8p 号染色体抑癌基因 SH2D4A 的功能进行功能表征和分子剖析。在该项目的下一阶段，我们的目标是通过鉴定 8p 染色体缺失的 HCC 中必需的基因来扩大该项目，这些基因与肿瘤进展和对肿瘤微环境的反应相关。为此，我们确定 FOXM1 在具有野生型 8p 染色体的 HCC 细胞中是必需的，而 PARD3/PARD6B 在具有 8p 染色体缺失的 HCC 细胞中是必需的。在此提出的项目中，我们的目标是剖析具有或不具有 8p 染色体缺失的 HCC 中与炎症 IL-6 信号传导相关的必需基因。因此，我们将从功能上剖析 FOXM1（目标 1）和 PARD3/PARD6B（目标 2）在有或没有染色体 8p 缺失的 HCC 中的作用。此外，我们将使用我们的工程化 8p 缺失染色体和相应的野生型细胞（有或没有 IL-6 暴露）来识别 8p 染色体相关的必需基因（目标 3），并通过功能性剖析具有 8p 染色体缺失和 STAT3 激活的 HCC 中必需的候选基因。