Functional characterization of the chromosome 8p tumor suppressor gene interaction with tumor microenvironment in human hepatocellular carcinoma

人肝细胞癌中染色体 8p 抑癌基因与肿瘤微环境相互作用的功能特征

• 批准号: 260074059
• 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
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/260074059?language=en
• 关键词: Functional; characterization; chromosome; 8p; tumor

Liver cancer is the third leading cause of cancer death worldwide and more than 85% of all liver cancer cases are hepatocellular carcinoma (HCC). The high mortality rate of HCC is mainly caused by metastasis or by de novo multifocal tumor formation in the diseased liver. In previous work using an integrative genomic and transcriptomic approach, I have shown that loss of chromosome 8p is observed in 45% of patients and is associated with poor outcome. A 10-gene 'driver' signature that predicts outcome in HCC contains six potential tumor suppressor genes (TSGs) on chromosome 8p, the bona fide TSG DLC1 and two novel TSGs, namely SORBS3 and SH2D4A. Clonogenicity assays, cell migration assays and xenograft mouse models confirmed the tumor suppressor function of SH2D4A and SORBS3. Therefore, this unbiased approach was effective in identifying a prognostic gene signature and two novel TSGs. My unpublished studies show that the gene expression profiles of patients with chromosome 8p deletion exhibit expression patterns characteristic of inhibition of interleukin-6 (IL-6) signaling. In addition, I was able to show that SH2D4A functions by repressing STAT3 signaling, whereas, SORBS3 inhibits IL-6 signaling through increase of estrogen receptor alpha (ERalpha) signaling. Thus, the first objective of this application is to elucidate the role of the recently identified TSGs SORBS3 and SH2D4A in IL-6 signaling. IL-6 signaling has been shown to be critically involved in inflammation, and especially in tumorigenesis and metastasis of HCC suggesting that SORBS3 and SH2D4A may functionally collaborate to inhibit IL-6 signaling. To this end, it will be functionally analyzed how chromosome 8p TSGs SORBS3 and SH2D4A modulate IL-6 signaling. In addition, I will investigate the effect of loss of a single versus multiple TSGs and determine the functional consequence of the loss of multiple TSGs. To elucidate the influence of SORBS3 and SH2D4A on the tumor microenvironment, an orthotopic mouse model and HCC patient samples will be studied in regard to tumor cell growth, immune cell infiltration and cytokine profiles. These findings may lead to the development of novel approaches for HCC patients with reduced SORBS3 and SH2D4A expression, thus, leading to improved HCC treatment and patient survival.

肝癌是世界范围内癌症死亡的第三大原因，超过85%的肝癌病例是肝细胞癌（HCC）。肝癌的高死亡率主要是由于转移或在病变肝脏中的多灶性肿瘤形成所引起的。在以前的工作中，使用一个整合的基因组和转录组学的方法，我已经表明，染色体8 p的损失是在45%的患者中观察到的，并与不良的结果。一个10个基因的“驱动”签名，预测肝癌的结果包含6个潜在的肿瘤抑制基因（TSG）在染色体8 p，真正的TSG DLC 1和两个新的TSG，即SORBS 3和SH 2D 4A。克隆形成试验、细胞迁移试验和异种移植小鼠模型证实了SH 2D 4A和SORBS 3的肿瘤抑制功能。因此，这种无偏的方法在鉴定预后基因标签和两种新的TSG中是有效的。我未发表的研究表明，染色体8 p缺失患者的基因表达谱表现出抑制白细胞介素-6（IL-6）信号传导的特征性表达模式。此外，我能够证明SH 2D 4A通过抑制STAT 3信号传导发挥作用，而SORBS 3通过增加雌激素受体α（ER α）信号传导抑制IL-6信号传导。因此，本申请的第一个目的是阐明最近鉴定的TSGSORBS 3和SH 2D 4A在IL-6信号传导中的作用。IL-6信号转导已被证明与炎症，特别是HCC的肿瘤发生和转移密切相关，这表明SORBS 3和SH 2D 4A可能在功能上协同抑制IL-6信号转导。为此，将从功能上分析染色体8 p TSGs SORBS 3和SH 2D 4A如何调节IL-6信号传导。此外，我将研究单一与多个TSG的损失的影响，并确定多个TSG的损失的功能后果。为了阐明SORBS 3和SH 2D 4A对肿瘤微环境的影响，将研究原位小鼠模型和HCC患者样品的肿瘤细胞生长、免疫细胞浸润和细胞因子谱。这些发现可能导致SORBS 3和SH 2D 4A表达降低的HCC患者的新方法的开发，从而改善HCC治疗和患者生存。