Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma.
Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma.
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DOI：
10.1002/hep.28684
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发表时间：
2016-09
期刊：
影响因子：
13.5
通讯作者：
Roessler, Stephanie
中科院分区：
文献类型：
--
作者：
Ploeger, Carolin;Waldburger, Nina;Fraas, Angelika;Goeppert, Benjamin;Pusch, Stefan;Breuhahn, Kai;Wang, Xin Wei;Schirmacher, Peter;Roessler, Stephanie
几种慢性炎症性肝病，例如慢性B或丙型肝炎病毒感染和脂肪性肝炎，已被证明易患肝细胞癌（HCC）。在慢性肝病患者中，白细胞介素-6（IL-6）血清水平升高，并且在HCC发展时增加更多。然而，在肝癌发生过程中IL-6信号转导的影响和调节机制仍然不清楚。在这里，我们可以表明染色体8 p缺失患者的基因表达谱与IL-6信号传导增加相关。此外，染色体8 p肿瘤抑制基因SH 2D 4A（含Src同源2结构域4A）和SORBS 3（含Sorbin和Src同源3结构域3）与单个基因相比一起对细胞生长和克隆形成产生更大的抑制。SH 2D 4A和SORBS 3在HCC细胞中的过表达导致IL-6靶基因表达降低，并减少信号转导和转录激活因子3（STAT 3）信号转导。原位和体外免疫共沉淀试验表明，SH 2D 4A直接与STAT 3相互作用，从而将STAT 3保留在细胞质中并抑制STAT 3的转录活性。另一方面，SORBS 3共激活雌激素受体α（ERα）信号传导，间接导致STAT 3信号传导的抑制。在人HCC组织中，SH 2D 4A与浸润性调节性和细胞毒性T细胞群呈正相关，表明在染色体8 p丢失的HCC亚组中具有不同的免疫表型。因此，基因连锁的肿瘤抑制因子SH 2D 4A和SORBS 3在功能上协同抑制HCC中的STAT 3信号传导。染色体8 p肿瘤抑制基因SORBS 3和SH 2D 4A在物理上和功能上相连，并提供了抑制HCC细胞中STAT 3介导的IL-6信号传导的分子机制。
Several chronic inflammatory liver diseases, e.g. chronic hepatitis B or C viral infection and steatohepatitis, have been shown to predispose to the development of hepatocellular carcinoma (HCC). In patients with chronic liver disease, interleukin-6 (IL-6) serum levels are elevated and increase even more when HCC develops. However, the impact and regulatory mechanisms of IL-6 signaling during hepatocarcinogenesis are still poorly defined. Here, we could show that gene expression profiling of patients with chromosome 8p loss correlated with increased IL-6 signaling. In addition, the chromosome 8p tumor suppressor genes SH2D4A (Src homology 2 domain containing 4A) and SORBS3 (Sorbin and Src homology 3 domain containing 3) together exerted greater inhibition of cell growth and clonogenicity compared to a single gene. Overexpression of SH2D4A and SORBS3 in HCC cells led to decreased IL-6 target gene expression and reduced Signal Transducer and Activator of Transcription 3 (STAT3) signaling. In situ and in vitro co-immunoprecipitation assays revealed that SH2D4A directly interacts with STAT3 thereby retaining STAT3 in the cytoplasm and inhibiting STAT3 transcriptional activity. On the other hand, SORBS3 co-activated estrogen receptor α (ERα) signaling leading indirectly to repression of STAT3 signaling. In human HCC tissues, SH2D4A was positively associated with infiltrating regulatory and cytotoxic T cell populations suggesting distinct immunophenotypes in HCC subgroups with chromosome 8p loss. Thus, the genetically linked tumor suppressors SH2D4A and SORBS3 functionally cooperate to inhibit STAT3 signaling in HCC. The chromosome 8p tumor suppressor genes SORBS3 and SH2D4A are physically and functionally linked and provide a molecular mechanism of inhibiting STAT3-mediated IL-6 signaling in HCC cells.
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