Prognostic significance of SOCS1 and SOCS3 tumor suppressors and oncogenic signaling pathway genes in hepatocellular carcinoma
Prognostic significance of SOCS1 and SOCS3 tumor suppressors and oncogenic signaling pathway genes in hepatocellular carcinoma
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DOI：
10.1186/s12885-020-07285-3
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发表时间：
2020-08-17
期刊：
影响因子：
3.8
通讯作者：
Ilangumaran, Subburaj
中科院分区：
文献类型：
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作者：
Khan, Md Gulam Musawwir;Ghosh, Amit;Ilangumaran, Subburaj
背景 由于频繁的表观遗传抑制，SOCS1 和 SOCS3 基因被认为是肝细胞癌 (HCC) 中的肿瘤抑制基因。与这一观点一致，缺乏 SOCS1 或 SOCS3 的小鼠表现出对二乙基亚硝胺 (DEN) 诱导的 HCC 的易感性增加。由于 SOCS1 和 SOCS3 是细胞因子和生长因子信号传导的重要调节因子，它们的丢失可能会激活致癌信号传导途径。因此，我们研究了SOCS1/SOCS3与关键致癌信号通路基因之间的相关性及其在HCC中的预后意义。方法从cBioportal平台检索包含临床和转录组数据的HCC癌症基因组图谱数据集。使用GraphPad PRISM软件评估SOCS1或SOCS3的表达与致癌途径基因之间的相关性。使用 UALCAN 平台评估负相关基因对患者生存的影响，并对缺乏 Socs1 或 Socs3 的小鼠的再生肝脏和 DEN 诱导的 HCC 组织中的表达进行定量。最后，使用Cox比例风险模型评估SOCS1和SOCS3与选定致癌信号通路的基因结合时的预测潜力。结果SOCS1在HCC和邻近正常组织之间的表达具有可比性，但较高的SOCS1表达预示着良好的预后。相比之下，SOCS3 在 HCC 中的表达显着较低，但缺乏预测潜力。 SOCS1或SOCS3表达与细胞周期关键基因、受体酪氨酸激酶、生长因子和MAPK信号通路的相关性多为正相关，而非负相关。在负相关基因中，只有少数基因在 HCC 中表达升高并预测生存。许多PI3K通路基因与SOCS1和/或SOCS3表现出相互排他性，并表现出独立的预测能力。在与 SOCS1 和/或 SOCS3 负相关的基因中，只有 CDK2 和 AURKA 在肝细胞特异性 Socs1 或 Socs3 缺陷小鼠的肝脏再生和 DEN 诱导的肿瘤中显示出相应的调节，并预测患者的生存。 Cox比例风险模型确定SOCS1或SOCS3与CXCL8和DAB2的组合具有高度预测性。结论SOCS1在HCC中的表达具有独立的预后价值，而SOCS3的表达则没有。当与其他致癌信号通路基因结合时，SOCS1 表达的预测潜力会增加。
BackgroundSOCS1 and SOCS3 genes are considered tumor suppressors in hepatocellular carcinoma (HCC) due to frequent epigenetic repression. Consistent with this notion, mice lacking SOCS1 or SOCS3 show increased susceptibility to diethylnitrosamine (DEN)-induced HCC. As SOCS1 and SOCS3 are important regulators of cytokine and growth factor signaling, their loss could activate oncogenic signaling pathways. Therefore, we examined the correlation between SOCS1/SOCS3 and key oncogenic signaling pathway genes as well as their prognostic significance in HCC.MethodsThe Cancer Genome Atlas dataset on HCC comprising clinical and transcriptomic data was retrieved from the cBioportal platform. The correlation between the expression of SOCS1 or SOCS3 and oncogenic pathway genes was evaluated using the GraphPad PRISM software. The inversely correlated genes were assessed for their impact on patient survival using the UALCAN platform and their expression quantified in the regenerating livers and DEN-induced HCC tissues of mice lacking Socs1 or Socs3. Finally, the Cox proportional hazards model was used to evaluate the predictive potential of SOCS1 and SOCS3 when combined with the genes of select oncogenic signaling pathways.ResultsSOCS1 expression was comparable between HCC and adjacent normal tissues, yet higher SOCS1 expression predicted favorable prognosis. In contrast, SOCS3 expression was significantly low in HCC, yet it lacked predictive potential. The correlation between SOCS1 or SOCS3 expression and key genes of the cell cycle, receptor tyrosine kinase, growth factor and MAPK signaling pathways were mostly positive than negative. Among the negatively correlated genes, only a few showed elevated expression in HCC and predicted survival. Many PI3K pathway genes showed mutual exclusivity with SOCS1 and/or SOCS3 and displayed independent predictive ability. Among genes that negatively correlated with SOCS1 and/or SOCS3, only CDK2 and AURKA showed corresponding modulations in the regenerating livers and DEN-induced tumors of hepatocyte-specific Socs1 or Socs3 deficient mice and predicted patient survival. The Cox proportional hazards model identified the combinations of SOCS1 or SOCS3 with CXCL8 and DAB2 as highly predictive.ConclusionsSOCS1 expression in HCC has an independent prognostic value whereas SOCS3 expression does not. The predictive potential of SOCS1 expression is increased when combined with other oncogenic signaling pathway genes.