Immunology graduate program, Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, University of Sherbrooke, 3001 North 12th avenue, Sherbrooke, QC, J1H 5N4, Canada.
Cell biology graduate program, Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, University of Sherbrooke, 3001 North 12th avenue, Sherbrooke, QC, J1H 5N4, Canada.
BMC Cancer. 2020 Aug 17;20(1):774. doi: 10.1186/s12885-020-07285-3.
SOCS1 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.
The 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.
SOCS1 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.
SOCS1 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.
SOCS1 和 SOCS3 基因被认为是肝细胞癌 (HCC) 的肿瘤抑制因子，因为它们经常受到表观遗传抑制。与这一观点一致的是，缺乏 SOCS1 或 SOCS3 的小鼠对二乙基亚硝胺 (DEN) 诱导的 HCC 更敏感。由于 SOCS1 和 SOCS3 是细胞因子和生长因子信号的重要调节剂，它们的缺失可能会激活致癌信号通路。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。
从 cBioportal 平台检索包含临床和转录组数据的 HCC 的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 平台评估反相关基因对患者生存的影响，并在缺乏 Socs1 或 Socs3 的小鼠的再生肝脏和 DEN 诱导的 HCC 组织中定量这些基因的表达。最后，使用 Cox 比例风险模型来评估 SOCS1 和 SOCS3 与选定的致癌信号通路基因结合时的预测潜力。
SOCS1 表达在 HCC 与相邻正常组织之间无差异，但 SOCS1 高表达预示着良好的预后。相反，SOCS3 在 HCC 中表达显著降低，但缺乏预测能力。SOCS1 或 SOCS3 表达与细胞周期、受体酪氨酸激酶、生长因子和 MAPK 信号通路的关键基因之间的相关性大多为正相关而非负相关。在负相关基因中，只有少数在 HCC 中表达上调并预测生存。许多 PI3K 通路基因与 SOCS1 和/或 SOCS3 相互排斥，具有独立的预测能力。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 缺失小鼠的再生肝脏和 DEN 诱导的肿瘤中表现出相应的调节作用，并预测患者的生存。Cox 比例风险模型确定了 SOCS1 或 SOCS3 与 CXCL8 和 DAB2 的组合具有高度预测性。
HCC 中 SOCS1 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 表达的预测潜力增加。
