Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
Cancer Sci. 2021 Sep;112(9):3455-3468. doi: 10.1111/cas.15043. Epub 2021 Jul 12.
Clinical reports indicate that gastric cancer (GC) has a high mortality rate, but its pathological mechanism remains poorly understood. This work integrated bioinformatics analysis with experimental verification to explore novel biomarkers of gastric cancer. First, weighted gene coexpression network analysis was applied to screen significant genes correlated with GC development. Gene set enrichment analysis was also used to unearth the most relevant biological functions of significant genes. As a result, we discovered homeobox C9 (HOXC9) as a novel oncogene in GC, primarily through negatively regulating immune response. High expression of HOXC9 predicted a poor prognosis in GC patients, and knocking down HOXC9 efficiently enhanced the interferon-gamma (IFNγ)-dependent apoptosis in two GC cell lines as well as organoids from patients. Furthermore, cleaved caspase-3/7 and phosphorylated signal transducer and activator of transcription 1 (p-STAT1) were also significantly enhanced in HOXC9 knockdown cells and organoids treated with IFNγ. Mechanistically, we found that HOXC9 inhibited the death-associated protein kinase 1 (DAPK1) and its downstream retinoic acid-inducible gene-I (RIG1) to generate GC IFNγ resistance. In summary, we identified and confirmed that HOXC9 generates IFNγ resistance in GC by inhibiting the DAPK1/RIG1/p-STAT1 axis.
临床报告表明胃癌（GC）死亡率较高，但其病理机制仍不清楚。本研究通过整合生物信息学分析和实验验证，探索胃癌的新型生物标志物。首先，应用加权基因共表达网络分析筛选与 GC 发生发展相关的显著基因。同时，还进行了基因集富集分析以揭示显著基因最相关的生物学功能。结果发现，同源盒 C9（HOXC9）是 GC 中的一种新型癌基因，主要通过负向调控免疫反应发挥作用。HOXC9 高表达预示 GC 患者预后不良，敲低 HOXC9 可有效增强两种 GC 细胞系以及患者来源的类器官中干扰素-γ（IFNγ）依赖性凋亡。此外，HOXC9 敲低细胞和用 IFNγ处理的类器官中，cleaved caspase-3/7 和磷酸化信号转导和转录激活因子 1（p-STAT1）也显著增强。在机制上，我们发现 HOXC9 通过抑制死亡相关蛋白激酶 1（DAPK1）及其下游视黄酸诱导基因-I（RIG1）来产生 GC IFNγ 抵抗。总之，我们鉴定并证实 HOXC9 通过抑制 DAPK1/RIG1/p-STAT1 轴在 GC 中产生 IFNγ 抵抗。
