Liu Guanglong, Huang Kaihua, Lin Bingheng, Zhang Renyi, Zhu Yu, Dong Xiaoyu, Wu Chaosong, Zhu Huacong, Lin Jiabao, Bao Ming, Li Shenglong, Zheng Ruinian, Jing Fangyan
Department of Pathology, Nanfang Hospital and School of Basic Medical Sciences, Southern Medical University, China.
Department of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167690. doi: 10.1016/j.bbadis.2025.167690. Epub 2025 Jan 23.
Pyroptosis and macrophage pro-inflammatory activation play an important role in hepatocellular carcinoma (HCC) progression. However, the specific regulatory mechanisms remain unclear. We identified pyroptosis-related differentially expressed genes (DEGs) based on the GSE4183 and GSE44861 datasets as well as EVenn database. Expression levels of key genes were detected by qRT-PCR. IKZF1 was overexpressed in colon cancer cells and tumor-bearing mice, and its functions were assessed by various cell biology assays in vitro and in vivo. To investigate the interactions between IKZF1 and macrophages, a co-culture system was constructed. The activator RO8191 or inhibitor ruxolitinib of the JAK/STAT pathway was employed to confirm whether IKZF1 inhibited colon cancer development by regulating JAK2/STAT5 pathway. Pyroptosis-related hub genes RBBP7, HSP90AB1, and RBBP4 were highly expressed, while IKZF1, NLRP1, and PYCARD were lowly expressed. These hub genes had good performance in distinguishing colon cancer from controls. Furthermore, overexpression of IKZF1 inhibited tumor growth and promoted pyroptosis. Overexpression of IKZF1 suppressed cell proliferation, metastasis, and inactivated JAK2/STAT5 signaling pathway in colon cancer cells. Furthermore, upregulation of IKZF1 promoted M1 macrophage polarization while inhibiting M2 macrophage polarization in vivo and in vitro by inhibiting the JAK2/STAT5 signaling pathway. This study identifies IKZF1 as a potential biomarker inactivating JAK2/STAT5 pathway for colon cancer.
细胞焦亡和巨噬细胞促炎激活在肝细胞癌（HCC）进展中起重要作用。然而，具体的调控机制仍不清楚。我们基于GSE4183和GSE44861数据集以及EVenn数据库鉴定了细胞焦亡相关的差异表达基因（DEG）。通过qRT-PCR检测关键基因的表达水平。IKZF1在结肠癌细胞和荷瘤小鼠中过表达，其功能通过体外和体内的各种细胞生物学试验进行评估。为了研究IKZF1与巨噬细胞之间的相互作用，构建了共培养系统。采用JAK/STAT途径的激活剂RO8191或抑制剂鲁索替尼来确认IKZF1是否通过调节JAK2/STAT5途径抑制结肠癌的发展。细胞焦亡相关的枢纽基因RBBP7、HSP90AB1和RBBP4高表达，而IKZF1、NLRP1和PYCARD低表达。这些枢纽基因在区分结肠癌和对照方面表现良好。此外，IKZF1的过表达抑制肿瘤生长并促进细胞焦亡。IKZF1的过表达抑制结肠癌细胞的增殖、转移并使JAK2/STAT5信号通路失活。此外，IKZF1的上调通过抑制JAK2/STAT5信号通路在体内和体外促进M1巨噬细胞极化，同时抑制M2巨噬细胞极化。本研究确定IKZF1是一种使结肠癌JAK2/STAT5途径失活的潜在生物标志物。
