Department of Abdominal Oncology, The Cancer Center of the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
Digestive Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong Province 518107, China.
Biochem Pharmacol. 2021 Jul;189:114396. doi: 10.1016/j.bcp.2020.114396. Epub 2020 Dec 25.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a poor 5-year survival rate of approximately 6%, mostly due to poor treatment response and early progression. The S100 gene family participates in various pathophysiological processes in various malignancies. S100A16 is a member of the S100 family, which is abnormally expressed in PDAC; however, its biological functions and mechanisms of action remain unclear. We analysed the Gene Expression Omnibus (GEO) public database and the gene ChIP data collected in our previous study of human PDAC cell line PANC-1 cocultured with M2 macrophages to identify differentially expressed genes (DEGs). Twenty-three overexpressed genes were identified by screening. Then, the selected genes were analysed using The Cancer Genome Atlas (TCGA) database to assess whether they have significant impact on the overall survival (OS) of PDAC patients. Of the 14 DEGs identified, S100A16 was associated with poor prognosis and was selected for further investigation; the results indicate that S100A16 is positively correlated with epithelial-mesenchymal transition (EMT)-related genes in the TCGA dataset. Subsequent in vitro and in vivo experiments demonstrated that S100A16 induces the EMT to promote the metastasis of human PDAC cells and that the effect is mediated by the enhanced expression of TWIST1 and activation of the STAT3 signalling pathway. The antitumour effect of gemcitabine (GEM) was enhanced in combination with S100A16 downregulation. In conclusion, our findings suggest that S100A16 is a novel potential therapeutic target for human PDAC treatment.
胰腺导管腺癌 (PDAC) 是最致命的癌症之一，其 5 年生存率约为 6%，主要原因是治疗反应差和早期进展。S100 基因家族参与各种恶性肿瘤的多种病理生理过程。S100A16 是 S100 家族的成员，在 PDAC 中异常表达；然而，其生物学功能和作用机制尚不清楚。我们分析了基因表达综合数据库 (GEO) 和我们之前研究中收集的人类 PDAC 细胞系 PANC-1 与 M2 巨噬细胞共培养的基因 ChIP 数据，以鉴定差异表达基因 (DEGs)。通过筛选鉴定出 23 个过表达基因。然后，使用癌症基因组图谱 (TCGA) 数据库分析选定的基因，以评估它们是否对 PDAC 患者的总生存 (OS) 有显著影响。在鉴定的 14 个 DEGs 中，S100A16 与不良预后相关，并被选为进一步研究的对象；结果表明，S100A16 与 TCGA 数据集中的上皮间质转化 (EMT) 相关基因呈正相关。随后的体外和体内实验表明，S100A16 通过增强 TWIST1 的表达和激活 STAT3 信号通路诱导 EMT 促进人 PDAC 细胞的转移。与 S100A16 下调联合使用吉西他滨 (GEM) 增强了抗肿瘤作用。总之，我们的研究结果表明，S100A16 是人类 PDAC 治疗的一个新的潜在治疗靶点。
