Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, PR China; Department of Oncology, Shanghai Medical College, Fudan University, PR China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China.
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, PR China; Department of Oncology, Shanghai Medical College, Fudan University, PR China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China.
Cancer Lett. 2018 Apr 1;418:167-175. doi: 10.1016/j.canlet.2018.01.017. Epub 2018 Jan 11.
Pancreatic cancer is the most lethal tumor. CA125 (gene symbol MUC16) is an important serum marker for pancreatic cancer diagnosis and treatment. High serum CA125 is related to metabolic tumor burden and poor prognosis. The circulating Treg subset is another independent prognostic factor for pancreatic cancer. Our unpublished data indicated that the circulating Treg proportion might be related to the serum CA125 level. However, the potential relationship and underlying mechanism of MUC16 and Treg in pancreatic cancer tissues remain unclear. In this study, we found that pancreatic cancer tissues were positive for both MUC16 C terminal (MUC16c) and Foxp3 expression and that their expression was correlated. MUC16c released into the cytoplasm via EGF induction significantly increased IL-6 expression and secretion. The PI3K/AKT pathway may participate in the regulation of IL-6 expression and secretion. By treating CD4 T cells with IL-6 or co-culturing the cells with pancreatic cancer cells, tumor-derived IL-6 was identified to promote Foxp3 expression and Treg differentiation, which was significantly inhibited by the JAK2 inhibitor AG-490. In sum, our study demonstrated that the relationship between the MUC16c level and Foxp3 expression in the local tumor environment was consistent with that of the serum CA125 level and circulating Treg proportion in the systemic environment. MUC16c promoted Foxp3 expression and tumor-associated Treg enrichment in tumor tissues through tumor-secreted IL-6 activation of the JAK2/STAT3 pathway. These findings may provide deeper insight into potential pancreatic cancer therapy approaches.
胰腺癌是最致命的肿瘤。CA125（基因符号 MUC16）是诊断和治疗胰腺癌的重要血清标志物。高血清 CA125 与代谢肿瘤负担和预后不良有关。循环 Treg 亚群是胰腺癌的另一个独立预后因素。我们未发表的数据表明，循环 Treg 比例可能与血清 CA125 水平有关。然而，MUC16 和 Treg 在胰腺癌组织中的潜在关系和潜在机制尚不清楚。在这项研究中，我们发现胰腺癌组织同时表达 MUC16 C 端（MUC16c）和 Foxp3，且其表达呈相关性。EGF 诱导的 MUC16c 释放到细胞质中，显著增加了 IL-6 的表达和分泌。PI3K/AKT 通路可能参与了 IL-6 的表达和分泌的调节。通过用 IL-6 处理 CD4 T 细胞或与胰腺癌细胞共培养，鉴定出肿瘤来源的 IL-6 可促进 Foxp3 的表达和 Treg 分化，而 JAK2 抑制剂 AG-490 可显著抑制其分化。总之，我们的研究表明，局部肿瘤环境中 MUC16c 水平与 Foxp3 表达之间的关系与系统环境中血清 CA125 水平和循环 Treg 比例之间的关系一致。MUC16c 通过肿瘤分泌的 IL-6 激活 JAK2/STAT3 通路，促进 Foxp3 的表达和肿瘤相关 Treg 的富集。这些发现可能为潜在的胰腺癌治疗方法提供更深入的见解。
