School of Medicine, Chung Shan Medical University Hospital, Taiwan, China.
Clin Cancer Res. 2013 Aug 1;19(15):4092-103. doi: 10.1158/1078-0432.CCR-12-3439. Epub 2013 Jun 6.
Interleukin-10 (IL-10) determines virus persistent infection and promotes viral-associated tumor progression via tumor immune escape. However, the role of IL-10 in tumor progression and prognosis in lung adenocarcinoma remains controversial.
To investigate how IL-10 is regulated by HPV E6, IL-10 promoter was constructed to understand which transcriptional factor could be responsible for its transcription. To verify which molecule could be responsible for IL-10-mediated soft agar growth and invasion capability, PCR array and mechanistic strategies were conducted. IL-10 and CIP2A mRNA levels in lung tumors from patients with lung cancer were determined by real-time reverse transcription PCR. The prognostic value of both molecules on survival was estimated by Cox regression model.
Mechanistic studies showed that IL-10 protein and mRNA expression was decreased in E6 knockdown TL1 cells and increased in E6- overexpressing TL4 cells. In addition, IL-10 transcription was predominantly regulated by E6-mediated phosphorylation of cAMP response element-binding protein (CREB) and C/enhancer-binding protein β (C/EBPβ) via phosphoinositide 3-kinase (PI3K) signaling pathway. IL-10-mediated tumor aggressiveness in vitro and in vivo occurs through increased CIP2A expression via PI3K signaling pathway. Among patients, IL-10 mRNA expression in lung tumors was positively correlated with CIP2A mRNA expression. Cox-regression analysis showed that IL-10 and CIP2A mRNA levels may independently predict survival in patients with lung adenocarcinoma, especially in patients with E6-positive tumors.
IL-10 production from lung tumors and immune cells promotes lung adenocarcinoma aggressiveness and patients with poor survival. We thus suggest that PI3K inhibitor combined with chemotherapy may potentially enhance tumor regression and improve patients' outcome and life quality.
白细胞介素-10（IL-10）通过肿瘤免疫逃逸决定病毒持续感染，并促进病毒相关肿瘤的进展。然而，IL-10 在肺腺癌中的肿瘤进展和预后中的作用仍存在争议。
为了研究 HPV E6 如何调节 IL-10，构建了 IL-10 启动子，以了解哪个转录因子可能负责其转录。为了验证哪些分子可能负责 IL-10 介导的软琼脂生长和侵袭能力，进行了 PCR 阵列和机制策略。通过实时逆转录 PCR 测定肺癌患者肺肿瘤中 IL-10 和 CIP2A mRNA 的水平。通过 Cox 回归模型估计这两种分子对生存的预后价值。
机制研究表明，E6 敲低 TL1 细胞中 IL-10 蛋白和 mRNA 表达降低，E6 过表达 TL4 细胞中 IL-10 表达增加。此外，IL-10 转录主要受 E6 介导的 cAMP 反应元件结合蛋白（CREB）和 C/增强子结合蛋白β（C/EBPβ）磷酸化通过磷脂酰肌醇 3-激酶（PI3K）信号通路调节。IL-10 通过 PI3K 信号通路介导体外和体内肿瘤侵袭性，通过增加 CIP2A 表达。在患者中，肺肿瘤中 IL-10 mRNA 表达与 CIP2A mRNA 表达呈正相关。Cox 回归分析显示，IL-10 和 CIP2A mRNA 水平可能独立预测肺腺癌患者的生存，尤其是在 E6 阳性肿瘤患者中。
来自肺肿瘤和免疫细胞的 IL-10 产生促进肺腺癌侵袭性和患者预后不良。因此，我们建议联合使用 PI3K 抑制剂和化疗可能潜在地增强肿瘤消退，改善患者的预后和生活质量。
