Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.
Cancer Commun (Lond). 2019 Jul 9;39(1):41. doi: 10.1186/s40880-019-0386-4.
BACKGROUND: The interaction between CD137 and its ligand (CD137L) plays a major role in the regulation of immune functions and affects cancer immunotherapy. CD137 is a cell surface protein mainly located on activated T cells, and its regulation and functions in immune cells are well established. However, the expression of CD137 and its regulation in cancer cells remain poorly understood. The main purposes of this study were to examine the expression of CD137 in pancreatic cancer cells and to investigate its underlying mechanisms. METHODS: Cells containing inducible K-Ras expression vector or with different K-Ras mutational statuses were used as in vitro models to examine the regulation of CD137 expression by K-Ras. Various molecular assays were employed to explore the regulatory mechanisms. Tumor specimens from 15 pancreatic cancer patients and serum samples from 10 patients and 10 healthy donors were used to test if the expression of CD137 could be validated in clinical samples. RESULTS: We found that the CD137 protein was expressed on the cell surface in pancreatic cancer tissues and cancer cell lines. Enzyme-linked immunosorbent assay revealed no difference in the levels of secreted CD137 in the sera of patients and healthy donors. By using the K-Ras inducible cell system, we further showed that oncogenic K-Ras up-regulated CD137 through the activation of MAPK (mitogen-activated protein kinases) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathways, as evidenced by significantly reduced CD137 mRNA expression led by genetic silencing of MAPK1 and p65, the key proteins involved in the respective pathways. Furthermore, we also found that the NF-κB pathway was mainly stimulated by the K-Ras-induced secretion of interleukin-1α (IL-1α) which promoted the transcription of the CD137 gene in pancreatic cancer cell lines. Analysis of the TCGA (the cancer genome atlas) database also revealed a significant correlation between IL-1α and CD137 expression (r = 0.274) in tumor samples from pancreatic cancer patients (P < 0.001). CONCLUSIONS: The present study has demonstrated that the CD137 protein was expressed on pancreatic cancer cell surface, and has identified a novel mechanism by which K-Ras regulates CD137 in pancreatic cancer cells through MAPK and NF-κB pathways stimulated by IL-1α.
背景：CD137 与其配体（CD137L）的相互作用在调节免疫功能方面起着重要作用，并影响癌症免疫治疗。CD137 是一种主要位于活化 T 细胞表面的细胞表面蛋白，其在免疫细胞中的调节和功能已得到充分证实。然而，CD137 在癌细胞中的表达及其调节仍知之甚少。本研究的主要目的是检测胰腺癌细胞中 CD137 的表达，并探讨其潜在机制。
方法：使用含有诱导型 K-Ras 表达载体的细胞或具有不同 K-Ras 突变状态的细胞作为体外模型，研究 K-Ras 对 CD137 表达的调节作用。采用各种分子检测方法探讨调节机制。检测了 15 例胰腺癌患者的肿瘤标本和 10 例患者和 10 例健康供者的血清样本，以验证 CD137 的表达是否可在临床样本中得到验证。
结果：我们发现 CD137 蛋白在胰腺癌组织和癌细胞系的细胞表面表达。酶联免疫吸附试验显示，患者和健康供者血清中分泌的 CD137 水平无差异。通过使用 K-Ras 诱导细胞系统，我们进一步表明，致癌性 K-Ras 通过激活丝裂原活化蛋白激酶（MAPK）和核因子 kappa-轻链增强子的 B 细胞（NF-κB）途径上调 CD137，这是通过 MAPK1 和 p65 的遗传沉默导致的 CD137 mRNA 表达显著降低所证明的，MAPK1 和 p65 是各自途径中的关键蛋白。此外，我们还发现 NF-κB 途径主要受 K-Ras 诱导的白细胞介素-1α（IL-1α）分泌刺激，促进了胰腺癌细胞系中 CD137 基因的转录。对 TCGA（癌症基因组图谱）数据库的分析也显示，在胰腺癌患者的肿瘤样本中，IL-1α与 CD137 的表达之间存在显著相关性（r=0.274）（P<0.001）。
结论：本研究表明 CD137 蛋白在胰腺癌细胞表面表达，并确定了一种新的机制，即 K-Ras 通过 IL-1α 刺激的 MAPK 和 NF-κB 途径调节胰腺癌细胞中的 CD137。
Cancer Commun (Lond). 2019-7-9
J Mol Med (Berl). 2010-9-24
Zhonghua Xin Xue Guan Bing Za Zhi. 2015-7
Cancers (Basel). 2025-3-24
Front Oncol. 2022-9-14
J Adv Pharm Technol Res. 2022
Int Rev Cell Mol Biol. 2018-8-20
Cancer Res. 2017-9-18
Clin Cancer Res. 2016-3-15
Zotero 插件
