Amlexanox通过调节TBK1-NF-κB信号通路抑制胰腺癌恶性转化的分子机制研究

Pancreatic cancer is the most aggressive malignancies among digestive system neoplasms. Elucidating molecular mechanisms and identifying effective therapeutic target is of crucial importance for the prognoses of patients with pancreatic cancer. Activation of NF-κB signaling pathway is involved in metastases and chemotherapeutic resistance in breast cancer and melanoma. TBK1 is a potential activator of NF-κB, however, the correlation between pancreatic cancer and TBK1-NF-κB pathway is still not yet been well clarified. Here we show that, TBK1 is over expressed in pancreatic cancer compared with normal or adenoma controls. Moreover, Amlexanox, a drug for oral ulceration, could repress the migration of pancreatic cancer cell lines. Therefore, we hypothesize that Amlexanox could inhibit pancreatic cancer progression by targeting TBK1-NF-κB signaling pathway. In this study, we will demonstrate the correlation between pancreatic cancer progression and TBK1-NF-κB pathway activation through in vitro molecular experiments. We will also testify the efficacy of Amlexanox on pancreatic cancer in vivo by utilizing Patient-derived xenograft models. This study will provide theoretical and experimental evidence for the development of novel drugs against TBK1 and also the application of Amlexanox towards the effective management of patient with pancreatic cancer.

胰腺癌是最具侵袭性的消化道恶性肿瘤，阐明胰腺癌转移的分子机理并探索有效治疗靶点对于改善胰腺癌患者的预后具有重要意义。研究表明，NF-κB信号通路在乳腺癌、黑色素瘤等恶性肿瘤的侵袭转移过程中发挥了重要作用。TBK1可以激活NF-kB，然而TBK1-NF-kB信号通路在胰腺癌中的作用目前并不清楚。本课题组研究结果显示，TBK1在胰腺癌中的表达水平显著高于正常胰腺及癌前病变组织，Amlexanox可显著抑制胰腺癌细胞系的迁移。由此我们提出假设，Amlexanox可通过调节TBK1-NF-kB信号通路来抑制胰腺癌的恶性转化。本项目拟通过体外实验阐明TBK1-NF-kB信号通路与胰腺癌细胞恶性生物学行为的相关性；并通过裸鼠胰腺癌PDX移植瘤模型研究Amlexanox对胰腺癌的抑制作用。预期研究成果将为针对TBK1-NF-κB信号通路的新药研发以及Amlexanox在胰腺癌治疗中的应用奠定理论基础。

胰腺癌是最具侵袭性的消化道恶性肿瘤。我们前期工作证实TBK1在胰腺癌中高表达，且Amlexanox可显著抑制胰腺癌细胞的迁移能力，但TBK1-NF-κB信号通路促进胰腺癌恶性转化和Amlexanox治疗胰腺癌的作用机制目前并不清楚。按照项目研究计划，通过细胞实验、分子生物学实验和荷瘤裸鼠模型，探究了Amlexanox通过调控TBK1-NF-κB信号通路抑制胰腺癌恶性转化的具体作用及其机制。本项目通过临床病理资料分析TBK1-NF-κB信号通路与胰腺癌临床病理参数的相关性，体外实验验证TBK1与胰腺癌细胞恶性进展的关系，体内外实验探讨Amlexanox对胰腺癌的抑制作用及分子机制。实验结果证实了TBK1与胰腺癌预后、间质评分、免疫评分和免疫细胞浸润等临床病理参数密切相关，调控TBK1表达能够影响胰腺癌细胞增殖、凋亡和迁移等恶性生物学行为，进一步证实Amlexanox可通过调控TBK1-NF-κB信号通路抑制胰腺癌恶性转化。以上研究结果表明，TBK1在胰腺癌临床诊疗中具有重要应用价值，Amlexanox能够通过调控TBK1-NF-κB信号通路抑制胰腺癌的恶性进展，这为进一步开展以TBK1为治疗靶点的肿瘤药物研发提供实验依据。