β-arrestin 2负调控TLR9信号抑制肺腺癌的增殖与转移

Lung adenocarcinoma is the most common type of lung cancer. It has a poor prognosis and high mortality rate in patients in late stage and/or with recurrent conditions. However, the mechanisms by which genes play a critical role in lung cancer metastasis and recurrence remain elusive. Recently, it has been demonstrated by us and others that immune functions contribute to cancer metastasis and the recurrence process. Toll-like receptors (TLRs) play a fundamental role in modulation of human immune function and inflammatory responses. Importantly, our recent results have shown that TLR9 participates in lung cancer metastasis. β-arrestin 2 (β-Arr2) regulates TLR-mediated signaling pathways; however, the role of β-Arr2 and TLR9 in lung adenocarcinoma metastasis and recurrence are not known yet. Our proposal focuses on the mechanisms by which β-Arr2 and TLR9 contribute to lung adenocarcinoma metastasis and recurrence. We will define the effects and modulatory mechanisms of overexpression of β-Arr2 and/or inhibition of TLR9 and chemotherapy on lung adenocarcinoma metastasis and recurrence. We will utilize overexpression of β-Arr2 in lung adenocarcinoma cells to define the role of β-Arr2 and TLR9-mediated signaling pathways in lung adenocarcinoma invasiveness. We will use lung adenocarcinoma in mice and human lung adenocarcinoma samples to investigate the effects ofβ-Arr2 and TLR9-mediated signaling pathways on lung adenocarcinoma metastasis and recurrence during chemotherapy. The successful completion of this proposal will identify new approaches for the treatment of patients with lung adenocarcinoma.

Toll样受体(TLR)9和β-arrestin（β-Arr）2均与肿瘤转移有关，前期研究发现两者共用PI3K/Akt分别抑制和促进肺癌细胞凋亡，最近发现β-Arr2负调控免疫细胞TLRs信号级联, 推测β-Arr2与TLR9的分子交谈将影响肺腺癌的进展。为此，本研究拟围绕肺腺癌细胞和临床标本，借助基因转染、MTT、FACS、EMSA、WB、激光共聚焦、免疫共沉淀和移植瘤模型等技术手段，①观察β-Arr2对TLR9介导的细胞凋亡转移的影响;②判断β-Arr2、TLR9、TRAF6及Akt 的表达及共定位关系;③ 测定TLR9、MyD88、TRAF6及Akt/GSK-3β的表达及其磷酸化水平;④检测PI3K、IRAK/IKK活性与NF-κB结合活性;⑤分析TLR9及其下游分子、β-Arr2表达状态与腺癌转移和化疗抵抗的关系。以阐明β-Arr2对TLR9介导的肺腺癌增殖和转移的调控作用与机制

Toll样受体(TLR)9和β-arrestin（β-Arr）2均与肿瘤转移有关，前期研究发现两者共用PI3K/Akt分别抑制和促进肺癌细胞凋亡，最近发现β-Arr2负调控免疫细胞TLRs信号级联, 推测β-Arr2与TLR9的分子交谈将影响肺腺癌的进展。为此，本研究拟围绕肺腺癌细胞和临床标本，借助基因转染、MTT、FACS、EMSA、WB、激光共聚焦、免疫共沉淀和移植瘤模型等技术手段，①观察β-Arr2对TLR9介导的细胞凋亡转移的影响;②判断β-Arr2、TLR9、TRAF6及Akt 的表达及共定位关系;③ 测定TLR9、MyD88、TRAF6及Akt/GSK-3β的表达及其磷酸化水平;④检测PI3K、IRAK/IKK活性与NF-κB结合活性;⑤分析TLR9及其下游分子、β-Arr2表达状态与腺癌转移和化疗抵抗的关系。以阐明β-Arr2对TLR9介导的肺腺癌增殖和转移的调控作用与机制。