OLR1激活CXCL12/CXCR4信号通路促进非小细胞肺癌发生发展的分子机制研究

It has been well proved that immune and inflammatory responses played a significant role in the initiation, promotion and progression of lung cancer. Numerous immune and inflammatory factors have been identified as the function in maintaining the malignant state of lung cancer. Oxidized low density lipoprotein receptor 1 (OLR1) has been well-studied in regulating immune and inflammatory responses. However, the mechanisms involving OLR1 in the development and progression of lung cancer remained unknown. In our pilot study, the expression levels of OLR1 were elevated in lung cancer cell lines and tissues, compared to relative bronchial epithelial cells and normal tissues. Elevated expression of OLR1 was associated with poorly differentiated, advanced stage, and poor prognosis in lung cancer. OLR1 overexpression was shown to enhance cell proliferation, migration, and invasion of lung cancer cells. Microarrays and cell cultures studies were adopted in screening and preliminarily verified downstream genes and pathways of OLR1. Subsequently, it was observed that CXCL12, CXCR4, and NF-κB were inhibited after silencing OLR1. Therefore, we proposed our hypothesis of OLR1 promoting tumorigenesis and progression of lung cancer through activating NF-κB and subsequent CXCL12/CXCR4 signal pathway. Cell lines, animal models, and clinical samples would be implemented in the current study to reveal the mechanism of CXCL12/CXCR4 signal pathway activated by OLR1 through regulating NF-κB activation. The present study involving OLR1/NF-κB/CXCR4 pathway in promoting the malignant state of lung cancer would support the exploration of potential candidate targets in developing novel therapeutics and reveal the molecular mechanisms in the initiation, promotion and progression of lung cancer.

免疫及炎症反应在肺癌的发生发展中发挥重要作用，多种免疫及炎症因子被证实参与肺癌的恶性进程。既往研究表明，氧化低密度脂蛋白受体1（OLR1）参与一系列免疫与炎症反应，但OLR1在肺癌发生发展中的作用尚不清楚。我们前期发现，OLR1在肺癌细胞系和组织中高表达，且与肿瘤分化差、分期晚、预后不良相关；OLR1提高肺癌细胞的增殖、迁移、侵袭能力；基因芯片及细胞实验表明，沉默OLR1抑制CXCL12、CXCR4的表达以及NF-κB的活化。据此我们提出假说：OLR1通过调控NF-κB活化，激活CXCL12/CXCR4信号通路促进肺癌的发生发展。本项目拟通过体外细胞实验、体内动物模型及临床样本，揭示OLR1调控NF-κB活化，进而激活CXCL12/CXCR4信号通路的新机制，阐明OLR1/NF-κB/CXCR4通路促进肺癌恶性进程的新观点，为寻找肺癌治疗的潜在靶点和诠释肺癌发生发展的分子机制提供科学依据。

免疫及炎症反应在肺癌的发生发展中发挥重要作用，多种免疫及炎症因子被证实参与肺癌的恶性进程。既往研究表明，氧化低密度脂蛋白受体1（OLR1）参与一系列免疫与炎症反应，但OLR1在肺癌发生发展中的作用尚不清楚。我们前期发现，OLR1在肺癌细胞系和组织中高表达，且与肿瘤分化差、分期晚、预后不良相关；OLR1提高肺癌细胞的增殖、迁移、侵袭能力；基因芯片及细胞实验表明，沉默OLR1抑制CXCL12、CXCR4的表达以及NF-κB的活化。本研究发现，OLR1通过调控NF-κB活化，激活CXCL12/CXCR4信号通路促进肺癌的发生发展。本项目通过体外细胞实验、体内动物模型及临床样本，揭示OLR1调控NF-κB活化，进而激活CXCL12/CXCR4信号通路的新机制，阐明OLR1/NF-κB/CXCR4通路促进肺癌恶性进程的新观点，为寻找肺癌治疗的潜在靶点和诠释肺癌发生发展的分子机制提供科学依据。