炎性信号通路IL-1β/IRAK1调控自噬促进肺癌发生与进展的分子机制

Lung cancer remains one of the commonest malignancies with highest morbidity and mortality, and the PFS in five years is very low. Smoking cigarettes is the dominant risk factor in patients with lung cancer. Clarify the mechanism in lung cancer development is the best way to prevent and improve the treatment of lung cancer. The occurrence of inflammation and lung cancer is closely related and progress has been confirmed, but the molecular mechanism is remains unclear. Autophagy and the relationship between lung cancer has been attracted considerable attention, become a hot issue in the field of cancer research. Our study found that in human lung cancer cell line and lung cancer tissues, interleukin-1β/interleukin-1 receptor-associated kinase 1 (IL- 1β/IRAK1) inflammatory signaling pathways activated and significantly correlated with autophagy genes ATG4A and ATG7 expression. IL-1β, IL-6 and other inflammatory cytokines could up regulate autophagy related genes both in transcription and translation level. In this study, we proposed to found the mouse lung inflammation and lung cancer by intraperitoneal injection of NNK and smoking cigarettes, we will use mouse lung carcinoma model and human clinical tissue specimens to analysis inflammatory signaling pathways activation and autophagy gene expression and the relationship between the formation and malignant progress of lung cancer; To investigate the molecular mechanism of inflammation signaling regulate autophagy genes, we use the biological information technology and software to analysis promoter of autophagy related genes and find a positioning transcription factor binding sites, detect which transcription factor or pathways is regulate by inflammatory signaling; Blocking inflammation signaling in animal models of lung cancer and knockout autophagy genes, then detect the influence of the occurrence and development of lung cancer; Validate the molecular mechanism in clinical specimens and sent clinical data to retrospective study. To explore the role of inflammation and autophagy in lung cancer formation and malignant progress and the underline mechanism, this study will provide a new insights or method for the clinical treatment of lung cancer.

肺癌是发病率和死亡率最高的恶性肿瘤之一。阐明肺癌发生发展机制是预防及提高肺癌治疗效果的基础。炎症与肺癌的发生和进展已被证实有密切联系，但分子机制不明。自噬与肺癌的关系亦受到相当的关注，成为肿瘤研究领域的热点问题。我们前期研究发现在人肺癌细胞系，原位癌和肺癌组织中炎性信号通路激活与自噬基因ATG4A和ATG7等表达显著相关，IL-1β、IL-6等炎性细胞因子在转录与翻译水平上调自噬相关基因。本课题拟采用NNK腹腔注射同时吸烟诱导小鼠肺炎癌模型和人肺癌临床组织标本分析炎症和自噬基因表达与肺癌形成和恶性进展的关系；采用生物信息技术和软件分析定位自噬基因启动子区的转录因子结合位点，探索炎症信号调控自噬基因的分子机制；在肺癌动物模型上阻断炎症信号及敲除自噬基因对肺癌发生发展的影响；最后在临床标本分子机制验证和临床资料回顾研究。探讨炎症促进自噬在肺癌进展中的作用和机制，将为肺癌的临床治疗提供新的思路。

肺癌是发病率和死亡率最高的恶性肿瘤之一。其发生和进展的分子机制尚未完全明确。阐明肺癌发生发展机制是预防及提高肺癌治疗效果的基础。炎症与肺癌的发生和进展已被证实有密切联系，肺癌细胞和间质细胞分泌致炎因子，相互作用形成炎性微环境，进而促进肺癌进展。自噬与肺癌亦有密切关系，自噬在肺癌中的作用是个“双刃剑”，在肺癌中表达缺失的CK1α可以作为内源性自噬诱导因子，通过激活细胞自噬抑制肺上皮细胞恶变和肺癌细胞生长，高水平的自噬成为肺癌化疗抵抗的重要因素，成为肿瘤研究领域的热点问题。我们前期研究发现在人肺癌细胞系，原位癌和肺癌组织中炎性信号通路激活与ATG4A和ATG7等表达显著相关，IL-1β、IL-6等炎性细胞因子在转录与翻译水平上调ATG4A和ATG7基因的表达。后续采用生物信息技术和软件分析ATG4A启动子区的转录因子结合位点，发现ATG4A启动子区存在甲基化位点，且S-腺苷甲硫氨酸（SAM）可以抑制ATG4A的表达；CBP/P300乙酰化复合物可以结合到ATG4A启动子区并上调其表达水平。IL-1β通过磷酸化CBP/P300乙酰化复合物上调ATG4A的mRNA和蛋白表达水平。ATG4A在细胞水平和裸鼠皮下成瘤实验中均能促进肺癌的生长，在人肺癌组织芯片中，免疫组化结果显示ATG4A在癌中高表达，阳性率70%。炎性信号通路相关分子IL-1β，IRAK1和ATG4A在肺癌细胞系和肺癌样本中呈现良好的表达相关性。在NNK腹腔注射同时吸烟诱导小鼠肺炎癌模型和标本中炎症和自噬基因表达与肺癌形成和恶性进展也有密切关系；在肺癌动物模型上阻断炎症信号通路可以抑制肺癌的发生发展。本研究探讨了炎症促进自噬在肺癌进展中的作用和机制，为肺癌的临床治疗提供新的思路。