双歧杆菌调控PTEN/Akt通路活化FoxO3a影响非小细胞肺癌细胞转移的机制研究

Invasion and metastasis is the leading cause of pulmonary carcinoma death. Respiratory tissue and intestinal tissue have the similar structural homology, intestinal lesions could cause the pulmonary damage, imbalance of intestinal flora can directly or indirectly affect the pulmonary function and airway remodeling. As the most typical microorganism, bifidobacterium can regulate the tumor related immune therapy. More research begins to focus on its molecular mechanism, it is found that the Bifidobacterium can inhibit the PI3K/Akt signal transduction pathway to produce the anti-inflammatory and anti-colon cancer effect. In a model of small nude mice suffered from human small cell carcinoma of lung, bifidobacterium was found that its effect can reach the lung and regulate the anti-tumor response through the whole body. FoxO3a is the important signal factor during PI3K/Akt signal transduction pathway, FoxO3a has lower expression in pulmonary cancer tissue especially low differentiated cancer tissues, suggesting FoxO3a is closely related with the malignant degree of cancer and lymphatic metastasis. Applicant has always played close attention on the invasive and metastatic mechanism of pulmonary cancer and focus on the role of PTEN/Akt/FOXO signal transduction pathway in pulmonary cancer. Therefore, we give this hypothesis: bifidobacterium can inhibit the PI3K/Akt signal pathway to active the FoxO3a and inhibit the development of pulmonary cancer. If this hypothesis can be verified, the probiotics-regulated FoxO3a expression may be a new potential mechanism for pulmonary therapy and prevention.

肺癌侵袭和转移是肺癌病人主要死亡原因。呼吸道与肠道结构同源性，肠道病变可引起肺损害，肠道菌群微生态失衡影响肺功能、气道重塑等。肠道益生菌通过各种途径抑制肿瘤的发生发展，双歧杆菌是人体肠道内典型优势菌，可调节肿瘤的免疫治疗。双歧杆菌对肿瘤防治向分子水平的深入发现其可抑制PI3K/Akt信号通路而起抗炎及抗结肠癌作用。小鼠肺癌模型可证实双歧杆菌可参与全身抗肺癌反应的过程且作用能达到肺部。FoxO3a是PI3K/AKT信号通路中重要的下游信号分子，在肺癌组织尤其是低分化癌组织中呈低表达与肺癌的恶性程度及淋巴结转移密切相关。申请者既往研究一直关注肺癌侵袭转移的机制，聚焦PTEN/Akt/FOXO通路在非小细胞癌中的作用。因此我们提出假设：双歧杆菌通过抑制PI3K/Akt，活化FoxO3a，抑制NSCLC发生发展。若此假说成立，则益生菌调节FoxO3a表达很可能成为治疗或预防肺癌发生发展新的重要机制

肺癌侵袭和转移是肺癌病人主要死亡原因。呼吸道与肠道结构同源性，肠道病变可引起肺损害，肠道菌群微生态失衡影响肺功能、气道重塑等。肠道益生菌通过各种途径抑制肿瘤的发生发展，双歧杆菌是人体肠道内典型优势菌，可调节肿瘤的免疫治疗。通过益生菌调节“肠肺轴”微生态提高肿瘤治疗疗效的研究国内外尚无报道。本研究旨在验证我们基于“肠肺轴”理论的假设，并探究双歧杆菌在协同肺癌化疗过程中的作用机制。首先，我们在小鼠皮下荷瘤模型中的实验结果支持了临床上双歧杆菌协同化疗可以提高铂类化疗疗效的现象。其次，我们通过肠道菌群的分析、肠道与瘤体代谢组学以及瘤体蛋白组学的联合分析，发现组氨酸代谢水平的升高与CLPP蛋白表达水平的下降是双歧杆菌协同顺铂抑制肺癌细胞增殖的关键靶点。我们进一步在体外通过流式方法检测组氨酸干预下顺铂对肺癌细胞的杀伤作用， Western blotting方法检测组氨酸对凋亡蛋白Caspase3以及CLPP蛋白表达的影响。同时通过分子结合实验验证组氨酸与CLPP蛋白之间的互作关系。结果发现，双歧杆菌通过调节菌群结构，改善肠道微生态，上调肠道与瘤体内组氨酸代谢水平，下调CLPP蛋白表达水平并通过与组氨酸的结合改变其结构，抑制其水解错误折叠蛋白的功能，从而增加化疗对肿瘤的杀伤作用。

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