Raf激酶结合蛋白ACBD3通过MAPK通路调控肺癌发生的机制研究

肺癌是全球死亡率最高的恶性肿瘤，其发生及转移机制尚不明确，临床上也缺乏有效治疗措施和早期诊断指标。作为MAPK通路主干蛋白的Raf激酶，通过与其结合蛋白相互作用，参与调控癌症的发生发展。前期研究发现酰基辅酶A结合结构域蛋白3（ACBD3）在肺癌中高表达，是Raf激酶的结合蛋白，特异性敲除ACBD3可以抑制肺癌细胞增殖、侵袭等生物过程，并影响MAPK通路ERK的磷酸化激活。初步推测ACBD3对MAPK通路具有重要的调控作用。ACBD3通过与多种结合蛋白相互作用，调控诸多生理病理过程，但至今还没有对ACBD3的结合蛋白进行过系统的比较研究。本研究拟对ACBD3在不同EGF激活状态下的结合蛋白进行系统鉴定，明确ACBD3与Raf激酶的结合区域和结构特征。通过体内体外实验,阐明ACBD3通过MAPK通路调控肺癌发生的相关机制，验证临床抑制剂针对ACBD3的治疗效果，为肺癌的诊断和治疗提供新的靶标。

Lung cancer is the malignant tumor with the highest mortality rate in the world. The mechanism of occurrence and metastasis of lung cancer is not clear. There is a lack of effective early diagnosis and treatment measures in clinical practice. Raf kinases, the key proteins of the MAPK pathway, participate in regulating the occurrence and development of cancers through its binding proteins. Our experiments found that acyl-coenzyme A binding domain containing 3(ACBD3) was overexpressed in lung cancer. It was further found that ACBD3 was interacted with the three Raf kinases. The specific knockout of ACBD3 could inhibit the proliferation and invasion of lung cancer cells. ACBD3 affected the phosphorylation activation of ERK in the MAPK pathway. We hypothesize that ACBD3 is a key regulator in the MAPK pathway. ACBD3 regulates many physiological and pathological processes through its binding proteins. So far no systematic identification of ACBD3 interactome has been carried out. In this study, we will systematically identify ACBD3 interactomes under different EGF-stimulated conditions, and clarify the binding regions and structural characteristics of ACBD3 and Raf kinases. We will explore the mechanism by which ACBD3 regulates lung carcinogenesis through MAPK pathway, and verify the therapeutic effect of clinical inhibitors. This study will provide a new target for the diagnosis and treatment of lung cancer.