研究LKB1在肺癌转移中对赖氨酰氧化酶的调控机制

项目名称： 研究LKB1在肺癌转移中对赖氨酰氧化酶的调控机制

项目编号： No.30871284

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 季红斌

作者单位： 中国科学院上海生命科学研究院

项目金额： 36万元

中文摘要： 肺癌作为全球范围内所有癌症中的头号杀手，其五年存活率大约为15％。前期的研究发现抑癌基因LKB1在人类非小细胞肺癌中存在着相当比例的功能性缺失的突变，同时LKB1的缺失对于肺癌的进展尤其是转移起着非常重要的作用。但人们对于LKB1如何影响肺癌转移的分子机制还知之甚少。基于人类肺癌样本和体内小鼠肺癌模型的整合性研究，我们鉴定了赖氨酰氧化酶LOX作为LKB1下游的一个重要信号介导分子，通过胞外基质的重构，尤其是胶原组分的交联，在LKB1缺失的情况下介导了肺癌的转移。LKB1的功能性缺失通过mTOR-HIF-1a信号通路导致LOX表达上调。在肺癌小鼠模型中通过抑制LOX可显著减轻肺癌的发生和恶性转移。LKB1基因的功能性缺失引起小鼠肺部肿瘤中LOX的表达上调，引起肿瘤组织中胶原的过量沉积，进而激活b1-integrin下游FAK和SRC信号导致细胞侵袭能力的增强来促进转移。临床研究发现LOX的血清活性与肺癌转移及预后密切相关。我们的研究结果阐明了LKB1基因的功能性缺失促进肺癌转移的机制，暗示了LOX 可能作为一个应用于早期诊断的血清学标记，并为将来肺癌的靶向治疗提供新的分子靶标。

中文关键词： 非小细胞肺癌；抑癌基因LKB1；赖氨酰氧化酶；胞外基质

英文摘要： Lung cancer represents the leading cause of cancer mortality worldwide with 5-year survival rate approximately 15%. Previous studies have identified a novel tumor suppressor gene Liver kinase B1 (LKB1), which is frequently mutated in human Non-Small-Cell Lung Cancer, and plays an important role in cancer progression, especially metastasis. However, the molecular mechanisms involved remain largely unknown. Through integrative studies on human lung cancer samples and animal models, We have identified lysyl oxidase (LOX) as an essential mediator of LKB1-deficiency-elicited lung cancer progression through ECM remodeling, especially collagen matrix cross-linking. LKB1 loss triggered the up-regulation of LOX expression through the mTOR-HIF-1αignaling axis. LOX inhibition in de novo mouse models significantly alleviate LKB1-deficient lung cancer malignancy and invasion. LKB1 loss results in increased LOX expression, leading to excess collagen cross-linking in the tumors, which promotes cancer cell invasion through activation of FAK and SRC downstream of βintegrin signaling. Clinical studies further show LOX serum activity strongly correlates with lung cancer metastasis and poor prognosis. Our study provides mechanistic insights into how LKB1 loss promotes lung cancer progression and metastasis, and identifies LOX as an effective biomarker for early diagnosis and molecular target essential for lung cancer targeted therapy.

英文关键词： Non-Small-Cell Lung Cancer; Tumor suppressor gene LKB1； Lysyl Oxidase； Extracellular matrix