LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling
LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling
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LKB1 通过赖氨酰氧化酶和细胞外基质重塑抑制肺癌进展
DOI：
10.1073/pnas.1004952107
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发表时间：
2010-11-02
影响因子：
11.1
通讯作者：
Ji, Hongbin
中科院分区：
文献类型：
--
作者：
Gao, Yijun;Xiao, Qian;Ji, Hongbin
LKB 1功能丧失突变，在类似于30%的人肺腺癌中观察到，显著促进肺癌恶性进展。我们发现LKB 1通过mTOR-HIF-1 α信号轴负调控赖氨酰氧化酶（LOX）介导肺癌进展。LOX活性的抑制显著地延缓肺癌恶性进展。LOX表达上调触发了Lkb 1缺陷型肺肿瘤中过量的胶原沉积，此后通过激活β 1整合素信号传导导致癌细胞增殖和侵袭力增强。高LOX水平和活性与不良预后和转移相关。我们的研究结果提供了LKB 1功能丧失如何通过细胞外基质微环境重塑促进肺癌恶性化的证据，并将LOX确定为肺癌患者疾病治疗的潜在靶点。
LKB1 loss-of-function mutations, observed in similar to 30% of human lung adenocarcinomas, contribute significantly to lung cancer malignancy progression. We show that lysyl oxidase ( LOX), negatively regulated by LKB1 through mTOR-HIF-1 alpha signaling axis, mediates lung cancer progression. Inhibition of LOX activity dramatically alleviates lung cancer malignancy progression. Up-regulated LOX expression triggers excess collagen deposition in Lkb1-deficient lung tumors, and thereafter results in enhanced cancer cell proliferation and invasiveness through activation of beta 1 integrin signaling. High LOX level and activity correlate with poor prognosis and metastasis. Our findings provide evidence of how LKB1 loss of function promotes lung cancer malignancy through remodeling of extracellular matrix microenvironment, and identify LOX as a potential target for disease treatment in lung cancer patients.