LKB1 通过赖氨酰氧化酶和细胞外基质重塑抑制肺癌进展。
LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling.
机构信息
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
出版信息
Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18892-7. doi: 10.1073/pnas.1004952107. Epub 2010 Oct 18.
LKB1 loss-of-function mutations, observed in ∼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-1α 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 β1 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.
LKB1 失活突变存在于约 30%的人类肺腺癌中，显著促进了肺癌的恶性进展。我们发现赖氨酰氧化酶（LOX）受到 LKB1 通过 mTOR-HIF-1α信号通路的负调控，介导了肺癌的进展。LOX 活性的抑制显著缓解了肺癌的恶性进展。上调的 LOX 表达在 Lkb1 缺失的肺肿瘤中引发胶原过度沉积，随后通过激活β1 整合素信号通路促进癌细胞增殖和侵袭。高 LOX 水平和活性与预后不良和转移相关。我们的研究结果提供了证据，证明 LKB1 失活功能如何通过重塑细胞外基质微环境促进肺癌的恶性进展，并确定 LOX 作为肺癌患者疾病治疗的潜在靶点。
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