LKB1 modulates lung cancer differentiation and metastasis. LKB1 modulates lung cancer differentiation and metastasis

Inherited mutation in LKB1 results in the Peutz-Jeghers syndrome (PJS), characterized by intestinal hamartomas and a modestly increased frequency of gastrointestinal and breast cancer1. Somatic inactivation of LKB1 occurs in human lung adenocarcinoma2-4, but its tumor suppressor role in this tissue is unknown. Here we show that somatic Lkb1 deficiency strongly cooperates with somatic K-rasG12D activating mutation to accelerate the development of mouse lung tumorigenesis. Lkb1 deficiency in the setting of K-rasG12D mutation (K-ras Lkb1L/L) was associated with decreased tumor latency and increased tumor aggressiveness including metastasis. Furthermore, tumors from K-ras Lkb1L/L mice demonstrated histologies--squamous, adenosquamous and large cell--not seen with K-rasG12D mutation, Ink4a/Arf inactivation, or p53 inactivation alone or in combination. Experiments in vitro suggest that LKB1 suppresses lung tumorigenesis and progression through both p16INK4a-ARF-p53 dependent and independent mechanisms. These data indicate that LKB1 regulates lung tumor progression and differentiation. Keywords: cancer research Overall design: To analyze the role of LKB1 in lung cancer progression and differentiation, we have dissected the lung tumors from mice with/without lkb1 loss and performed the microarray analyses to compare their gene expression pattern. In addition, we have also performed microarray analysis in both A549 and H2126 cell lines after reconsistitution of either wt-lkb1 or the kinase dead form of lkb1 (lkb1-KD) to confirm what we observed from in vivo studies.

LKB1的胚系突变会导致波伊茨-耶格综合征（Peutz-Jeghers syndrome, PJS），该病以肠道错构瘤为特征，并会轻度增加胃肠道与乳腺癌的发病风险¹。LKB1的体细胞失活可见于人类肺腺癌²⁻⁴，但其在该组织中的抑癌作用尚未明确。本研究证实，Lkb1体细胞缺失可与K-rasG12D激活突变协同，显著加速小鼠肺肿瘤发生。携带K-rasG12D突变且Lkb1条件性缺失的小鼠（K-ras Lkb1L/L），其肿瘤潜伏期缩短、侵袭性增强，且可发生远处转移。此外，K-ras Lkb1L/L小鼠的肿瘤组织呈现出鳞状、腺鳞状及大细胞等组织学亚型，而单独或联合存在K-rasG12D突变、Ink4a/Arf失活或p53失活的肿瘤均未出现此类亚型。体外实验结果显示，LKB1可通过p16INK4a-ARF-p53依赖与非依赖两种途径抑制肺肿瘤的发生与进展。上述数据表明，LKB1可调控肺肿瘤的进展与分化。
关键词：癌症研究
整体实验设计：为解析LKB1在肺癌进展与分化中的作用，我们对携带/不携带Lkb1缺失的小鼠肺肿瘤组织进行解剖取材，通过基因芯片分析比较二者的基因表达谱。此外，我们还在A549与H2126细胞系中分别重组表达野生型LKB1（wt-lkb1）或激酶失活型LKB1（lkb1-KD），并开展基因芯片分析，以验证体内实验所得结论。