Accumulation of gene alteration and its signal transduction pathway from development of lung cancer to metastasis.

肺癌发生到转移的基因改变积累及其信号转导途径。为了研究肺腺癌发生过程中遗传异常的积累，我们检查了小肺腺癌的遗传改变，并分析了这些肿瘤的杂合性缺失（LOH）。在非常早期的腺癌中检测到等位基因丢失，并且随着肿瘤的恶性进展，染色体17p上loh的频率增加。即使在小的肺腺癌中也发现了异质性遗传改变。为了寻找人类肺癌癌变的信号转导，我们检测了79例肺癌中MAPK和STAT3的表达、MAPK磷酸化和STAT3磷酸化。癌组织与正常肺组织MAPK表达水平无差异。正常肺组织中phosphoMAPK的浓度明显高于癌组织。STAT3的表达与phosphoMAPK的表达呈负相关。磷酸酶STAT3在腺癌中的表达明显高于鳞状细胞癌。这些结果提示JAK/STAT信号转导通路可能比MAPK级联在人肺腺癌的癌变过程中发挥更重要的作用。我们在166例肺癌中寻找突变。其中，我们在外显子3上发现了4个突变，它们位于稳定β-catenin的突变靶区。我们的研究结果表明，β-catenin的激活突变，换句话说，Wnt信号转导通路的激活，发生在一小部分肺癌中。

Accumulation of gene alteration and its signal transduction pathway from development of lung cancer to matastasis.To study the accumulation of genetic abnormalities in the course of pulmonary adenocarcinogenesis, we examined genetic alteration in small pulmonary adenocarcinoma and analyzed loss of heterozygosity (LOH) in these tumors.Allelic losses were detected in very early adenocarcinoma and the frequently of LOHs on chromosome 17p increased during malignant progression of the tumor. Heterogenous genetic alterations were determined even in small pulmonary adenocarcinoma.In the search for the signal transduction to carcinogenesis in human lung cancer, we examined the expression of MAPK and STAT3, MAPK phosphorylation, and STAT3 phosphorylation in 79 Lung cancers. There was no difference in the MAPK expression level between cancerous tissues and normal lung tissues. The concentration of phosphoMAPK was significantly higher in normal lung tissues than in cancer tissues. STAT3 expression has a tendency to inversely correlate with phosphoMAPK expression. The increased cases of phosphos STAT3 were significantly more frequent in adenocarcinoma than in squamous cell carcinoma. These results suggest that the JAK/STAT signal transduction pathway may play a more significant role than the MAPK cascade in the carcinogenesis of human pulmonary adenocarcinoma.We searched for mutations in 166 lung cancers. Among them, we identified 4 alterations in exon3, which were in the target region of mutation for stabilizing β-catenin. Our findings suggest that activating mutations of β-catenin, in other words, Wnt signal transduction pathway activation, occurs in small subset of lung cancer.