Study for molecular mechanism of human lung adenocarcinoma.

在这三年中，我们主要进行了以下三个研究项目，以明确肺腺癌的发病机制和恶性进展的分子机制。采用抑制减法杂交（SSH）方法比较了4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）在A/J小鼠肺组织中诱导腺瘤的表达谱。表面活性剂相关蛋白A （SP-A）和溶菌酶mrna在腺瘤组织中的转录水平明显高于正常肺组织。我们从同一患者身上建立了永生化的人非典型腺瘤性增生（AAH）细胞系（PL16T）和人非肿瘤性支气管上皮细胞系（PL16B）。采用SSH方法比较PL16T与PL16B的表达谱。在PL16T中检测到肿瘤相关钙信号传感器2 （TACSTD2）和S100钙结合蛋白A2 （S100A2）的特征性高转录。我们的研究结果表明，TACSTD2和S100A2在肺腺癌浸润前阶段的AAH中选择性高表达，并且高表达一直保持到病变发展为细支气管肺泡癌（BAC），这是人肺腺癌的原位期和更晚期。利用人肺腺癌切除标本，采用SSH方法比较Noguchi C型腺癌（早期但晚期的细支气管肺泡癌）与同例原位病变的进展区表达谱。Bax抑制剂-1 （BI-1）、TACSTDI、线粒体细胞色素c氧化酶II和FJL12770在晚期病变中显著高转录。BI-1基因在BAC和细支气管肺泡（BA）扩散癌中的表达明显高于不含BA成分的癌。BI-1基因的表达仅限于生长缓慢的肿瘤细胞。

For the three years, we mainly performed the following three research projects to make clear the molecular mechanisms of the pathogenesis and the malignant progression of the lung adenocarcinoma.1.The expression profile of adenoma induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mouse was compared with that of normal lung tissue by suppression subtractive hybridization (SSH). The mRNAs of surfactant-associated protein A (SP-A) and lysozyme showed characteristically higher transcription in the adenoma tissue than normal lung.2.We established an immortalized human atypical adenomatous hyperplasia (AAH) cell line (PL16T) and a human non-neoplastic bronchial epithelial cell line (PL16B) from the same patient. The expression profile of PL16T was compared with that of PL16B by SSH method. The characteristically high transcription of tumor-associated calcium signal transducer 2 (TACSTD2) and S100 calcium binding protein A2 (S100A2) was detected in PL16T. Our findings indicate that TACSTD2 and S100A2 are selectively and highly expressed in AAH, which is preinvasive stage of lung adenocaricnoma, and the high expression is preserved until the lesion progresses to bronchioloalveolar carcinoma (BAC), which is in situ stage of human lung adenocarcinoma and more advanced stages.3.Using the resected material of human lung adenocarcinoma case, the expression profile of advanced area in Noguchi type C adenocarcinoma (early but advanced bronchioloalveolar carcinoma) was compared with that of in situ lesion of the same case by SSH method. The significantly high transcription of Bax inhibitor-1 (BI-1), TACSTDI, mitochondrial cytochrome c oxidase II, and FJL12770 was detected in adnvanced lesion. The BI-1 gene expression in tumor specimens was significantly higher in BAC and carcinoma with bronchioloalveolar (BA) spreading than carcinomas without BA component. The BI-1 gene expression was restricted to the tumor cells with lepidic growth.