The mechanisms of pulmonary carciniogenesis in idiopathic pulmonary fibrosis

特发性肺纤维化（IPF）患者发生肺癌的风险增加。为了确定IPF恶性转化的关键分子，我们利用cDNA阵列分析了肺癌和IPF（肺癌/IPF）患者肺肿瘤和配对肺组织的表达谱。通过实时RT-PCR，在肺癌/IPF患者的肿瘤样本中经常发现Smad4基因表达降低。此外，本研究还采用聚合酶链反应-单链构象多态性（PCR- sscp）和甲基化特异性PCR （MSP）进行了TGF-β II型受体和Smad4基因的突变分析和Smad4启动子的甲基化状态分析，并进行了测序分析。在8个肿瘤样本中未检测到突变，但发现了Smad4基因转录的改变。我们的研究结果表明，Smad4失活可能在TGF-β过表达的IPF患者的肺癌发生或进展中起重要作用，Smad4转录的改变可能是其中一种机制。这些发现可用于改善肺癌IPF患者的治疗。

Patients with Idiopathic pulmonary fibrosis (IPF) have an increased risk of developing lung cancer. To identify the key molecules involved in malignant transformation in IPF, we analyzed the expression profiles of lung tumor and paired lung tissue from patients with lung cancer and IPF (lung cancer/IPF) by cDNA array. Reduced expression of the Smad4 gene was frequently identified in tumor samples from lung cancers/IPF patients in real-time RT-PCR. In addition, mutational analysis of TGF-β type II receptor and Smad4 genes and analysis of the methylation status of the Smad4 promoter were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and methylation specific PCR (MSP) with subsequent sequencing analysis in this study. No mutation was detected in the eight tumor samples, but alterations of the Smad4 gene transcription were identified. Our findings indicated that Smad4 inactivation may play an important role in pulmonary carcinogensis or progression of lung cancer in IPF patients in which TGF-β is overexpressed, and that the alteration of Smad4 transcription may be one mechanism. These findings could be used to improve treatment of lung cancer patients with IPF.