DNA methylation markers of surfactant proteins in lung cancer

Abstract

Abstract. Surfactant proteins play important roles in lung surfactant function and innate immunity. The DNA methylation state of 11 CpG sites of surfactant protein (SP)-A1, -B, -C, and -D was determined using universal bead arrays. A total of 90 cancerous and non-cancerous tissues from 23 patients with adenocarcinoma and 22 with squamous cell carcinoma were studied. These were divided into a training set and a testing set. The results indicate that DNA methylation profiling of these CpGs is associated with lung cancer. Four CpG sites, SP-A1_370, SP-A1_1080, SP-D_1170, and SP-D_1370, were hypomethylated in cancer and were significantly associated with both adenocarcinoma and squamous cell carcinoma, indicating that they have the potential to be used as biomarkers for lung cancer diagnosis and treatment. Normal lung tissues with a higher level of unmethylated SP-A1_1468 and SP-D_1170 CpG exhibited a higher level of SP-A1 and SP-D gene transcripts indicating that CpG methylation may play a role in gene expression. When the non-cancerous tissues were compared to cancerous tissues in patients with adenocarcinoma, the methylation profile results of these 46 samples (23 cancerous and 23 non-cancerous) could be clustered into 4 groups by agglomerative nesting. The percentage of tumor samples in each group was 0, 58, 91, and 100, respectively. A similar pattern was observed in squamous cell carcinoma patients. We speculate that SP-A1 and SP-D are subject to methylation/demethylation regulatory mechanisms and are involved in lung cancer pathogenesis by virtue of their function in innate host defense and/or regulation of inflammation.

Surfactant protein D suppresses lung cancer progression by downregulation of epidermal growth factor signaling

“…The genetic abnormalities in SP-D are associated with lung cancer pathogenesis. 13,14 Reduced SP-D expression in BAL fluid has relevance to subsequent lung cancer risk. 15 The level of SP-D in BAL fluid of patients with idiopathic pulmonary fibrosis (IPF) is decreased 31 and the incidence of lung cancer is increased in patients with IPF.…”

“…The genetic abnormalities in SP-D were associated with lung cancer pathogenesis. 13,14 Reduced SP-D expression in bronchoalveolar lavage (BAL) fluid was linked to subsequent lung cancer risk. 15 Although these studies suggested that SP-D suppressed lung cancer progression, the particular mechanisms remain unknown.…”

DNA Methylation and Nonsmall Cell Lung Cancer

“…Furthermore, CpG methylation density is very important due to a fact that low-density CpG methylation would merely repress a weak promoter, while high-density methylation is required for inhibition of a strong promoter (Bird, 1992). Global hypomethylation (Esteller and Herman, 2002) and regional promoter CGIs hypomethylation (Chilukamarri et al, 2007;Lin et al, 2007b;Kim et al, 2008) may activate proto-oncogenes, loss gene imprinting, and reactivate transposable elements. Nevertheless, hypermethylated CGIs may suppress the expression of genes that contribute to tumor suppression, chromatin condensation, and DNA repair (Baylin, 2005).…”

DNA methylation profile and expression of surfactant protein A2 gene in lung cancer

“…CpG sites (or islands) are short stretches of DNA with a high cytosine and guanine content (i.e., CG content), with a phosphodiester bond connecting the two residues. Significant differences in the methylation status of two CpG sites of the SFTPA1 gene in lung cancer tissue compared to adjacent non-cancerous (NC) lung tissue have already been reported by us (19). These observations pointed to the possibility that SFTPA1 is a potential biomarker that could be used for diagnosis and treatment of lung cancer (8).…”

“…We have previously shown alterations in the DNA methylation profile of genes that encode innate immunity molecules, the surfactant proteins in lung cancer (19). We concluded that methylation/demethylation of CpG sites of the SFTPA1 and SP-D promoters results in altered gene expression and this in turn may contribute to the development of lung inflammatory disease and lung cancer (19). …”