trypsinogen and Carcinoma--Non-Small-Cell-Lung

The serine protease family member PRSS3 (trypsinogen-IV) has been implicated as a putative tumor suppressor gene due to its loss of expression, which is correlated with promoter hypermethylation, in esophageal squamous cell carcinoma and gastric adenocarcinoma. As epigenetic alteration is common in non-small cell lung cancer (NSCLC), we sought to determine if promoter hypermethylation of PRSS3 occurred in this disease, and if it was associated with clinical features of NSCLC or tobacco-related exposures in these patients. Using methylation-specific PCR, we determined the promoter hypermethylation status of PRSS3 in a case series study of primary NSCLC, and found methylation of this gene to be common, occurring in 53% (86 of 166) of tumors examined. There was no association of this alteration with patient demographics, tumor features, or exposure histories of the patients. The lack of association is of interest, as it may suggest a lack of specific selection for inactivation of this gene. On the other hand, the high prevalence of this alteration makes PRSS3 methylation an attractive biomarker for use in diagnostic or screening applications in NSCLC.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; CpG Islands; DNA Methylation; Epigenesis, Genetic; Female; Gene Silencing; Genes, Tumor Suppressor; Humans; Lung Neoplasms; Male; Middle Aged; Promoter Regions, Genetic; Smoking; Trypsin; Trypsinogen

Distant metastasis is the predominant cause of death in early-stage non-small cell lung cancer (NSCLC). Currently, it is impossible to predict the occurrence of metastasis at early stages and thereby separate patients who could be cured by surgical resection alone from patients who would benefit from additional chemotherapy. In this study, we applied a comparative microarray approach to identify gene expression differences between early-stage NSCLC patients whose cancer ultimately did or did not metastasize during the course of their disease. Transcriptional profiling of 82 microarrays from two patient groups revealed differential expression of several gene families including known predictors of metastasis (e.g., matrix metalloproteinases). In addition, we found S100P, S100A2, trypsinogen C (TRY6), and trypsinogen IVb (PRSS3) to be overexpressed in tumors that metastasized during the course of the disease. In a third group of 42 patients, we confirmed the induction of S100 proteins and trypsinogens in metastasizing tumors and its significant correlation with survival by real-time quantitative reverse transcription-PCR. Overexpression of S100A2, S100P, or PRSS3 in NSCLC cell cultures led to increased transendothelial migration, corroborating the role of S100A2, S100P, and PRSS3 in the metastatic process. Taken together, we provide evidence that expression of S100 proteins and trypsinogens is associated with metastasis and predicts survival in early stages of NSCLC. For the first time, this implicates a role of S100 proteins and trypsinogens in the metastatic process of early-stage NSCLC.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Movement; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; S100 Proteins; Trypsinogen