Six Candidate Proneural Factor Messenger RNAs for the Differentiation of Neuroendocrine and Non-Neuroendocrine Carcinomas of the Lung

Background: Lung neuroendocrine carcinomas, i.e., small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC), and non-neuroendocrine carcinomas, e.g. squamous cell carcinoma and adenocarcinoma are both thought to arise from the same endoderm as respiratory epithelium. However, it is not clear how neuroendocrine carcinomas acquire and maintain their neuroendocrine features. To date, 19 proneural factors that function in the development of the fetal neural system and differentiation of neuroendocrine cells of endodermal origin have been identified. In this study, we investigated the specificity of proneural factor expression in SCLC, lung LCNEC, lung squamous cell carcinoma and lung adenocarcinoma.Methods: RNA was extracted from 3 SCLCs, 3 LCNECs, 10 invasive squamous cell carcinomas and 10 invasive adenocarcinomas. Specific PCR primers were generated for the 19 proneural factors and messenger RNA copy numbers were measured using reverse transcription real time PCR. Differences in expression were then statistically analysed.Results: Insulinoma-associated protein 1(INSM1) and mammalian achaete-scute homolog (MASH) 1 mRNA was significantly higher in SCLCs than in squamous cell carcinomas. Oligodendrocyte transcription factor (OLIG)1 and mammalian atonal homolog (MATH)2 mRNA levels were significantly lower in SCLCs and squamous cell carcinomas than in adenocarcinomas. OLIG2 mRNA levels were significantly lower in LCNECs than in adenocarcinomas. MATH3 mRNA levels in LCNECs were significantly higher than in both squamous cell carcinomas and adenocarcinomas.Conclusion: INSM1, MASH1, OLIG1, OLIG2, MATH2 and MATH3 are candidate proneural factors that could potentially differentiate lung neuroendocrine carcinomas from non-neuroendocrine carcinomas. In particular, MATH3 might be an LCNEC-specific factor.