NEUROD1 is highly expressed in extensive disease small cell lung cancer by promoting migration

Abstract

Recent genomic analyses revealed that aberrant expression of specific transcription factors such as neurogenic differentiation (NEUROD1) as well as achaete-scute homolog1 (ASCL1) have been observed in Small cell lung cancer (SCLC). Previous studies bases on SCLC cell lines and surgical specimens showed that mRNA expression and target genes of NEUROD1 are largely distinct from those of ASCL1, however, protein level and expression patterns or these transcription factors in clinical samples as well as its relation to clinicopathological characteristics such as disease stages have not been elucidated. We retrospectively analyzed specimens from 95 SCLC patients between June 1988 and December 2017, and immunohistochemical (IHC) staining of NEUROD1 as well as ASCL1 was performed. Furthermore, we examined the gain or loss of function of the NEUROD1 gene on proliferation and migration by transfection in SCLC cell lines. The IHC score of NEUROD1 was significantly higher in extensive disease (ED) samples than those in limited disease (LD) samples (median score 160 vs 80; P=0.0389), whereas we found that proportion of tumors with ASCL–1 high⁄NEUROD1–low were lower in ED SCLC than that of LD SCLC (15% vs 40%). Expression of ASCL1 or NEUROD1 itself did not affect the survival of SCLC patients or sensitivity to cytotoxic agents. Our vitro data showed that upregulation of NEUROD1 in SCLC cells promoted transwell migration irrespective of ASCL1 expression, which could account for the association of NEUROD1 expression with ED SCLC. Our finding indicates that NEUROD1 expression increases in ED SCLC by promoting migration and metastasis of SCLC cells.