MA11.03 INSM1 is a Novel Biomarker and a Crucial Regulator of the Neuroendocrine Differentiation Pathway in Neuroendocrine Tumors of the Lung

Abstract

Insulinoma-associated protein 1 (INSM1) is expressed predominantly in embryonic developing neuroendocrine (NE) tissues, and the expression is significantly reduced/restricted in adult tissues. We previously revealed that INSM1 is expressed exclusively in small cell lung cancer (SCLC) compared to non-small cell lung cancer (NSCLC). The significance of the expression of INSM1 in lung cancer has been largely unknown. We investigated the utility of INSM1 as a novel immunohistochemical marker and researched the biological significance in lung cancer cell lines. We compared INSM1 as an immunohistochemical marker for NE tumors of the lung to conventional markers (chromogranin A (CGA), synaptophysin (SYP), and CD56). To elucidate the biological function of INSM1 in the NE differentiation pathway, we conducted INSM1 gene knockdown/overexpression experiments using human lung cancer cell lines. INSM1 was expressed in 100% of SCLCs (44/44), large cell neuroendocrine cell carcinomas (7/7), and Carcinoids (11/11), but was not expressed in NSCLCs (90 adenocarcinomas and 47 squamous cell carcinomas). This novel immnohistochemical marker showed high sensitivity and specificity when compared to conventional NE markers. We demonstrated that knockdown of INSM1 expression resulted in significant reduction of NE molecules in SCLC cell lines, and overexpression of INSM1 induced NE differentiation in NSCLC cell lines. INSM1 was a superior NE immunohistochemical marker when compared to conventional markers. Furthermore, our biological molecular experiments revealed that INSM1 is a critical upstream regulator of the NE differentiation pathway in SCLC cell lines. The elucidation of the significance of INSM1 expression in lung cancer strongly supports the diagnosis of NE tumors of the lung and promotes the understanding of the molecular biology of these tumors.