Insulinoma-Associated-1: From Neuroendocrine Tumor Marker to Cancer Therapeutics

• Published in: Molecular cancer research Vol. 17; no. 8; pp. 1597 - 1604
• Main Authors: Chen, Chiachen, Notkins, Abner L, Lan, Michael S
• Format: Journal Article
• Language: English
• Published: United States 01.08.2019
• Subjects: Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Humans; Molecular Targeted Therapy; Neuroendocrine Tumors - diagnosis; Neuroendocrine Tumors - drug therapy; Neuroendocrine Tumors - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-19-0286

Insulinoma-associated-1 (IA-1 or INSM1) encodes a zinc-finger transcription factor, which was isolated from a human insulinoma subtraction library, with specific expression patterns, predominantly in developing neuroendocrine tissues and tumors. INSM1 is key in early pancreatic endocrine, sympatho-adrenal lineage, and pan-neurogenic precursor development. gene ablation results in impairment of pancreatic β cells, catecholamine biosynthesis, and basal progenitor development during mammalian neocortex maturation. Recently, INSM1 has emerged as a superior, sensitive, and specific biomarker for neuroendocrine tumors. INSM1 regulates downstream target genes and exhibits extranuclear activities associated with multiple signaling pathways, including Sonic Hedgehog, PI3K/AKT, MEK/ERK , ADK, p53, Wnt, histone acetylation, LSD1, cyclin D1, Ascl1, and N-myc. Novel strategies targeting INSM1-associated signaling pathways facilitate the suppression of neuroendocrine tumor growth. In addition, INSM1 promoter-driven reporter assay and/or suicide gene therapy are promising effective therapeutic approaches for targeted specific neuroendocrine tumor therapy. In this review, the current knowledge of the biological role of INSM1 as a neuroendocrine tumor biomarker is summarized, and novel strategies targeting multiple signaling pathways in the context of INSM1 expression in neuroendocrine tumors are further explored. IMPLICATIONS: Neuroendocrine transcription factor (INSM1) may serve as a neuroendocrine biomarker for the development of novel cancer therapeutics against neuroendocrine tumors.