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

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. Insm1 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/ERK1/2, 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.

[1]  M. Breslin,et al.  5′-Iodotubercidin represses insulinoma-associated-1 expression, decreases cAMP levels, and suppresses human neuroblastoma cell growth , 2019, Journal of Biological Chemistry.

[2]  Youdinghuan Chen,et al.  INSM1 Is More Sensitive and Interpretable than Conventional Immunohistochemical Stains Used to Diagnose Merkel Cell Carcinoma , 2018, The American journal of surgical pathology.

[3]  M. Lan,et al.  Targeted deletion of Insm2 in mice result in reduced insulin secretion and glucose intolerance , 2018, Journal of Translational Medicine.

[4]  C. Birchmeier,et al.  Haploinsufficiency of Insm1 Impairs Postnatal Baseline β-Cell Mass , 2018, Diabetes.

[5]  S. Mukhopadhyay,et al.  Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections , 2018, Modern Pathology.

[6]  M. Cheatham,et al.  Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1 , 2018, Nature.

[7]  M. Breslin,et al.  Sonic hedgehog signaling pathway promotes INSM1 transcription factor in neuroendocrine lung cancer. , 2018, Cellular signalling.

[8]  F. Rodriguez,et al.  INSM1 Expression Is Frequent in Primary Central Nervous System Neoplasms but Not in the Adult Brain Parenchyma , 2018, Journal of neuropathology and experimental neurology.

[9]  S. Mukhopadhyay,et al.  Insulinoma‐associated protein 1 is a sensitive and specific marker of neuroendocrine lung neoplasms in cytology specimens , 2018, Cancer cytopathology.

[10]  Christiane Haffner,et al.  Insm1 Induces Neural Progenitor Delamination in Developing Neocortex via Downregulation of the Adherens Junction Belt-Specific Protein Plekha7 , 2018, Neuron.

[11]  Y. Akagi,et al.  Insulinoma-associated protein 1 (INSM1) is a useful marker for pancreatic neuroendocrine tumor , 2018, Medical Molecular Morphology.

[12]  S. Mukhopadhyay,et al.  Insulinoma‐associated protein 1 (INSM1) differentiates carcinoid tumourlets of the lung from pulmonary meningothelial‐like nodules , 2018, Histopathology.

[13]  R. Lloyd,et al.  Insulinoma‐associated 1: A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma) , 2018, Journal of cutaneous pathology.

[14]  S. Iwasaki,et al.  LSD1 Inhibitor T-3775440 Inhibits SCLC Cell Proliferation by Disrupting LSD1 Interactions with SNAG Domain Proteins INSM1 and GFI1B. , 2017, Cancer research.

[15]  P. Illei,et al.  INSM1 Demonstrates Superior Performance to the Individual and Combined Use of Synaptophysin, Chromogranin and CD56 for Diagnosing Neuroendocrine Tumors of the Thoracic Cavity , 2017, The American journal of surgical pathology.

[16]  T. Kameya,et al.  A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: Analysis of 37 cases. , 2017, Gynecologic oncology.

[17]  S. McWeeney,et al.  REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation–differentiation balance in the developing brain , 2017, Proceedings of the National Academy of Sciences.

[18]  M. Breslin,et al.  Ectopic expression of a small cell lung cancer transcription factor, INSM1 impairs alveologenesis in lung development , 2016, BMC Pulmonary Medicine.

[19]  M. Breslin,et al.  Tumor-specific promoter-driven adenoviral therapy for insulinoma , 2016, Cellular Oncology.

[20]  Takaaki Ito,et al.  Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer. , 2015, The American journal of pathology.

[21]  C. Birchmeier,et al.  Insm1 controls the differentiation of pulmonary neuroendocrine cells by repressing Hes1. , 2015, Developmental biology.

[22]  M. Breslin,et al.  INSM1 increases N-myc stability and oncogenesis via a positive-feedback loop in neuroblastoma , 2015, Oncotarget.

[23]  R. Lloyd,et al.  INSM1: A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and Neuroepithelial Neoplasms. , 2015, American journal of clinical pathology.

[24]  Anna B. Osipovich,et al.  Insm1 promotes endocrine cell differentiation by modulating the expression of a network of genes that includes Neurog3 and Ripply3 , 2014, Development.

[25]  M. Breslin,et al.  Extra-nuclear activity of INSM1 transcription factor enhances insulin receptor signaling pathway and Nkx6.1 expression through RACK1 interaction. , 2014, Cellular signalling.

[26]  M. Selbach,et al.  Insm1 controls development of pituitary endocrine cells and requires a SNAG domain for function and for recruitment of histone-modifying factors , 2013, Development.

[27]  M. Breslin,et al.  Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas , 2012, Cancer Gene Therapy.

[28]  M. Breslin,et al.  Functional role of an islet transcription factor, INSM1/IA‐1, on pancreatic acinar cell trans‐differentiation , 2012, Journal of cellular physiology.

[29]  Roman K. Thomas,et al.  A crucial requirement for Hedgehog signaling in small cell lung cancer , 2011, Nature Medicine.

[30]  M. Lan,et al.  Expression of insulinoma-associated 2 (INSM2) in pancreatic islet cells is regulated by the transcription factors Ngn3 and NeuroD1. , 2011, Endocrinology.

[31]  M. Breslin,et al.  Insulinoma-associated antigen-1 zinc-finger transcription factor promotes pancreatic duct cell trans-differentiation. , 2010, Endocrinology.

[32]  M. Breslin,et al.  INSM1 promoter-driven adenoviral herpes simplex virus thymidine kinase cancer gene therapy for the treatment of primitive neuroectodermal tumors. , 2009, Human gene therapy.

[33]  M. Breslin,et al.  Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  M. Breslin,et al.  Zinc Finger Transcription Factor INSM1 Interrupts Cyclin D1 and CDK4 Binding and Induces Cell Cycle Arrest* , 2009, Journal of Biological Chemistry.

[35]  M. Pollak,et al.  Insulin and insulin-like growth factor signalling in neoplasia , 2008, Nature Reviews Cancer.

[36]  S. Pääbo,et al.  Insulinoma-Associated 1 Has a Panneurogenic Role and Promotes the Generation and Expansion of Basal Progenitors in the Developing Mouse Neocortex , 2008, Neuron.

[37]  E. Bellefroid,et al.  Xenopus zinc finger transcription factor IA1 (Insm1) expression marks anteroventral noradrenergic neuron progenitors in Xenopus embryos , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[38]  M. Breslin,et al.  Identification of an INSM1-binding site in the insulin promoter: negative regulation of the insulin gene transcription. , 2008, The Journal of endocrinology.

[39]  D. Gerrelli,et al.  Transient expression of the conserved zinc finger gene INSM1 in progenitors and nascent neurons throughout embryonic and adult neurogenesis , 2008, The Journal of comparative neurology.

[40]  C. Birchmeier,et al.  Insm1 (IA-1) is a crucial component of the transcriptional network that controls differentiation of the sympatho-adrenal lineage , 2008, Development.

[41]  J. Joly,et al.  Ol-insm1b, a SNAG family transcription factor involved in cell cycle arrest during medaka development. , 2007, Developmental biology.

[42]  M. Breslin,et al.  Neurogenin 3 recruits CBP co‐activator to facilitate histone H3/H4 acetylation in the target gene INSM1 , 2007, FEBS letters.

[43]  L. Nguyen,et al.  Proneural bHLH and Brn proteins coregulate a neurogenic program through cooperative binding to a conserved DNA motif. , 2006, Developmental cell.

[44]  Yusuke Nakamura,et al.  Gene expression profiles of small-cell lung cancers: molecular signatures of lung cancer. , 2006, International journal of oncology.

[45]  C. Birchmeier,et al.  The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells. , 2006, Genes & development.

[46]  M. Breslin,et al.  INSM1 functions as a transcriptional repressor of the neuroD/beta2 gene through the recruitment of cyclin D1 and histone deacetylases. , 2006, The Biochemical journal.

[47]  M. Breslin,et al.  The insulinoma-associated 1: a novel promoter for targeted cancer gene therapy for small-cell lung cancer , 2006, Cancer Gene Therapy.

[48]  R. F. Luco,et al.  IA1 is NGN3‐dependent and essential for differentiation of the endocrine pancreas , 2006, The EMBO journal.

[49]  M. Breslin,et al.  NeuroD1/E47 Regulates the E-box Element of a Novel Zinc Finger Transcription Factor, IA-1, in Developing Nervous System* , 2003, Journal of Biological Chemistry.

[50]  N. Pedersen,et al.  Transcriptional gene expression profiling of small cell lung cancer cells. , 2003, Cancer research.

[51]  M. Lan,et al.  The zinc-finger transcription factor INSM1 is expressed during embryo development and interacts with the Cbl-associated protein. , 2002, Genomics.

[52]  M. Breslin,et al.  Expression of a Novel Zinc-Finger cDNA, IA-1, Is Associated with Rat AR42J Cells Differentiation into Insulin-Positive Cells , 2002, Pancreas.

[53]  M. Breslin,et al.  Neuroendocrine differentiation factor, IA-1, is a transcriptional repressor and contains a specific DNA-binding domain: identification of consensus IA-1 binding sequence. , 2002, Nucleic acids research.

[54]  M. Murphy,et al.  The Corepressor mSin3a Interacts with the Proline-Rich Domain of p53 and Protects p53 from Proteasome-Mediated Degradation , 2001, Molecular and Cellular Biology.

[55]  M. Tsai,et al.  Regulation of the Pancreatic Islet-Specific GeneBETA2 (neuroD) by Neurogenin 3 , 2000, Molecular and Cellular Biology.

[56]  T. Shioda,et al.  The Smad4 Activation Domain (SAD) Is a Proline-rich, p300-dependent Transcriptional Activation Domain* , 2000, The Journal of Biological Chemistry.

[57]  M. Lan,et al.  Molecular characterization of the promoter region of a neuroendocrine tumor marker, IA-1. , 1997, Biochemical and biophysical research communications.

[58]  G. Mohapatra,et al.  Targeted expression of MYCN causes neuroblastoma in transgenic mice , 1997, The EMBO journal.

[59]  P. Tsichlis,et al.  The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal , 1996, Molecular and cellular biology.

[60]  R. Palmiter,et al.  Noradrenaline is essential for mouse fetal development , 1995, Nature.

[61]  R. Palmiter,et al.  Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development , 1995, Nature.

[62]  M. Lan,et al.  Genomic organization, 5'-upstream sequence, and chromosomal localization of an insulinoma-associated intronless gene, IA-1. , 1994, The Journal of biological chemistry.

[63]  M. Lan,et al.  IA-1, a new marker for neuroendocrine differentiation in human lung cancer cell lines. , 1993, Cancer research.

[64]  M. de Silva,et al.  A novel human insulinoma-associated cDNA, IA-1, encodes a protein with "zinc-finger" DNA-binding motifs. , 1992, The Journal of biological chemistry.

[65]  J. Bergh,et al.  Increased expression of N-myc in human small cell lung cancer biopsies predicts lack of response to chemotherapy and poor prognosis. , 1987, American journal of clinical pathology.

[66]  B. Mackler,et al.  Further studies on the structural requirements for polypeptide-mediated histamine release from rat mast cells. , 1979, The Biochemical journal.

[67]  V. Mutt,et al.  Chemical determination of polypeptide hormones. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[68]  Harris Gw.  DEVELOPMENT AND PRESENT STATUS OF NEUROENDOCRINOLOGY , 1965 .

[69]  J. Bishop,et al.  INSM1 is a Sensitive and Specific Marker of Neuroendocrine Differentiation in Head and Neck Tumors , 2018, The American journal of surgical pathology.

[70]  M. Breslin,et al.  Detection of neuroendocrine tumors using promoter-specific secreted Gaussia luciferase. , 2016, International journal of oncology.

[71]  M. Breslin,et al.  Adenoviral insulinoma-associated protein 1 promoter-driven suicide gene therapy with enhanced selectivity for treatment of neuroendocrine cancers. , 2013, The Ochsner journal.

[72]  E. Lander,et al.  Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[73]  G. Harris.  [DEVELOPMENT AND PRESENT STATUS OF NEUROENDOCRINOLOGY]. , 1965, Deutsche medizinische Wochenschrift.

[74]  H. Grosse.  [Diabetes and cancer]. , 1956, Deutsche Zeitschrift fur Verdauungs- und Stoffwechselkrankheiten.