Interplay: The Essential Role between INSM1 and N-Myc in Aggressive Neuroblastoma

SIMPLE SUMMARY: Neuroblastoma (NB) is a cancer that starts in certain very early forms of nerve cells of the sympathetic nervous system, most often found in an embryo or fetus. Symptoms may include bone pain, an abdominal mass, frequent urination, limping, anemia, spinal cord weakness, or bruising of the eye area. N-Myc is a key driver of high-risk NB. An elevated expression of N-Myc often predicts a poorer prognosis, in both time to tumor progression and overall survival rate. We discovered a transcription factor, insulinoma-associated-1 (INSM1), as the downstream target gene of N-Myc. INSM1 has emerged as a novel NB biomarker that plays a critical role in facilitating NB tumor cell development. Both N-Myc and INSM1 demonstrate high clinical relevance to NB. Therefore, further understanding the association of INSM1 and N-Myc functions in aggressive NB should be beneficial for future NB treatment. ABSTRACT: An aggressive form of neuroblastoma (NB), a malignant childhood cancer derived from granule neuron precursors and sympathoadrenal lineage, frequently comprises MYCN amplification/elevated N-Myc expression, which contributes to the development of neural crest-derived embryonal malignancy. N-Myc is an oncogenic driver in NB. Persistent N-Myc expression during the maturation of SA precursor cells can cause blockage of the apoptosis and induce abnormal proliferation, resulting in NB development. An insulinoma-associated-1 (INSM1) zinc-finger transcription factor has emerged as an NB biomarker that plays a critical role in facilitating tumor cell growth and transformation. INSM1 plays an essential role in sympathoadrenal cell differentiation. N-Myc activates endogenous INSM1 through an E2-box of the INSM1 proximal promoter, whereas INSM1 enhances N-Myc stability via RAC-α-serine/threonine protein kinase (AKT) phosphorylation in NB. The ectopic expression of INSM1 stimulates NB tumor growth in contrast to the knockdown of INSM1 that inhibits NB cell proliferation. The clinical pathological result and bioinformatics analysis show that INSM1 is a strong diagnostic and a prognostic biomarker for the evaluation of NB progression. The INSM1/N-Myc expression shows high clinical relevance in NB. Therefore, targeting the INSM1/N-Myc-associated signaling axis should be a feasible approach to identifying new drugs for the suppression of NB tumor growth.