9 Citations (Scopus)


Neuroblastoma is the second most common pediatric malignancy and has a high rate of spontaneous remission. Uncovering the mechanisms underlying neuroblastoma cell differentiation is critical for therapeutic purposes. A neuroblastoma cell line (N2a) treated with either serum withdrawal (<2.5%) or melatonin (>0.1 nmol/L) for 24 hours was used as a cell differentiation research model. Interestingly, the hyaluronan synthase 3 (HAS3) protein was induced in differentiated N2a cells. N2a-allografted nude mice received an intraperitoneal injection of melatonin (40 or 80 mg/kg/day for 3 weeks). The mean tumor volume in mice treated with 80 mg/kg melatonin was smaller than that in PBS-treated mice (1416.3 and 3041.3 mm3, respectively, difference = 1625 mm3, *P = 0.0003, n = 7 per group). Compared with the vector control group, N2a cells with forced HAS3 overexpression showed significantly increased neuron length (*P = 0.00082) and neurite outgrowth (*P = 0.00059). Intracellular changes in autophagy, including distorted mitochondria with abnormal circular inner membranes, were detected by transmission electron microscopy (TEM). Our study demonstrated that HAS3-mediated signaling activated by physiological concentrations of melatonin (>0.1 nmol/L) triggered significant N2a cell differentiation. These results provide molecular data with potential clinical relevance for therapeutic drug development.

Original languageEnglish
Pages (from-to)4821-4835
Number of pages15
JournalCancer Medicine
Issue number10
Publication statusPublished - Jan 1 2019


  • autophagy
  • hyaluronan synthase 3
  • melatonin
  • N2a cell differentiation
  • neuroblastoma

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research


Dive into the research topics of 'Melatonin promotes neuroblastoma cell differentiation by activating hyaluronan synthase 3-induced mitophagy'. Together they form a unique fingerprint.

Cite this