Restore the brake on tumor progression

Biochem Pharmacol. 2017 Aug 15:138:1-6. doi: 10.1016/j.bcp.2017.04.003. Epub 2017 Apr 5.

Abstract

Sonic hedgehog (Shh) signaling plays a key role in regulation of normal development. The negative feedback mechanism mediated by the transcriptional factor, Gli3, acts to finely tune Shh signaling, providing tight control of normal developmental processes. Hyperactivation of Shh signaling often leads to many human malignancies, including basal cell carcinoma and medulloblastoma (MB). However, how tumor cells sustain the aberrant activation of Shh signaling is still not completely understood. We recently revealed that during MB formation, tumor cells express Nestin, a type VI intermediate filament protein, which maintains uncontrolled Shh signaling by abolishing negative feedback by Gli3. Therefore, Nestin expression is a necessary step for MB formation. These findings highlight the novel function of Nestin in regulating Shh signaling, as well as the important role of a disrupted negative feedback mechanism in MB tumorigenesis. Further, restoration of the intrinsic negative feedback by repressing Nestin expression represents a promising approach to treat MB as well as other Shh signaling associated malignancies.

Keywords: Medulloblastoma; Negative feedback loop; Nestin; Sonic hedgehog; Therapeutic target.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Cerebellar Neoplasms / drug therapy*
  • Cerebellar Neoplasms / metabolism
  • Cerebellar Neoplasms / pathology
  • Cerebellar Neoplasms / physiopathology
  • Disease Progression
  • Feedback, Physiological / drug effects
  • Hedgehog Proteins / metabolism*
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Medulloblastoma / drug therapy*
  • Medulloblastoma / metabolism
  • Medulloblastoma / pathology
  • Medulloblastoma / physiopathology
  • Models, Biological*
  • Molecular Targeted Therapy
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism*
  • Nestin / antagonists & inhibitors*
  • Nestin / metabolism
  • Signal Transduction / drug effects
  • Tumor Burden
  • Zinc Finger Protein Gli3

Substances

  • Antineoplastic Agents
  • GLI3 protein, human
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • NES protein, human
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Nestin
  • SHH protein, human
  • Zinc Finger Protein Gli3