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Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
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Sonic Hedgehog-Gli1 signaling pathway might become an effective therapeutic target in gastrointestinal neuroendocrine

Takashi Shida1, Mitsuko Furuya, Takashi Nikaido

  • 1Departments of Molecular Pathology, General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Cancer Biology & Therapy
|November 15, 2006
PubMed

Insights

Hedgehog (Hh) signaling is upregulated in aggressive gastrointestinal neuroendocrine carcinomas (NECs). Targeting this pathway with cyclopamine suppressed NEC growth and invasion, suggesting a new therapeutic strategy.

Area of Science:

  • Oncology
  • Gastroenterology
  • Molecular Biology

Background:

  • Gastrointestinal neuroendocrine carcinomas (NECs) are highly aggressive with poor prognosis.
  • Aberrant expression of human achaete-scute homologue gene 1 (hASH1) is observed in NECs.
  • Notch, Wnt, and Hedgehog (Hh) signaling pathways are implicated in gastrointestinal stem cell self-renewal and carcinogenesis.

Purpose of the Study:

  • To investigate the role of Hedgehog (Hh) signaling in the pathophysiology of gastrointestinal NECs.
  • To evaluate the therapeutic potential of targeting Hh signaling in NECs.

Main Methods:

  • Quantitative real-time RT-PCR and immunohistochemistry to assess Gli1 expression in NECs, carcinoid tumors, adenocarcinomas, and normal mucosa.
  • In vitro studies using NEC cell lines treated with cyclopamine, a Hh signaling inhibitor.
  • Analysis of cell proliferation, invasion, apoptosis, and gene expression changes (Gli1, Ptch1, Snail, hASH1, E-cadherin) following cyclopamine treatment.

Main Results:

  • Hedgehog (Hh) signaling, indicated by Gli1 expression, was significantly upregulated in NECs compared to adenocarcinomas and normal tissues.
  • Cyclopamine treatment suppressed NEC cell proliferation and invasion, and induced apoptosis in vitro.
  • Cyclopamine treatment led to downregulation of Gli1, Ptch1, Snail, and hASH1, and upregulation of E-cadherin in NEC cells.

Conclusions:

  • Hedgehog (Hh) signaling plays a critical role in the development and progression of gastrointestinal NECs.
  • Inhibition of Hh signaling via cyclopamine demonstrates therapeutic efficacy by reducing tumor viability and altering tumor cell characteristics.
  • Targeting the Hh pathway with cyclopamine or its derivatives represents a promising therapeutic strategy for NECs.

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