Sonic hedgehog-Gli1 signaling pathway might become an effective therapeutic target in gastrointestinal neuroendocrine carcinomas
Autor: | Kenji Oda, Takashi Shida, Keiji Koda, Masaru Miyazaki, Takashi Nikaido, Takashi Kishimoto, Hiroshi Ishikura, Yukio Nakatani, Masakazu Hasegawa, Mitsuko Furuya |
---|---|
Rok vydání: | 2006 |
Předmět: |
Male
Cancer Research Pathology medicine.medical_specialty Cyclopamine Adenocarcinoma Biology medicine.disease_cause Zinc Finger Protein GLI1 Gastrointestinal epithelium chemistry.chemical_compound GLI1 Cell Line Tumor medicine Humans Hedgehog Proteins RNA Neoplasm Sonic hedgehog Hedgehog In Situ Hybridization Aged DNA Primers Gastrointestinal Neoplasms Aged 80 and over Oncogene Proteins Pharmacology Gastrointestinal tract Reverse Transcriptase Polymerase Chain Reaction Wnt signaling pathway Middle Aged digestive system diseases Neuroendocrine Tumors Oncology chemistry Trans-Activators biology.protein Molecular Medicine Female Carcinogenesis Signal Transduction |
Zdroj: | Cancer Biology & Therapy. 5:1530-1538 |
ISSN: | 1555-8576 1538-4047 |
DOI: | 10.4161/cbt.5.11.3458 |
Popis: | Gastrointestinal neuroendocrine carcinomas (NECs) are extremely aggressive and poorly prognostic. We showed previously that human achaete-scute homologue gene 1 (hASH1), a basic helix-loop-helix transcription factor regulated by Notch, was aberrantly expressed in NECs. To date, no effective therapeutic strategies for NECs have been investigated. Notch, Wnt and Hedgehog (Hh) signalings are important for stem cell self-renewal and carcinogenesis in the gastrointestinal epithelium. In this study, we showed that Hh signaling was clearly upregulated in NECs in Gli1-dependent manner. Specific therapeutic effects of cyclopamine on NECs were also demonstrated. RT-PCR showed that among eight frozen samples (three NECs, one carcinoid tumor, three adenocarcinomas and one normal mucosa), the band intensities of Gli1 were the strongest in NECs, moderately strong in a carcinoid tumor, very weak in adenocarcinomas and undetectable in a normal mucosa. In real-time RT-PCR, the expression levels of Gli1 in NECs were 108.4, 28.6 and 16.3 times higher than that in an adenocarcinoma. In immunohistochemistry using 25 paraffin-embedded tissues, all twelve NECs and three of six carcinoid tumors showed positive stainings for Gli1, whereas six of seven adenocarcinomas were negative. In vitro, RT-PCR showed that NEC cell lines expressed Gli1 mRNA significantly. Administration of cyclopamine suppressed cell proliferation and invasion, and induced apoptosis in NECs. In cyclopamine-treated NECs, downregulation of Gli1, Ptch1, Snail and hASH1, and upregulation of E-cadherin were demonstrated at mRNA levels. Such effects were not observed in a Gli1-negative colonic adenocarcinoma cell line or in control alkaloid-treated NECs. Hh signaling may play a crucial role in the pathophysiology of NECs. Blockade of Hh pathway using cyclopamine or its synthetic derivatives might open an effective therapeutic strategy to NECs, not only by suppressing tumor viability but also by altering tumor cell nature. |
Databáze: | OpenAIRE |
Externí odkaz: |