Back to Search Start Over

The sonic hedgehog signaling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth

Authors :
Jean-Jacques Helwig
Didier Jacqmin
Sylvie Rothhut
Catherine Coquard
Sabrina Danilin
Valérian Dormoy
Lionel Thomas
Thierry Massfelder
Hervé Lang
Véronique Lindner
Développement et physiopathologie de l'intestin et du pancréas
Institut National de la Santé et de la Recherche Médicale (INSERM)
Service de pathologie
Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse)
Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA)
Service d'urologie
Nouvel Hôpital Civil de Strasbourg
This study was sponsored by INSERM, University of Strasbourg and the French Ligue Contre le Cancer (Comités du Bas-Rhin et du Haut-Rhin et Comité National, recipient TM).
BMC, Ed.
Source :
Molecular Cancer, Molecular Cancer, BioMed Central, 2009, 8 (1), pp.123. ⟨10.1186/1476-4598-8-123⟩, Molecular Cancer, Vol 8, Iss 1, p 123 (2009)
Publication Year :
2009
Publisher :
HAL CCSD, 2009.

Abstract

Background Human clear cell renal cell carcinoma (CRCC) remains resistant to therapies. Recent advances in Hypoxia Inducible Factors (HIF) molecular network led to targeted therapies, but unfortunately with only limited clinical significance. Elucidating the molecular processes involved in kidney tumorigenesis and resistance is central to the development of improved therapies, not only for kidney cancer but for many, if not all, cancer types. The oncogenic PI3K/Akt, NF-kB and MAPK pathways are critical for tumorigenesis. The sonic hedgehog (SHH) signaling pathway is crucial to normal development. Results By quantitative RT-PCR and immunoblot, we report that the SHH signaling pathway is constitutively reactivated in tumors independently of the von Hippel-Lindau (VHL) tumor suppressor gene expression which is inactivated in the majority of CRCC. The inhibition of the SHH signaling pathway by the specific inhibitor cyclopamine abolished CRCC cell growth as assessed by cell counting, BrdU incorporation studies, fluorescence-activated cell sorting and β-galactosidase staining. Importantly, inhibition of the SHH pathway induced tumor regression in nude mice through inhibition of cell proliferation and neo-vascularization, and induction of apoptosis but not senescence assessed by in vivo studies, immunoblot and immunohistochemistry. Gli1, cyclin D1, Pax2, Lim1, VEGF, and TGF-β were exclusively expressed in tumors and were shown to be regulated by SHH, as evidenced by immunoblot after SHH inhibition. Using specific inhibitors and immunoblot, the activation of the oncogenic PI3K/Akt, NF-kB and MAPK pathways was decreased by SHH inhibition. Conclusions These findings support targeting SHH for the treatment of CRCC and pave the way for innovative and additional investigations in a broad range of cancers.

Details

Language :
English
ISSN :
14764598
Database :
OpenAIRE
Journal :
Molecular Cancer, Molecular Cancer, BioMed Central, 2009, 8 (1), pp.123. ⟨10.1186/1476-4598-8-123⟩, Molecular Cancer, Vol 8, Iss 1, p 123 (2009)
Accession number :
edsair.doi.dedup.....d1de0e8937ca923a4c168123fde4888a