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The sonic hedgehog signaling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth
- 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.
- Subjects :
- MESH: Signal Transduction
Cancer Research
Apoptosis
MESH: Veratrum Alkaloids
medicine.disease_cause
Mice
0302 clinical medicine
MESH: Reverse Transcriptase Polymerase Chain Reaction
MESH: Animals
Sonic hedgehog
0303 health sciences
biology
Reverse Transcriptase Polymerase Chain Reaction
Veratrum Alkaloids
MESH: Carcinoma, Renal Cell
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Kidney Neoplasms
3. Good health
Oncology
Hypoxia-inducible factors
Von Hippel-Lindau Tumor Suppressor Protein
030220 oncology & carcinogenesis
Molecular Medicine
MESH: Cell Division
[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Cell Division
Signal Transduction
MESH: Cell Line, Tumor
Blotting, Western
Mice, Nude
[SDV.CAN]Life Sciences [q-bio]/Cancer
lcsh:RC254-282
03 medical and health sciences
[SDV.CAN] Life Sciences [q-bio]/Cancer
Cell Line, Tumor
MESH: Cell Proliferation
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
medicine
MESH: Mice, Nude
Animals
Humans
MESH: Blotting, Western
Hedgehog Proteins
Protein kinase B
Carcinoma, Renal Cell
MESH: Mice
PI3K/AKT/mTOR pathway
030304 developmental biology
Cell Proliferation
MESH: Humans
Research
MESH: Apoptosis
Cancer
MESH: Hedgehog Proteins
medicine.disease
MESH: Von Hippel-Lindau Tumor Suppressor Protein
Clear cell renal cell carcinoma
Cancer research
biology.protein
MESH: Kidney Neoplasms
Carcinogenesis
Kidney cancer
Subjects
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