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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-12-16

AUTHORS

Valérian Dormoy, Sabrina Danilin, Véronique Lindner, Lionel Thomas, Sylvie Rothhut, Catherine Coquard, Jean-Jacques Helwig, Didier Jacqmin, Hervé Lang, Thierry Massfelder

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 beta-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-beta 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. More... »

PAGES

123-123

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1476-4598-8-123

DOI

http://dx.doi.org/10.1186/1476-4598-8-123

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1009815086

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20015350


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43 Lim1
44 MAPK pathway
45 NF-kB
46 PAX2
47 PI3K/Akt
48 RT-PCR
49 SHH inhibition
50 Shh pathway
51 Sonic hedgehog
52 VEGF
53 activation
54 additional investigation
55 advances
56 apoptosis
57 beta-galactosidase staining
58 broad range
59 cancer
60 cancer types
61 carcinoma
62 cell carcinoma
63 cell counting
64 cell growth
65 cell proliferation
66 cell renal cell carcinoma
67 cell sorting
68 clear cell renal cell carcinoma
69 clinical significance
70 counting
71 cyclin D1
72 cyclopamine
73 development
74 expression
75 findings
76 fluorescence-activated cell sorting
77 gene expression
78 growth
79 hedgehog
80 human clear cell renal cell carcinoma
81 human renal cell carcinoma
82 immunoblot
83 immunohistochemistry
84 incorporation studies
85 induction
86 induction of apoptosis
87 inhibition
88 inhibitor cyclopamine
89 inhibitors
90 investigation
91 kidney cancer
92 kidney tumorigenesis
93 limited clinical significance
94 majority
95 majority of ccRCC
96 mice
97 molecular networks
98 molecular processes
99 network
100 normal development
101 nude mice
102 oncogenic PI3K/AKT
103 orchestral role
104 pathway
105 process
106 proliferation
107 quantitative RT-PCR
108 range
109 recent advances
110 regression
111 renal cell carcinoma
112 resistance
113 role
114 senescence
115 significance
116 sorting
117 specific inhibitor
118 specific inhibitor cyclopamine
119 staining
120 study
121 suppressor gene expression
122 therapy
123 treatment
124 treatment of ccRCC
125 tumor growth
126 tumor regression
127 tumor suppressor gene expression
128 tumorigenesis
129 tumors
130 types
131 vivo studies
132 von Hippel-Lindau (VHL) tumor suppressor gene expression
133 way
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