The sonic hedgehog signaling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth.
The sonic hedgehog signaling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth.
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DOI：
10.1186/1476-4598-8-123
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发表时间：
2009-12-16
期刊：
影响因子：
37.3
通讯作者：
Massfelder T
中科院分区：
文献类型：
--
作者：
Dormoy V;Danilin S;Lindner V;Thomas L;Rothhut S;Coquard C;Helwig JJ;Jacqmin D;Lang H;Massfelder T
人类透明细胞肾细胞癌（CRCC）仍然对治疗有抵抗力。缺氧诱导因子（HIF）分子网络的最新进展导致了靶向治疗，但不幸的是临床意义有限。阐明肾肿瘤发生和耐药性中涉及的分子过程对于开发改进的疗法至关重要，不仅适用于肾癌，而且适用于许多（如果不是全部）癌症类型。致癌 PI3K/Akt、NF-kB 和 MAPK 通路对于肿瘤发生至关重要。声波刺猬 (SHH) 信号通路对于正常发育至关重要。通过定量 RT-PCR 和免疫印迹，我们报告 SHH 信号通路在肿瘤中持续重新激活，独立于 von Hippel-Lindau (VHL) 肿瘤抑制基因表达，而 VHL 肿瘤抑制基因在大多数 CRCC 中失活。通过细胞计数、BrdU 掺入研究、荧光激活细胞分选和 β-半乳糖苷酶染色评估，特异性抑制剂环杷明对 SHH 信号通路的抑制消除了 CRCC 细胞生长。重要的是，通过体内研究、免疫印迹和免疫组织化学评估，SHH途径的抑制通过抑制细胞增殖和新血管形成以及诱导细胞凋亡而不是衰老来诱导裸鼠肿瘤消退。 Gli1、cyclin D1、Pax2、Lim1、VEGF 和 TGF-β 仅在肿瘤中表达，并显示受 SHH 调节，SHH 抑制后的免疫印迹证明了这一点。使用特异性抑制剂和免疫印迹，通过抑制 SHH 降低致癌 PI3K/Akt、NF-kB 和 MAPK 通路的激活。这些发现支持以SHH为目标治疗CRCC，并为广泛癌症的创新和额外研究铺平了道路。
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. 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. 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.
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影响因子：
5.2
作者：
Bar, Eli E.;Chaudhry, Aneeka;Eberharta, Charles G.
通讯作者：
Eberharta, Charles G.
影响因子：
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Kaelin, William G., Jr.
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11.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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