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Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo
Jonas Sjölund, … , Börje Ljungberg, Håkan Axelson
Jonas Sjölund, … , Börje Ljungberg, Håkan Axelson
Published December 13, 2007
Citation Information: J Clin Invest. 2008;118(1):217-228. https://doi.org/10.1172/JCI32086.
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Research Article Oncology Article has an altmetric score of 6

Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo

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Abstract

Loss of the tumor suppressor gene von Hippel–Lindau (VHL) plays a key role in the oncogenesis of clear cell renal cell carcinoma (CCRCC). The loss leads to stabilization of the HIF transcription complex, which induces angiogenic and mitogenic pathways essential for tumor formation. Nonetheless, additional oncogenic events have been postulated to be required for the formation of CCRCC tumors. Here, we show that the Notch signaling cascade is constitutively active in human CCRCC cell lines independently of the VHL/HIF pathway. Blocking Notch signaling resulted in attenuation of proliferation and restrained anchorage-independent growth of CCRCC cell lines. Using siRNA targeting the different Notch receptors established that the growth-promoting effects of the Notch signaling pathway were attributable to Notch-1 and that Notch-1 knockdown was accompanied by elevated levels of the negative cell-cycle regulators p21Cip1 and/or p27Kip1. Treatment of nude mice with an inhibitor of Notch signaling potently inhibited growth of xenotransplanted CCRCC cells. Moreover, Notch-1 and the Notch ligand Jagged-1 were expressed at significantly higher levels in CCRCC tumors than in normal human renal tissue, and the growth of primary CCRCC cells was attenuated upon inhibition of Notch signaling. These findings indicate that the Notch cascade may represent a novel and therapeutically accessible pathway in CCRCC.

Authors

Jonas Sjölund, Martin Johansson, Sugata Manna, Carl Norin, Alexander Pietras, Siv Beckman, Elise Nilsson, Börje Ljungberg, Håkan Axelson

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Figure 1

Notch signaling pathway components are expressed in CCRCC cells and maintained in a HIF-1α– and HIF-2α–independent manner.

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Notch signaling pathway components are expressed in CCRCC cells and main...
(A) Immunoblots of SKRC-7, SKRC-10, SKRC-21, SKRC-17, SKRC-52, and Caki-2 cell lysates analyzed for indicated proteins. Actin was used as a control for equal loading of samples. (B) Q-PCR analyses of Jagged-1, Jagged-2, Notch-1, Notch-2, Hes-1, and Hey-1 mRNA expression in CCRCC cells. mRNA levels were normalized to succinate dehydrogenase complex subunit A (SDHA), tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHAZ), and ubiquitin C (UBC) expression. Data shown are mean + SD of representative experiment performed in triplicate. (C) 786-O, PRC3, and WT7 cell lysates were analyzed for pVHL, HIF-2α, Jagged-1, Notch-1, and Hes-1 expression by Western blot analyses. (D) VEGF, Hes-1, and Hey-1 mRNA levels in WT7, PRC3, and 786-O cells. Data shown are mean + SD of representative experiment performed in triplicate. (E) PRC3 and WT7 cells, transfected with control (c-si) or HIF-2α siRNA (siHIF-2α) for 6 hours and then incubated under either normoxic (21% O2) or hypoxic (1% O2) conditions for 24 hours prior to protein extract preparation, were subjected to immunoblotting of indicated proteins. (F) Q-PCR analyses of indicated mRNAs following control or HIF-1α siRNA (siHIF-1α) transfection of SKRC-10 cells. Treatment procedure (N, normoxia; H, hypoxia) and transfection were performed as indicated in E. Data shown are mean + SD of representative experiment performed in triplicate.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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