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01-09-2016 | Original Article

The expression of Cullin1 is increased in renal cell carcinoma and promotes cancer cell proliferation, migration, and invasion

Authors: Ji-Gen Ping, Fei Wang, Jin-Xian Pu, Ping-Fu Hou, Yan-Su Chen, Jin Bai, Jun-Nian Zheng

Published in: Tumor Biology | Issue 9/2016

Abstract

Cullin1 (Cul1) is a scaffold protein of the ubiquitin E3 ligase Skp1/Cullin1/Rbx1/F-box protein complex, which ubiquitinates a broad range of proteins involved in cell-cycle progression, signal transduction, and transcription. To investigate the role of Cul1 in the development of renal cell carcinoma (RCC), we evaluated the Cul1 expression by immunohistochemistry using a tissue microarray (TMA) containing 307 cases of RCC tissues and 34 normal renal tissues. The Cul1 expression was increased significantly in RCC and was correlated with renal carcinoma histology grade (P = 0.007), tumor size (P = 0.013), and pT status (P = 0.023). Also, we found that silencing of Cul1 leads to increased expression of p21 and p27 that could inhibit the cyclin D₁ and cyclin E₂ expressions and arrest cell cycle at the G1 phase. Furthermore, knockdown of Cul1 inhibits RCC cell migration and invasion abilities by up-regulating the expression of TIMP-1 which could inhibit the expression of MMP-9. Finally, using bioluminescence imaging, we found that Cul1 knockdown significantly reduced the tumor growth in vivo. Cul1 may constitute a potential therapeutic target in RCC.

Siegel R, Miller K, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.CrossRefPubMed

Spano D, Zollo M. Tumor microenvironment: a main actor in the metastasis process. Clin Exp Metastasis. 2012;29(4):381–95. doi:10.1007/s10585-012-9457-5. CrossRefPubMed

Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12(8):895–904. doi:10.1038/nm1469. CrossRefPubMed

Chondrogianni N, Gonos ES. Structure and function of the ubiquitin-proteasome system: modulation of components. Prog Mol Biol Transl Sci. 2012;109:41–74. doi:10.1016/b978-0-12-397863-9.00002-x. CrossRefPubMed

Sun Y. E3 ubiquitin ligases as cancer targets and biomarkers. Neoplasia. 2006;8(8):645–54. doi:10.1593/neo.06376.CrossRefPubMedPubMedCentral

Burrows AC, Prokop J, Summers MK. Skp1-Cul1-F-box ubiquitin ligase (SCFβTrCP)-mediated destruction of the ubiquitin-specific protease USP37 during G2-phase promotes mitotic entry. J Biol Chem. 2012;287(46):39021–9.CrossRefPubMedPubMedCentral

Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–79. doi:10.1146/annurev.biochem.67.1.425. CrossRefPubMed

Sarikas A, Hartmann T, Pan ZQ. The cullin protein family. Genome Biol. 2011;12(4):220.CrossRefPubMedPubMedCentral

Bai J, Yong HM, Chen FF, Mei PJ, Liu H, Li C, et al. Cullin1 is a novel marker of poor prognosis and a potential therapeutic target in human breast cancer. Ann Oncol: Off J Eur Soc Med Oncol/ESMO. 2013;24(8):2016–22. doi:10.1093/annonc/mdt147. CrossRef

10.

Bai J, Zhou Y, Chen G, Zeng J, Ding J, Tan Y, et al. Overexpression of Cullin1 is associated with poor prognosis of patients with gastric cancer. Hum Pathol. 2011;42(3):375–83. doi:10.1016/j.humpath.2010.09.003. CrossRefPubMed

11.

Liu W, Wang Y, Zhang C, Huang B, Bai J, Tian L. Cullin1 is up-regulated and associated with poor patients’ survival in hepatocellular carcinoma. Int J Clin Exp Pathol. 2015;8(4):4001–7.PubMedPubMedCentral

12.

Capitanio U, Montorsi F. Renal cancer. Lancet (London, England). 2015. doi:10.1016/s0140-6736(15)00046-x.

13.

Li. Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression. Int J Oncol. 2010;37(5). doi:10.3892/ijo_00000786.

14.

Haitel A, Wiener HG, Neudert B, Marberger M, Susani M. Expression of the cell cycle proteins p21, p27, and pRb in clear cell renal cell carcinoma and their prognostic significance. Urology. 2001;58(3):477–81.CrossRefPubMed

15.

Langner C, von Wasielewski R, Ratschek M, Rehak P, Zigeuner R. Biological significance of p27 and Skp2 expression in renal cell carcinoma. A systematic analysis of primary and metastatic tumour tissues using a tissue microarray technique. Virchows Archiv: Int J Pathol. 2004;445(6):631–6. doi:10.1007/s00428-004-1121-2. CrossRef

16.

Migita T, Oda Y, Naito S, Tsuneyoshi M. Low expression of p27(Kip1) is associated with tumor size and poor prognosis in patients with renal cell carcinoma. Cancer. 2002;94(4):973–9.CrossRefPubMed

17.

O’Hagan RC, Ohh M, David G, de Alboran IM, Alt FW, Kaelin Jr WG, et al. Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes Dev. 2000;14(17):2185–91.CrossRefPubMedPubMedCentral

18.

Yang X, Menon S, Lykke-Andersen K, Tsuge T, Di X, Wang X, et al. The COP9 signalosome inhibits p27(kip1) degradation and impedes G1-S phase progression via deneddylation of SCF Cul1. Curr Biol: CB. 2002;12(8):667–72.CrossRefPubMed

19.

Lu H, Cao X, Zhang H, Sun G, Fan G, Chen L, et al. Imbalance between MMP-2, 9 and TIMP-1 promote the invasion and metastasis of renal cell carcinoma via SKP2 signaling pathways. Tumour Biol: J Int Soc Oncodev Biol Med. 2014;35(10):9807–13. doi:10.1007/s13277-014-2256-7. CrossRef

20.

Sato A, Nagase H, Obinata D, Fujiwara K, Fukuda N, Soma M, et al. Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma. Int J Oncol. 2013;43(5):1441–6.PubMed

21.

22.

Moore CS, Crocker SJ. An alternate perspective on the roles of TIMPs and MMPs in pathology. Am J Pathol. 2012;180(1):12–6. doi:10.1016/j.ajpath.2011.09.008. CrossRefPubMed

23.

Uehara N, Yoshizawa K, Tsubura A. Vorinostat enhances protein stability of p27 and p21 through negative regulation of Skp2 and Cks1 in human breast cancer cells. Oncol Rep. 2012;28(1):105–10. doi:10.3892/or.2012.1758. PubMed

Title: The expression of Cullin1 is increased in renal cell carcinoma and promotes cancer cell proliferation, migration, and invasion
Authors: Ji-Gen Ping
Fei Wang
Jin-Xian Pu
Ping-Fu Hou
Yan-Su Chen
Jin Bai
Jun-Nian Zheng
Publication date: 01-09-2016
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 9/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-016-5151-6

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