RanGTPase: a candidate for Myc-mediated cancer progression.



Yuen, Hiu-Fung, Gunasekharan, Vignesh-Kumar ORCID: 0000-0002-2471-8485, Chan, Ka-Kui, Zhang, Shu-Dong ORCID: 0000-0002-7721-0167, Platt-Higgins, Angela, Gately, Kathy ORCID: 0000-0002-9616-424X, O'Byrne, Ken, Fennell, Dean A, Johnston, Patrick G, Rudland, Philip S ORCID: 0000-0002-7491-0846
et al (show 1 more authors) (2013) RanGTPase: a candidate for Myc-mediated cancer progression. Journal of the National Cancer Institute, 105 (7). 475 - 488.

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Abstract

<h4>Background</h4>Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown.<h4>Methods</h4>We investigated the effect of the v-myc myelocytomatosis viral oncogene homolog (Myc) on Ran expression by Western blot, chromatin immunoprecipitation, and luciferase reporter assays and the effects of Myc and Ran expression in cancer cells by soft-agar, cell adhesion, and invasion assays. The correlation between Myc and Ran and the association with patient survival were investigated in 14 independent patient cohorts (n = 2430) and analyzed with Spearman's rank correlation and Kaplan-Meier plots coupled with Wilcoxon-Gehan tests, respectively. All statistical tests were two-sided.<h4>Results</h4>Myc binds to the upstream sequence of Ran and transactivates Ran promoter activity. Overexpression of Myc upregulates Ran expression, whereas knockdown of Myc downregulates Ran expression. Myc or Ran overexpression in breast cancer cells is associated with cancer progression and metastasis. Knockdown of Ran reverses the effect induced by Myc overexpression in breast cancer cells. In clinical data, a positive association between Myc and Ran expression was revealed in 288 breast cancer and 102 lung cancer specimens. Moreover, Ran expression levels differentiate better or poorer survival in Myc overexpressing breast (χ2 = 24.1; relative risk [RR] = 9.1, 95% confidence interval [CI] = 3.3 to 24.7, P < .001) and lung (χ2 = 6.04; RR = 2.8, 95% CI = 1.2 to 6.3; P = .01) cancer cohorts.<h4>Conclusions</h4>Our results suggest that Ran is required for and is a potential therapeutic target of Myc-driven cancer progression in both breast and lung cancers.

Item Type: Article
Uncontrolled Keywords: Cell Line, Tumor, Humans, Breast Neoplasms, Lung Neoplasms, Neoplasm Invasiveness, Disease Progression, GTP Phosphohydrolases, ran GTP-Binding Protein, Proto-Oncogene Proteins c-myc, DNA Primers, Blotting, Western, Immunohistochemistry, Cell Adhesion, Gene Amplification, Gene Expression Regulation, Neoplastic, Gene Silencing, Up-Regulation, Genes, myc, Plasmids, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Kaplan-Meier Estimate
Depositing User: Symplectic Admin
Date Deposited: 22 Sep 2016 10:21
Last Modified: 20 Aug 2021 18:10
DOI: 10.1093/jnci/djt028
Open Access URL: http://jnci.oxfordjournals.org/content/105/7/475
URI: https://livrepository.liverpool.ac.uk/id/eprint/3003426