RanGTPase : a candidate for myc-mediated cancer progression

Yuen, Hui- Fung, Gunasekharan, Vignesh-Kumar, Chan, Kai-Kumar, Zhang, Shu-Dong, Platt-Higgins, Angela, Gately, Kathy, O'Byrne, Kenneth J., Fennell, Dean A., Johnston, Patrick G., Rudland, Philip S., & El-Tanani, Mohamed (2013) RanGTPase : a candidate for myc-mediated cancer progression. Journal of the National Cancer Institute, 105(7), pp. 475-488.

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Abstract

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Abstract

Background Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown.

Methods 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.

Results 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.

Conclusions 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. © 2013 The Author.

Impact and interest:

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15 citations in Web of Science®
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ID Code: 65785
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 12 months
Additional URLs:
Keywords: guanosine triphosphatase, luciferase, Ran protein, article, breast cancer, cancer cell, cancer growth, cancer patient, cancer prognosis, cancer survival, cell adhesion, cell invasion, chromatin immunoprecipitation, cohort analysis, gene expression, human, human cell, lung cancer, metastasis, myeloid leukemia, neoplasm, oncogene myc, priority journal, protein expression, upregulation, virus oncogene, Western blotting, Adult, Aged, Aged, 80 and over, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Disease Progression, DNA Primers, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, myc, GTP Phosphohydrolases, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Lung Neoplasms, Middle Aged, Neoplasm Invasiveness, Plasmids, Proto-Oncogene Proteins c-myc, ran GTP-Binding Protein, Up-Regulation
DOI: 10.1093/jnci/djt028
ISSN: 0027-8874
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2013 Oxford University Press
Deposited On: 08 Jan 2014 04:38
Last Modified: 11 Apr 2017 02:43

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