RanGTPase: a candidate for Myc-mediated cancer progression.

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.

• Authors: Hiu-Fung Yuen, Vignesh-Kumar Gunasekharan, Ka-Kui Chan, Shu-Dong Zhang, Angela Platt-Higgins, Kathy Gately, Ken O'Byrne, Dean A Fennell, Patrick G Johnston, Philip S Rudland, Mohamed El-Tanani
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 105 Issue 7 Pg. 475-88 (Apr 03 2013) ISSN: 1460-2105 [Electronic] United States
• PMID: 23468463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• RAN protein, human
• GTP Phosphohydrolases
• ran GTP-Binding Protein

Topics

• Adult
• Aged
• Aged, 80 and over
• Blotting, Western
• Breast Neoplasms (enzymology, metabolism, mortality, pathology)
• Cell Adhesion
• Cell Line, Tumor
• DNA Primers
• Disease Progression
• Female
• GTP Phosphohydrolases (genetics, metabolism)
• Gene Amplification
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Genes, myc
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Lung Neoplasms (enzymology, metabolism, mortality, pathology)
• Middle Aged
• Neoplasm Invasiveness
• Plasmids
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Up-Regulation
• ran GTP-Binding Protein (genetics, metabolism)