Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis

Lan Mo, Xiaoyong Zheng, Hong Ying Huang, Ellen Shapiro, Herbert Lepor, Carlos Cordon-Cardo, Tung Tien Sun, Xue Ru Wu

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Although ras is a potent mitogenic oncogene, its tumorigenicity depends on cellular context and cooperative events. Here we show that low-level expression of a constitutively active Ha-ras in mouse urothelium induces simple urothelial hyperplasia that is resistant to progression to full-fledged bladder tumors even in the absence of Ink4a/Arf. In stark contrast, doubling of the gene dosage of the activated Ha-ras triggered early-onset, rapidly growing, and 100% penetrant tumors throughout the urinary tract. Tumor initiation required superseding a rate-limiting step between simple and nodular hyperplasia, the latter of which is marked by the emergence of mesenchymal components and the coactivation of AKT and STAT pathways as well as PTEN inactivation. These results indicate that overactivation of Ha-ras is both necessary and sufficient to induce bladder tumors along a low-grade, noninvasive papillary pathway, and they shed light on the recent findings that ras activation, via point mutation, overexpression, or intensified signaling from FGF receptor 3, occurs in 70%-90% of these tumors in humans. Our results highlight the critical importance of the dosage/strength of Ha-ras activation in dictating its tumorigenicity - a mechanism of oncogene activation not fully appreciated to date. Finally, our results have clinical implications, as inhibiting ras and/or its downstream effectors, such as AKT and STAT3/5, could provide alternative means to treat low-grade, superficial papillary bladder tumors, the most common tumor in the urinary system.

Original languageEnglish (US)
Pages (from-to)314-325
Number of pages12
JournalJournal of Clinical Investigation
Volume117
Issue number2
DOIs
StatePublished - Feb 1 2007
Externally publishedYes

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ras Genes
Carcinogenesis
Urinary Bladder
Urinary Bladder Neoplasms
Oncogenes
Hyperplasia
Neoplasms
Fibroblast Growth Factor Receptors
Urothelium
Gene Dosage
Urinary Tract
Point Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mo, L., Zheng, X., Huang, H. Y., Shapiro, E., Lepor, H., Cordon-Cardo, C., ... Wu, X. R. (2007). Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. Journal of Clinical Investigation, 117(2), 314-325. https://doi.org/10.1172/JCI30062

Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. / Mo, Lan; Zheng, Xiaoyong; Huang, Hong Ying; Shapiro, Ellen; Lepor, Herbert; Cordon-Cardo, Carlos; Sun, Tung Tien; Wu, Xue Ru.

In: Journal of Clinical Investigation, Vol. 117, No. 2, 01.02.2007, p. 314-325.

Research output: Contribution to journalArticle

Mo, L, Zheng, X, Huang, HY, Shapiro, E, Lepor, H, Cordon-Cardo, C, Sun, TT & Wu, XR 2007, 'Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis', Journal of Clinical Investigation, vol. 117, no. 2, pp. 314-325. https://doi.org/10.1172/JCI30062
Mo, Lan ; Zheng, Xiaoyong ; Huang, Hong Ying ; Shapiro, Ellen ; Lepor, Herbert ; Cordon-Cardo, Carlos ; Sun, Tung Tien ; Wu, Xue Ru. / Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 2. pp. 314-325.
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