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  • Original Article
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Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis

Abstract

Mitogen-activated protein kinase (MAPK) and AKT pathways are frequently co-activated in melanoma through overexpression of receptor tyrosine kinases, mutations in their signaling surrogates, such as RAS and BRAF, or loss of negative regulators such as PTEN. As RAS can be a positive upstream regulator of PI3-K, it has been proposed that the loss of PTEN and the activation of RAS are redundant events in melanoma pathogenesis. Here, in genetically engineered mouse models of cutaneous melanomas, we sought to better understand the genetic interactions between HRAS activation and PTEN inactivation in melanoma genesis and progression in vivo. We showed that HRAS activation cooperates with Pten+/− and Ink4a/Arf−/− to increase melanoma penetrance and promote metastasis. Correspondingly, gain- and loss-of-function studies established that Pten loss increases invasion and migration of melanoma cells and non-transformed melanocytes, and such biological activity correlates with a shift to phosphorylation of AKT2 isoform and E-cadherin down-regulation. Thus, Pten inactivation can drive the genesis and promote the metastatic progression of RAS activated Ink4a/Arf deficient melanomas.

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Acknowledgements

C Nogueira was supported by a fellowship from FCT (PRAXIS/BD/21794/99). M Kim was supported by the Claudia Adams Barr Program, the Dermatology Foundation, and Melanoma Research Foundation. JH Dannenberg was supported by Damon-Runyon Cancer Research Foundation and the Dutch Cancer Society. This work was supported by grants from the NIH (UO1 CA84313; RO1 CA93947) to L Chin and from the Bankhead Coley Pilot Research Award and American Cancer Society Institutional Research Grant (#93-032-13) to M Kim. We thank Dr Jin Q Cheng (Moffitt Cancer Center) for helpful discussion and adenoviruses for PTEN and DN-AKT2 expression, and Dr Ronald A DePinho for critical reading of this paper.

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Correspondence to L Chin or M Kim.

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Nogueira, C., Kim, KH., Sung, H. et al. Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis. Oncogene 29, 6222–6232 (2010). https://doi.org/10.1038/onc.2010.349

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