Oncotarget

Research Papers:

Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation

Hyeran Sung, Krishna L. Kanchi, Xue Wang, Kristen S. Hill, Jane L. Messina, Ji-Hyun Lee, Youngchul Kim, Nathan D. Dees, Li Ding, Jamie K. Teer, Shengyu Yang, Amod A. Sarnaik, Vernon K. Sondak, James J. Mulé, Richard K. Wilson, Jeffrey S. Weber and Minjung Kim _

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Oncotarget. 2016; 7:23885-23896. https://doi.org/10.18632/oncotarget.8127

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Abstract

Hyeran Sung1,2, Krishna L. Kanchi3, Xue Wang1,2, Kristen S. Hill1,2, Jane L. Messina2,4,5, Ji-Hyun Lee6, Youngchul Kim7, Nathan D. Dees3, Li Ding3,8,9, Jamie K. Teer7, Shengyu Yang2,10, Amod A. Sarnaik2,4, Vernon K. Sondak2,4, James J. Mulé2,4, Richard K. Wilson3,9, Jeffrey S. Weber11, Minjung Kim1,2,4

1Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA

2Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA

3The Genome Institute, Washington University, St. Louis, MO, USA

4Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA

5Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA

6Department of Internal Medicine, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA

7Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA

8Department of Medicine, Washington University, St. Louis, MO, USA

9Department of Genetics, Washington University, St. Louis, MO, USA

10Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL, USA

11Department of Medicine, NYU Langone Medical Center, New York, NY, USA

Correspondence to:

Minjung Kim, e-mail: [email protected]

Keywords: melanoma, RASA1, RasGAP, R-Ras, whole genome sequencing

Received: January 15, 2016     Accepted: February 28, 2016     Published: March 16, 2016

ABSTRACT

Inactivation of Ras GTPase activating proteins (RasGAPs) can activate Ras, increasing the risk for tumor development. Utilizing a melanoma whole genome sequencing (WGS) data from 13 patients, we identified two novel, clustered somatic missense mutations (Y472H and L481F) in RASA1 (RAS p21 protein activator 1, also called p120RasGAP). We have shown that wild type RASA1, but not identified mutants, suppresses soft agar colony formation and tumor growth of BRAF mutated melanoma cell lines via its RasGAP activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform. Moreover, R-Ras increased and RASA1 suppressed Ral-A activation among Ras downstream effectors. In addition to mutations, loss of RASA1 expression was frequently observed in metastatic melanoma samples on melanoma tissue microarray (TMA) and a low level of RASA1 mRNA expression was associated with decreased overall survival in melanoma patients with BRAF mutations. Thus, these data support that RASA1 is inactivated by mutation or by suppressed expression in melanoma and that RASA1 plays a tumor suppressive role by inhibiting R-Ras, a previously less appreciated member of the Ras small GTPases.


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