Driver or passenger effects of augmented c-Myc and Cdc20 in gliomagenesis
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Ping Ji1,3, Xinhui Zhou1, Qun Liu1,2, Gregory N. Fuller1, Lynette M. Phillips1, Wei Zhang1
1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2Department of Neurosurgery, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
3Current affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, USA
Wei Zhang, e-mail: email@example.com
Keywords: Myc, Cdc20, RCAS/Ntv-a glia-specific mouse model, glial progenitor cell differentiation, glioblastoma
Received: October 29, 2015 Accepted: February 25, 2016 Published: March 14, 2016
Purpose: Cdc20 and c-Myc are commonly overexpressed in a broad spectrum of cancers, including glioblastoma (GBM). Despite this clear association, whether c-Myc and Cdc20 overexpression is a driver or passenger event in gliomagenesis remains unclear.
Results: Both c-Myc and Cdc20 induced the proliferation of primary glial progenitor cells. c-Myc also promoted the formation of soft agar anchorage-independent colonies. In the RCAS/Ntv-a glia-specific transgenic mouse model, c-Myc increased the GBM incidence from 19.1% to 47.4% by 12 weeks of age when combined with kRas and Akt3 in Ntv-a INK4a-ARF (also known as CDKN2A)-null mice. In contrast, Cdc20 decreased the GBM incidence from 19.1% to 9.1%. Moreover, cell differentiation was modulated by c-Myc in kRas/Akt3-induced GBM on the basis of Nestin/GFAP expression (glial progenitor cell differentiation), while Cdc20 had no effect on primary glial progenitor cell differentiation.
Materials and Methods: We used glial progenitor cells from Ntv-a newborn mice to evaluate the role of c-Myc and Cdc20 in the proliferation and transformation of GBM in vitro and in vivo. We further determined whether c-Myc and Cdc20 have a driver or passenger role in GBM development using kRas/Akt3 signals in a RCAS/Ntv-a mouse model.
Conclusions: These results suggest that the driver or passenger of oncogene signaling is dependent on cellular status. c-Myc is a driver when combined with kRas/Akt3 oncogenic signals in gliomagenesis, whereas Cdc20 overexpression is a passenger. Inhibition of cell differentiation of c-Myc may be a target for anti-glioma therapy.
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