RHPN2 Drives Mesenchymal Transformation in Malignant Glioma by Triggering RhoA Activation

被引：51

作者：

Danussi, Carla ^{[1
]}

Akavia, Uri David ^{[2
,6
]}

Niola, Francesco ^{[1
]}

Jovic, Andreja ^{[6
]}

Lasorella, Anna ^{[1
,3
,4
]}

Pe'er, Dana ^{[2
,6
]}

Iavarone, Antonio ^{[1
,4
,5
]}

机构：

[1] Columbia Univ, Inst Canc Genet, Med Ctr, New York, NY 10032 USA

[2] Columbia Univ, Dept Syst Biol, Med Ctr, New York, NY 10032 USA

[3] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10032 USA

[4] Columbia Univ, Dept Pathol, Med Ctr, New York, NY 10032 USA

[5] Columbia Univ, Dept Neurol, Med Ctr, New York, NY 10032 USA

[6] Columbia Univ, Dept Biol Sci, New York, NY 10032 USA

来源：

CANCER RESEARCH | 2013年 / 73卷 / 16期

关键词：

GLIOBLASTOMA; CANCER; PROTEIN; GTPASES; PHOSPHORYLATION; DIFFERENTIATION; RHOPHILIN-2; MIGRATION; INVASION; NETWORK;

D O I：

10.1158/0008-5472.CAN-13-1168-T

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Mesenchymal transformation is a hallmark of aggressive glioblastoma (GBM). Here, we report the development of an unbiased method for computational integration of copy number variation, expression, and mutation data from large datasets. Using this method, we identified rhophilin 2 (RHPN2) as a central genetic determinant of the mesenchymal phenotype of human GBM. Notably, amplification of the human RHPN2 gene on chromosome 19 correlates with a dramatic decrease in the survival of patients with glioma. Ectopic expression of RHPN2 in neural stem cells and astrocytes triggered the expression of mesenchymal genes and promoted an invasive phenotype without impacting cell proliferation. Mechanistically, these effects were implemented through RHPN2-mediated activation of RhoA, a master regulator of cell migration and invasion. Our results define RHPN2 amplification as a central genetic determinant of a highly aggressive phenotype that directs the worst clinical outcomes in patients with GBM. (C) 2013 AACR.

引用

页码：5140 / 5150

页数：11

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