SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans
SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans
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DOI：
10.1172/jci43690
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发表时间：
2011-03-01
影响因子：
15.9
通讯作者：
Cheng, Shi-Yuan
中科院分区：
文献类型：
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作者：
Liu, Kun-Wei;Feng, Haizhong;Cheng, Shi-Yuan
最近的合作努力将恶性胶质母细胞瘤根据其标志性的遗传损害细分为4个临床相关亚型。血小板衍生生长因子受体α(PDGFRA)的过度表达伴随着细胞周期蛋白依赖性激酶抑制因子2A(CDKN2A)基因(编码P16INK4A和P14ARF)的缺失。在这里，我们报告了PDGFRα的激活使Thk4a/Arf缺陷的小鼠星形胶质细胞和人脑胶质瘤细胞具有致瘤性。P16INK4a而不是p19ARF的修复抑制了PDGFRα促进的胶质瘤的形成。从机制上讲，PDGFRα中失去与SHP-2或PI3K结合能力的信号模块的取消显著减少了PDGFRα促进的肿瘤发生。此外，shRNAs或药物抑制剂抑制SHP-2可阻断PI3K与PDGFRα的相互作用，抑制下游的AKT/mTOR激活，并损害Ink4a/Arf-Null细胞的致瘤性，而激活的PI3K突变体的表达可挽救SHP-2抑制致瘤性的作用。在临床胶质母细胞瘤标本中，PDGFRα和PDGF-A共同表达，这种共同表达与SHP-2/AKT/mTOR信号通路的激活有关。综上所述，我们的数据表明，在Ink4a/Arf缺乏的胶质母细胞瘤中，过表达的PDGFRα通过受SHP-2活性调控的PI3K/AKT/mTOR介导的途径促进肿瘤的发生。这些发现从功能上验证了对胶质母细胞瘤的基因组分析，并确认SHP-2是治疗胶质母细胞瘤的潜在靶点。
Recent collaborative efforts have subclassified malignant glioblastomas into 4 clinical relevant subtypes based on their signature genetic lesions. Platelet-derived growth factor receptor alpha (PDGFRA) overexpression is concomitant with a loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of glioblastomas. Here we report that activation of PDGFR alpha conferred tumorigenicity to Thk4a/Arf-deficient mouse astrocytes and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF suppressed PDGFR alpha-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFR alpha that lost capacity to bind to SHP-2 or PI3K significantly diminished PDGFR alpha-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFR alpha, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. PDGFR alpha and PDGF-A are co-expressed in clinical glioblastoma specimens, and such co-expression is linked with activation of SHP-2/AKT/mTOR signaling. Together, our data suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFR alpha promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity. These findings functionally validate the genomic analysis of glioblastomas and identify SHP-2 as a potential target for treatment of glioblastomas.