Abstract 1561: AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization
Authors: Han Lei , Zhang Kai-Liang , Zhang Jun-Xia , Zeng Liang , Di Chun-Hui , Fee Brian , Rivas Miriam , Jiang Tao , Bigner Darrell , Kang Chun-Sheng , Adamson David Cory 
Published: May 2015

Background

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and is a leading cause of cancer-related death due to its invasive nature. Despite advances in radiation and chemotherapy following surgical resection of the tumor, the prognosis of GBM remains poor with an average survival time of less than one year. Accumulating evidence indicates the existence of tumor suppressor-like genes encoded on the 1p36 region. Recent investigations have reported Adherens Junctional Associated Protein-1 (AJAP1, also known as Shrew1) as another tumor suppressor-like gene on chromosome 1 in the 1p36 region. We and others also demonstrated that the AJAP1 promoter was highly methylated in a wide spectrum of glioma cell lines, and the loss of expression was associated with poorer survival in gliomas patients. However, the altered expression profiles of AJAP1 in gliomas as well as the underlying mechanisms of AJAP1 on glial cell migration and invasion are still poorly understood.

Methods

The gene profiles of AJAP1 in glioma patients were studied among four independent cohorts. Confocal imaging was used to analyze the AJAP1 localization. After AJAP1 over-expression in GBM cell lines, cellular polarity, cytoskeleton distribution, and anti-tumor effect were investigated in vitro and in vivo.

Results

AJAP1 expression was significantly decreased in gliomas compared with normal brain in REMBRANDT and CGCA cohorts. Additionally, low AJAP1 expression was associated with worse survival in GBMs in REMBRANDT and TCGA U133A cohorts and was significantly associated with classical and mesenchymal subtypes of GBMs among four cohorts. Confocal imaging indicated AJAP1 localized in cell membranes in low-grade gliomas and AJAP1 over-expressing GBM cells, but difficult to assess in high-grade gliomas due to its absence. AJAP1 over-expression altered the cytoskeleton and cellular morphology in vitro, and inhibited the tumor growth in vivo. Conclusion

In summary, gene profiling of gliomas showed that dysregulated AJAP1 exists in the early stage of gliomagenesis. In particular, AJAP1 expression is associated with low and high tumor grades, as well as the clinical outcome of patients with GBMs. Its over-expression predicts poor clinical outcome and may serve as a promising biomarker for intensive therapy, especially in Classical and Mesenchymal GBM patients. Few studies have investigated the function of AJAP1 and cytoskeleton regulation in gliomas. Further studies are warranted to explore the biological functions of AJAP1 that may improve our understanding of the initiation of gliomas and development of new biomarker and therapeutic target for individualized therapy of GBM.

Citation Format: Lei Han, Kai-Liang Zhang, Jun-Xia Zhang, Liang Zeng, Chun-Hui Di, Brian Fee, Miriam Rivas, Tao Jiang, Darrell Bigner, Chun-Sheng Kang, David Cory Adamson. AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1561. doi:10.1158/1538-7445.AM2014-1561