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Hu H.,Capital Medical University | Hu H.,Chinese Glioma Cooperative Group CGCG | Liu Y.,Capital Medical University | Liu Y.,Chinese Glioma Cooperative Group CGCG | And 3 more authors.
Tumor Biology | Year: 2015

Cancer is the greatest challenge to human health in our era. Perturbations of receptor tyrosine kinase (RTK) function contribute to a large chunk of cancer etiology. Current evidence supports that mutations in RTKs mediate receptor dimerization and result in ligand-independent kinase activity and tumorigenesis, indicating that mutation-introduced receptor dimerization is a critical component of oncogenesis RTK mutations. However, there are no specialized reviews of this important principle. In the current review, we discuss the physiological and harmless RTK function and subsequently examine mutation-introduced dimerization of RTKs and the role of these mutations in tumorigenesis. We also summarize the protein structure characteristics that are important for dimerization and introduce research methods and tools to predict and validate the existence of oncogenic mutations introduced by dimerization in RTKs. © 2015, International Society of Oncology and BioMarkers (ISOBM).

Wang Y.,Capital Medical University | Fan X.,Capital Medical University | Zhang C.,Capital Medical University | Zhang T.,Capital Medical University | And 8 more authors.
Neuroradiology | Year: 2014

Introduction: Phosphatase and tensin homolog (PTEN) loss and epidermal growth factor receptor (EGFR) amplification are common genetic alterations in malignant gliomas. This study aimed to investigate the anatomical relationship of tumor-related PTEN and EGFR expression in 140 patients with histologically confirmed de novo glioblastoma.Methods: Preoperative magnetic resonance images were retrospectively analyzed. The lesions of each patient were segmented manually and registered to a standard brain space. Overlaying of the lesions was performed, and specific brain regions associated with PTEN loss and EGFR amplification were identified by voxel-based lesion-symptom mapping analyses.Results: A cluster located in the right frontal lobe was found to be associated with high occurrence of PTEN loss, whereas a cluster in the right parietal lobe was demonstrated to be specifically associated with high occurrence of EGFR amplification. An overlap of the two clusters was observed at the posterior portion of the right parietal lobe.Conclusions: Based on voxel-based imaging analyses, our results suggest that genetic changes during the tumorigenic process may have anatomical specificity. We hope that this identified correlation between these biomarkers and the anatomical distribution of glioblastomas will help enhance our understanding of the molecular mechanisms underlying glioblastoma development and progression. © 2014, Springer-Verlag Berlin Heidelberg.

Borcherding N.,University of Iowa | Kusner D.,University of Iowa | Liu G.-H.,CAS Institute of Biophysics | Liu G.-H.,Beijing Institute for Brain Disorders Brain Tumor Center | Zhang W.,University of Iowa
Protein and Cell | Year: 2014

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the ROR family consisting of ROR1 and ROR2. RORs contain two distinct extracellular cysteine-rich domains and one transmembrane domain. Within the intracellular portion, ROR1 possesses a tyrosine kinase domain, two serine/threonine-rich domains and a proline-rich domain. RORs have been studied in the context of embryonic patterning and neurogenesis through a variety of homologs. These physiologic functions are dichotomous based on the requirement of the kinase domain. A growing literature has established ROR1 as a marker for cancer, such as in CLL and other blood malignancies. In addition, ROR1 is critically involved in progression of a number of blood and solid malignancies. ROR1 has been shown to inhibit apoptosis, potentiate EGFR signaling, and induce epithelial-mesenchymal transition (EMT). Importantly, ROR1 is only detectable in embryonic tissue and generally absent in adult tissue, making the protein an ideal drug target for cancer therapy. © 2014 The Author(s).

Zhang T.,Capital Medical University | Wang Y.,Capital Medical University | Fan X.,Capital Medical University | Ma J.,Capital Medical University | And 5 more authors.
Journal of the Neurological Sciences | Year: 2014

Accumulating evidence has suggested that tumor location is linked to the genetic profile of gliomas. Therefore, the aim of this study was to investigate the anatomical characteristics of p53-mutated glioblastomas. We also sought to provide new insight into the possible niche locations of cells of glioblastoma origin. In order to accomplish this, preoperative magnetic resonance images from 163 patients with primary glioblastomas were retrospectively analyzed. All tumors were manually marked and registered to the standard space. Using the voxel-based lesion-symptom mapping approach, voxels exhibiting the strongest correlations with p53 mutants were identified. T-values of voxels that were greater than 95% of the permutations were factored into the results of the mapping analysis. Distinct anatomical characteristics between p53-mutated and wild-type glioblastomas were demonstrated using this approach. More specifically, we found that p53-mutated glioblastomas were preferentially located in the frontal lobe in the area surrounding the rostral extension of the lateral ventricles. The distinct anatomical characteristics of p53-mutated and wild-type glioblastomas provide further evidence that these gliomas arise from distinct niche locations. © 2014 Elsevier B.V. All rights reserved.

Cai J.,Harbin Medical University | Cai J.,Chinese Glioma Cooperative Group CGCG | Chen J.,Capital Medical University | Chen J.,Chinese Glioma Cooperative Group CGCG | And 20 more authors.
Oncotarget | Year: 2015

Loss of ATRX leads to epigenetic alterations, including abnormal levels of DNA methylation at repetitive elements such as telomeres in murine cells. We conducted an extensive DNA methylation and mRNA expression profile study on a cohort of 82 patients with astrocytic tumors to study whether ATRX expression was associated with DNA methylation level in astrocytic tumors and in which cellular functions it participated.We observed that astrocytic tumors with lower ATRX expression harbored higher DNA methylation level at chromatin end and astrocytic tumors with ATRX-low had distinct gene expression profile and DNA methylation profile compared with ATRX-high tumors. Then, we uncovered that several ATRX associated biological functions in the DNA methylation and mRNA expression profile (GEP), including apoptotic process, DNA-dependent positive regulation of transcription, chromatin modification, and observed that ATRX expression was companied by MGMT methylation and expression. We also found that loss of ATRX caused by siRNA induced apoptotic cells increasing, reduced tumor cell proliferation and repressed the cell migration in glioma cells.Our results showed ATRX-related regulatory functions of the combined profiles from DNA methylation and mRNA expression in astrocytic tumors, and delineated that loss of ATRX impacted biological behaviors of astrocytic tumor cells, providing important resources for future dissection of ATRX role in glioma.

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