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The Expression Profile of FRAT1 in Human Gliomas

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The Expression Profile of FRAT1 in Human Gliomas BRAIN RESEARCH 1320 (2010) 152– 158 available at www.sciencedirect.com www.elsevier.com/locate/brainres Research Report The expression profile of FRAT1 in human gliomas Geng Guoa,1, Xinggang Maoa,1, Peng Wanga,1, Bolin Liua, Xiang Zhanga,⁎, Xiaofan Jianga, Chengliang Zhongb, Junli Huoa, Ji Jinc, Yuzhen Zhuod aDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 15# West Chang Le Road, Xi'an, Shaanxi Province 710032, People's Republic of China bDepartment of Health Statistics, Faculty of Preventative Medicine, Fourth Military Medical University, 17# West Chang Le Road, Xi'an, Shaanxi Province 710032, People's Republic of China cShanxi Medical University, 56# South Xin Jian Road, Taiyuan, Shanxi Province 030001, People's Republic of China dTianjin Institute of Acute Abdomen, Tianjin Nankai Hospital, 122# San Wei Road, Tianjin 300100, People's Republic of China ARTICLE INFO ABSTRACT Article history: FRAT1 was originally characterized as a protein frequently rearranged in advanced T cell Accepted 13 January 2010 lymphoma, which inhibits GSK-3-mediated phosphorylation of β-catenin and positively Available online 21 January 2010 regulates the Wnt signaling pathway. FRAT1 has been identified as a proto-oncogene involved in tumorigenesis. Previous studies have shown that FRAT1 is strikingly Keywords: overexpressed in some human cancers. However, the relationship between FRAT1 and FRAT1 human gliomas is unclear. In this study, we detected the expression of FRAT1 in human β-catenin gliomas by immunohistochemistry, Western blot and RT-PCR. FRAT1 was found to be Glioma specifically expressed in the majority of glioma samples, and their expression levels Immunohistochemistry increased markedly with the increase of WHO grades. In addition, there was a positive Western blot correlation between FRAT1 immunoreactivity score (IRS) and β-catenin IRS. Our results RT-PCR suggest that FRAT1 may be an important factor in the tumorigenesis and progression of gliomas, and could be used as a potential molecular marker for pathological diagnosis and a target for biological therapy. © 2010 Elsevier B.V. All rights reserved. 1. Introduction patients diagnosed with high-grade gliomas die within the first year, even after receiving multidisciplinary treatments, in- Gliomas are the most common primary neoplasms arising cluding surgical resection, radiotherapy and chemotherapy from the brain or spinal cord tissue, composing over 40% of all (Hess et al., 2004). New therapies based on a better under- such tumors and 78% of central nervous system malignancies standing of the molecular mechanisms of gliomagenesis are in adults (Buckner et al., 2007). This type of tumor is necessary to improve the outcome of treatment. Therefore, it is characterized by progressive overgrowth of glial tissue, diffuse essential for us to define specific tumor markers in tumori- and relentless invasion. Despite recent advances in treatment genesis and progression of gliomas, and to design more strategies, gliomas remain a poor prognosis in decades due to a effective therapeutic strategies (van den Bent et al., 2006). high rate of recurrence, which also decreased the effectiveness FRAT1 (frequently rearranged in advanced T cell lymphomas- of surgical therapy (Kaba and Kyritsis, 1997). Till now, half of 1) gene, which is a human homologue of mouse proto-oncogene ⁎ Corresponding author. Fax: +86 29 84775567. E-mail address: [email protected] (X. Zhang). 1 These authors contributed equally to this work. 0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2010.01.037 BRAIN RESEARCH 1320 (2010) 152– 158 153 Frat1 (Jonkers et al., 1997; Saitoh and Katoh, 2001), is located on expression of β-catenin increased gradually with the increase of human chromosome 10q24.1, encoding a 29-kDa protein pathological grade of glioma. There was a positive correlation comprising 279 amino acids. FRAT1 was initially cloned in a between FRAT1 IRS and β-catenin IRS (r=0.782, P<0.001). screen to identify genes that accelerate lymphomagenesis in Representative images of β-catenin immunostaining are oncogene-bearing transgenic mice (Freemantle et al., 2002). shown in Fig. 1 and the related results are shown in Tables 2 Its biological function, however, remained elusive until its and 3. Xenopus homolog GBP (GSK3-binding protein) was isolated (Yost et al., 1998). All FRAT/GBP homologs have an established role in Xenopus embryonic development through inhibition of 3. Discussion GSK-3 phosphorylation of β-catenin (Jonkers et al., 1999a; Saitoh et al., 2001; Yost et al., 1998), and they were thus shown to be a Our study focused on the relationship between tumorigenesis core component of the canonical Wnt pathway in Xenopus of gliomas and FRAT1 expression. Gliomas are one of the most (Dominguez and Green, 2000; Farr et al., 2000; Yost et al., 1998). aggressive human malignancies. Patients with the most Moreover, there are some supportive reports showing that malignant histopathologic subtype, glioblastoma, carry the FRAT1 plays a role in tumor progression (Jonkers et al., 1997, worst clinical prognosis, despite advanced surgery and 1999b; Saitoh et al., 2002; Wang et al., 2006). However, little is adjuvant radiotherapy and chemotherapy (van den Bent known about the relationship between FRAT1 and glioma. In the et al., 2006). Although the molecular and genetic basis present study we found that FRAT1 expression correlated underlying the pathogenesis and treatment resistance of positively with the increasing WHO grade of glioma and these tumors is becoming better understood in recent years, expression level of β-catenin, which may have important much still remains unclear at present (Sanson et al., 2004). It implications in both predicting the clinical prognosis and has been elucidated that many critical signal pathways understanding the biology of these tumors. important for the development of nervous system and neural stem cells also have great impact on the tumorigenesis of gliomas, such as Notch, BMP, EGFR, BMI1, Hedgehog, PTEN, 2. Results Wnt/β-catenin, etc., which might be aberrantly regulated in gliomas (Mao et al., 2009). Wnt/β-catenin signaling is a 2.1. Immunohistochemical study of FRAT1 conserved molecular mechanism in metazoan animals. This pathway broadly influence changes in gene expression that In our study, FRAT1 protein was overexpressed in brain govern embryogenesis and postnatal responses, such as cell gliomas. Immunopositive tumor cells showed primarily cyto- proliferation, cell-fate determination, cell survival, cell behav- plasmic labeling under light microscope. However, normal ior and migration during morphogenesis (Logan and Nusse, brain tissues had exceedingly weak or absent immunoreactiv- 2004). Abnormal Wnt/β-catenin signaling is associated with ity for this protein (Fig. 1I). The positive expression rate of many human diseases, including cancer, osteoporosis, aging FRAT1 was 66.7% (56/84), and its IRS was 4.07±3.60 for 84 cases and degenerative disorders (Clevers, 2006; Moon et al., 2004). of tumor specimen. The FRAT1 IRS (immunoreactivity score) As one essential regulator for the development of nervous were positively and markedly correlated with increasing WHO system, Wnt/β-catenin signaling participates in the process of grades (P<0.001). There were significant FRAT1 IRS differences almost all aspects of neural development, including stem between Grade I and Grade III (P<0.001), Grade I and Grade IV cell proliferation, maintenance and differentiation (Ille and (P<0.001), Grade II and Grade III (P=0.033), Grade II and Grade IV Sommer, 2005). Recently, Wnt/β-catenin signaling was (P<0.001), and Grade III and Grade IV (P=0.035) gliomas. reported to contribute to the formation of gliomas, and some Representative images of FRAT1 immunostaining are shown proteins involved in the Wnt/β-catenin pathway were abnor- in Fig. 1 and the related results are shown in Tables 1, 2, and 3. mally expressed in gliomas (Sareddy et al., 2009; Yu et al., 2007). In addition, it has been demonstrated that Wnt/β- 2.2. The mRNA and protein expressions of FRAT1 catenin signaling played important roles in the genesis of other tumors such as leukemia, colon cancers, etc. (Van der In this study, the mRNA and protein expression levels of Flier et al., 2007; Zhao et al., 2007). However, the exact ways FRAT1 were represented by the ratio of gray value of FRAT1 to that Wnt/β-catenin signaling acts on the tumorigenesis of that of internal control (β-actin or GAPDH) in Western blot and gliomas are not clarified. Therefore, this study focused on RT-PCR. The results of Western blot and RT-PCR were investigating the expression of FRAT1 on gliomas, in order to coincident with that of immunohistochemistry. The results provide more knowledge about the roles that Wnt/β-catenin showed that mRNA and protein expression levels of FRAT1 pathway plays during the tumorigenesis of gliomas. increased markedly with the increase in pathologic grade of FRAT1 has been identified as a positive regulator of the brain gliomas (P<0.001, Tables 2 and 3; Figs. 2 and 3). Wnt/β-catenin pathway, which can inhibit GSK3 activity and ultimately down-regulate β-catenin (Ferkey and Kimelman, 2.3. Expression of β-catenin and its correlation with 2002; Fraser et al., 2002; Giles et al., 2003). It has been proposed pathologic grade and FRAT1 expression in gliomas that activation of the Wnt signaling cascade can cause Dishevelled (Dvl) family protein to recruit FRAT/GBP into the The expression of β-catenin was detected in cytoplasm and/or β-catenin degradation complex, leading to dissociation of nucleus of glioma cells by immunohistochemistry. There GSK-3 from Axin and consequently stabilization of β-catenin was no expression of β-catenin in normal brain tissues. The (Li et al., 1999; Salic et al., 2000). This may result in the 154 BRAIN RESEARCH 1320 (2010) 152– 158 Fig. 1 – Representative sections for FRAT1 and β-catenin Immunoreactivity in normal control brain and glioma tissue.
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