Research ReportExpression of targeting protein for Xenopus kinesin-like protein 2 is associated with progression of human malignant astrocytoma
Research Highlights
►Demonstrated that a gene known as targeting protein for Xenopus kinesin-like protein 2 (TPX2) may serve as an attractive anticancer target for malignant astrocytoma. The high expression of TPX2 expression in malignant astrocytoma tissues and cells may be associated with the progression of malignant astrocytoma. This result may offer a novel approach to controlling malignant astrocytoma.
Introduction
Malignant astrocytomas are the most common form of primary brain tumor, of which glioblastoma multiforme (GBM) is the most frequent malignant type (Levin, 1999). Despite improvement in treatment strategies, the prognosis for patients with malignant astrocytoma remains poor (Wechsler-Reya and Scott, 2001). Multiple genetic aberrations have been described in malignant astrocytoma, including amplification, homozygous deletion and the mutation of multiple genes (Ichimura et al., 2000, Riemenschneider et al., 2003, Ohgaki and Kleihues, 2007, Balss et al., 2008, Parsons et al., 2008). Several important pathways involved in the regulation of cell division are disrupted in glioblastoma (Cancer Genome Atlas Research Network, 2008). With an improved understanding of the molecular pathogenesis of malignant astrocytoma, targeted molecular therapies have recently evolved (Chi and Wen, 2007, Ohgaki and Kleihues, 2007, Sathornsumetee et al., 2007). The identification of additional astrocytoma-associated tumor markers is thus important for further research on astrocytoma pathogenesis. The targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a cell cycle-associated human protein (Heidebrecht et al., 1997, Zhang et al., 1999) and its expression is tightly regulated by the cell cycle. The aberrant expression of TPX2 has been found in various malignant tumors (Bonatz et al., 1999, Hufton et al., 1999, Rudolph et al., 1999, Gruss et al., 2002, Krams et al., 2003, Tonon et al., 2005, Shigeishi et al., 2009, Kadara et al., 2009, Warner et al., 2009, Satow et al., 2010). These results suggest that TPX2 plays a role in the oncogenesis of some malignancies. However, the expression patterns of TPX2 in astrocytoma are unclear. In the present study, we investigated the expression of TPX2 in human astrocytoma and related cell lines in order to test whether a correlation existed between TPX2 protein levels and the grade of cell differentiation. In addition, we evaluated the proliferation and apoptosis of cells when the TPX2 gene was inhibited by RNA interference in order to examine the relationships between TPX2 and astrocytoma.
Section snippets
Expression of TPX2 in astrocytoma tissue
Positive TPX2 immunoreactivity was detected in the nuclear compartments of 35 out of 52 astrocytoma tissue samples tested, while no positive TPX2 staining was detected in the normal brain tissue (Table 1, Fig. 1A). Analysis of the positive-staining data showed that the TPX2 expression level in high-grade astrocytomas was significantly higher than that in low-grade astrocytomas (P = 0.045). Similar results were also obtained by real-time PCR (P < 0.001) and Western blot analysis (P = 0.003) (Fig. 1B
Discussion
In the present study, we present both clinical and experimental evidence that TPX2 expression affects the progression of human malignant astrocytoma. The mitotic spindle apparatus segregates and redistributes chromosomes during mitosis (Sharp et al., 2000) and is composed of a highly dynamic microtubule skeleton that is associated with a variety of proteins, including kinesin-like and microtubule-associated proteins (Desai and Mitchison, 1997). As a cell microtubule and cycle-associated human
Patients and tissue samples
Samples were obtained from 52 patients with newly diagnosed primary astrocytoma (5 PA, WHO grade I; 16 DA, WHO grade II; 13 AA, WHO grade III; 18 GBM, WHO IV), who had not received therapy before sample collection. Samples were collected between 2004 and 2006 in Changzheng Hospital, the Second Military Medical University (Shanghai, China). The research protocol was approved by the Ethics Committee of Second Military Medical University. All samples were confirmed by pathological examination
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2020, Molecular Therapy Nucleic AcidsEmerging microtubule targets in glioma therapy
2015, Seminars in Pediatric NeurologyCitation Excerpt :A recent study has unraveled an evolutionarily conserved antagonistic control of microtubule nucleation at γ-TuRC in yeasts and human breast cancer cell lines by KIF14 and the KIF5 protein, Cut7, which may be exploited potentially as targets in cancer therapy164 (described later). The targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a cell cycle–associated protein, and increased TPX2 expression has been found in various human cancers.235 In human gliomas, TPX2 overexpression has been reported in surgically resected high-grade astrocytic gliomas where it is significantly associated with decreased patient survival.235
Targeting protein for Xenopus kinesin-like protein 2 (TPX2) regulates γ-histone 2AX (γ-H2AX) levels upon ionizing radiation
2012, Journal of Biological ChemistryCitation Excerpt :The exact molecular mechanisms by which TPX2 impacts the ionizing radiation-dependent γ-H2AX levels remain to be determined. TPX2 has been proposed as a biomarker and effector for cancer progression based on its elevated levels in numerous malignancies that are correlated with disease progression (12–17, 19, 83). So far, the suspected involvement of TPX2 in these diseases has been mostly linked to its functions in mitosis and activation of Aurora A (84).
The Aurora-A/TPX2 complex: A novel oncogenic holoenzyme?
2010, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :Furthermore, several instances of TPX2 overexpression in tumor tissues and cell lines emerge from specific studies (Table 1). In some cases, TPX2 overexpression correlated positively with tumor grade and stage, with lympho-metastasis and negatively with the survival rate [75–77]. We further extended the analysis by screening the Oncomine cancer microarray database and data-mining platform (Oncomine 4.3 Research Edition, www.oncomine.org).
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Bin Li and Xiang-Qian Qi contributed equally to this work.