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Dean, Scott D

Dean, Scott D. shorter overall survival. Knockdown of TOPK with specific siRNA resulted in significantly decrease chordoma cell viability. Inhibition of TOPK with OTS514 significantly inhibited chordoma cell growth and proliferation, colony\forming capacity and ex lover vivo spheroid growth. Conclusions High expression of TOPK is an important predictor of poor prognosis in chordoma. Inhibition of TOPK resulted in significantly decrease chordoma cell proliferation and increase apoptosis. Our results indicate TOPK as a novel prognostic biomarker and therapeutic target for chordoma. spheroid growth. These results indicate TOPK as a novel prognostic biomarker and therapeutic target for chordoma. 1.?INTRODUCTION Chordomas are rare tumours arising from remnants of the embryological notochord. The annual incidence of chordomas in the United States is usually approximately two cases per million people, representing 1%\4% of all bone cancers. 1 , 2 The peak incidence of chordoma is usually between 40 and 60?years of age, with a slightly male predominance. 1 , 3 Chordomas most commonly arise within the sacrococcygeal area, vertebral body or skull base. 1 Although chordomas have undergone histologic and genetic analysis, the molecular mechanisms MN-64 driving these tumours are largely unknown. While chordomas are generally slow\growing, they are locally invasive and aggressive tumours with notorious resistance to standard chemotherapies and radiation. 3 , 4 , 5 Currently, no effective drugs exist for chordoma treatment. Therefore, surgical resection has remained the primary treatment modality for patients; however, its insidious course and proximity to vital neurovascular structures make total resection challenging if not possible. 2 Additionally, some chordoma patients already have metastatic diseases upon initial diagnosis. 3 , 6 , 7 The overall survival for chordoma patients is usually 68.4% at five years and 39.2% at 10?years, with a median overall survival of 7.8?years. 1 The strong chemotherapeutic resistance and lack of validated prognostic biomarkers in chordoma has highlighted the need for new and robust therapeutic targets. 2 , 3 , 5 , 8 Recent studies suggest that T\lymphokine\activated killer (T\LAK) cell\originated protein kinase (TOPK) has tumorigenic roles in various malignancies. 9 , 10 , 11 , 12 TOPK, also known as PDZ\binding kinase (PBK), is usually a 322\amino acid serine/threonine kinase encoded by the PBK gene on chromosome 8p21.1. Expression and activation of TOPK function as a mitogen\activated protein kinase kinase (MAPKK) which is essential for catalytic activity during mitosis. 9 Recent studies have shown that TOPK regulates mitosis through its governing of several DNA binding proteins. 13 While MN-64 TOPK expression is usually low or undetectable in healthy tissues, 9 it is overexpressed in lung malignancy, ovarian malignancy, renal malignancy, colorectal malignancy, prostate malignancy and haematologic malignancies and correlates MN-64 with worse outcomes. 11 , 14 , 15 , 16 , 17 , 18 , 19 Functionally, TOPK promotes malignancy cell growth and proliferation, dissemination and apoptotic resistance via numerous mechanisms. 9 Moreover, TOPK is usually upregulated in and promotes the proliferation and self\renewal of malignancy stem cells, thus prompting the aggression of multiple malignancies. 20 , 21 These findings have given TOPK acknowledgement as an emerging prognostic biomarker and therapeutic target with specificity for malignancy cells while sparing normal host tissue. Several TOPK\specific inhibitors have shown promising results MN-64 in pre\clinical works and are thus anticipated to be used in clinical trials in the near future. 9 , 11 , 12 , 22 In this study, we systemically investigated: (a) the expression of TOPK in chordoma patient tissues and cell lines; (b) the correlation of TOPK expression with patient clinicopathology and outcomes; (c) the function of TOPK in chordoma cell growth and proliferation; and (d) the effect of specific TOPK inhibitor on chordoma cell growth and proliferation in vitro and ex lover vivo three\dimensional environment. 2.?MATERIALS AND METHODS 2.1. Chordoma sample collection and tissue microarray The tissue microarray (TMA) was constructed from 55 individual chordoma patient specimens within a formalin\fixed paraffin\embedded (FFPE) block as previously explained. 23 , 24 The clinicopathological characteristics of the specimens were collected TSPAN16 and are layed out in Table?1, including age, gender, tumour location, recurrence, metastasis and disease status. The samples included 39 (70.9%) males and 16 (29.1%) females with an average age of 58.9?years old (range: 25\88?years old). The mean follow\up time was 80.9?months (range: 1.4\249.6?months). The most common tumour location was the sacrum (65.5%), followed by the lumbar spine (20.0%), thoracic spine (12.7%) and cervical spine (1.8%). Of these 55 patients, 25 (45.5%) developed disease recurrence and 12 (21.8%) developed distant metastasis..