Integrating Bioinformatics and Clinicopathological Research of Gastrointestinal Stromal Tumors: Identification of Aurora Kinase A as a Poor Risk Marker

Yen, Chueh-Chuan; Yeh, Chun‐Nan; Cheng, Chi‐Tung; Jung, Shih‐Ming; Huang, Shih‐Chiang; Chang, Ting-Wei; Jan, Yi-Yin; Tzeng, Cheng‐Hwai; Chao, Ta‐Chung; Chen, Yeng-Yang; Yang, Ching‐Yao; Ho, Ching‐Liang; Fletcher, Jonathan A.

doi:10.1245/s10434-012-2389-0

Cited by 28 publications

(35 citation statements)

References 30 publications

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“…Moreover, by reanalyzing a dataset of GIST, our group identified aurora kinase A (AURKA), along with other cell cycle and mitosis genes, as a prognostic factor for recurrence. In addition, AURKA is a potential treatment target (38,39). Therefore, cell cycle regulation genes are a crucial group of potential biomarkers or targets in sarcoma.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel

Chou

Yen

Chen

et al. 2016

International Journal of Oncology

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Abstract. Polo-like kinase 1 (PLK1), a serine/threonine kinase and an oncogene, is crucial in regulating cell cycle progression. PLK1 also has been demonstrated as a potential target of osteosarcoma (OS) by using short hairpin RNA libraries in lentiviral vectors for screening of protein kinase. In preclinical studies, GSK461364, a potent and selective ATP-competitive PLK1 inhibitor, showed antiproliferative activity against multiple tumor cell lines. In the present study, we evaluated the expression level of PLK1 in OS and explored the cytotoxic mechanism of GSK461364 against OS. PLK1 was significantly overexpressed in OS compared with normal osteoblasts and other types of sarcoma. GSK461364 inhibited PLK1 and caused mitotic arrest by inducing G2/M arrest in OS cells. Moreover, GSK461364 exerted a cytotoxic effect by inducing apoptosis in OS, and induced cellular senescence in OS cell lines, as indicated by an increased senescenceassociated β-galactosidase activity and enhanced DcR2 and interleukin-1α expression. In addition, we demonstrated a synergistic cytotoxic effect of GSK461364 and paclitaxel, possibly resulting from combined mitotic arrest. In conclusion, the present study revealed that PLK1 was overexpressed in OS and that GSK461364 exerted its cytotoxic effect on OS by inducing mitotic arrest and subsequent apoptosis and induced cellular senescence; therefore, senescence-associated markers can be used as treatment biomarkers, and a combination of GSK461364 and paclitaxel can potentially treat OS.

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Section: Discussionmentioning

confidence: 99%

Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel

Chou

Yen

Chen

et al. 2016

International Journal of Oncology

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“…119 Accumulating data revealed that AURKA was frequently amplified and overexpressed in GC, 36,[120][121][122] and AURKA amplification associated with significantly worse survival. 123 A recent study showed copy number gains of AUKRA were detected in a relative high percentage of GC samples (30.5%). A positive connection has been found between AURKA amplification and tumor progression, 124 suggesting that AURKA may have prognostic significance.…”

Section: Chromosome 20mentioning

confidence: 98%

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Liang

2015

Oncogene

128

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Gastric cancer (GC) is among the most common malignancy in the world with poor prognosis and limited treatment options. It has been established that gastric carcinogenesis is caused by a complex interaction between host and environmental factors. Copy number variation (CNV) refers to a form of genomic structural variation that results in abnormal gene copy numbers, including gene amplification, gain, loss and deletion. DNA CNV is an important influential factor for the expression of both protein-coding and non-coding genes, affecting the activity of various signaling pathways. CNV arises as a result of preferential selection that favors cancer development, and thus, targeting the amplified 'driver genes' in GC may provide novel opportunities for personalized therapy. The detection of CNVs in chromosomal or mitochondrial DNA from tissue or blood samples may assist the diagnosis, prognosis and targeted therapy of GC. In this review, we discuss the recent CNV discoveries that shed light on the molecular pathogenesis of GC, with a specific emphasis on CNVs that display diagnostic, prognostic or therapeutic significances in GC.

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“…All eligible studies were published between 2005 and 2014. All TNM Stages (I-IV) were considered in 18 studies (46.2%) (9,18,20,27,28,30,(34)(35)(36)(37)(38)40,43,44,50,55,56,58), non-metastatic solid tumors (including Stage I-III or localized disease, based solely on singlestage disease or mixture of tumor stages) were considered in 12 (30.8%) studies (22,29,31,33,39,41,42,46,48,51,53,54); metastatic solid tumors (Stage IV) patients were considered in four studies (10.2%) (23,45,49,57); disease stage was not available were considered in five studies (12.8%). Four studies analyzing AURKA mRNA expression used real-time reverse transcription PCR (RT-PCR) (20,34,35,45); one study analyzing AURKA gene amplification by fluorescence in situ hybridization (FISH) (54); the other one used immunohistochemical (IHC) staining and RT-PCR (47); and the remaining 33 studies applied a immunohistochemistry detection method (9,18,19,21-23,27-33, 36-44,46,48-53,55-58).…”

Section: Characteristics Of Identified Studiesmentioning

confidence: 99%

“…Four studies analyzing AURKA mRNA expression used real-time reverse transcription PCR (RT-PCR) (20,34,35,45); one study analyzing AURKA gene amplification by fluorescence in situ hybridization (FISH) (54); the other one used immunohistochemical (IHC) staining and RT-PCR (47); and the remaining 33 studies applied a immunohistochemistry detection method (9,18,19,21-23,27-33, 36-44,46,48-53,55-58). Eight studies were conducted in patients from European countries (19,21,28,32,36,40,55,57), four in patients from USA (18,20,37,45), three in Oceania countries (33,46,49), one in South America (50), and twenty-three in Asian countries (9,22,23,27,(29)(30)(31)34,35,38,39,(41)(42)(43)(44)47,48,(51)(52)(53)(54)56,58). One or more oncologic outcome parameters were analyzed on multivariate analysis in 33 studies <...>…”

Section: Characteristics Of Identified Studiesmentioning

confidence: 99%

Prognostic value of Aurora kinase A (AURKA) expression among solid tumor patients: a systematic review and meta-analysis

Zhang¹,

Li²,

Zhang³

et al. 2015

Japanese Journal of Clinical Oncology

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Objective: The prognostic significance of Aurora kinase A expression in cancer patients is currently under debate. Here, we conducted the first comprehensive meta-analysis of the prognostic relevance of Aurora kinase A associated with survival in solid tumors. Methods: Pubmed was searched for studies evaluating the Aurora kinase A expression and survival in solid tumors through 10 October 2014. The main outcome analyzed was overall survival and secondary outcomes were progression-free survival, disease-free survival and cancer-specific survival. Pooled hazard ratio and 95% confidence intervals were calculated to assess the association. Subgroup and sensitivity analyses were also conducted. Results: Thirty-nine eligible studies enrolling 5523 patients were identified. The high Aurora kinase A expression level was significantly associated with shorter overall survival (hazard ratio = 2.31; 95% confidence interval, 1.81-2.95). Further subgroup analyses showed that our results were stable irrespective of the disease sites, stages and methods of Aurora kinase A expression. The high Aurora kinase A expression level was also associated with progression-free survival (hazard ratio = 2.68; 95% confidence interval, 1.96-3.69), disease-free survival (hazard ratio = 1.91; 95% confidence interval, 1.45-2.51) and cancer-specific survival (hazard ratio = 2.13; 95% confidence interval, 1.38-3.29). Conclusions: Our present meta-analysis indicates that the Aurora kinase A is an effective prognosticator in solid tumors patients. Further studies are required to explore the clinical utility of Aurora kinase A in solid tumor.

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Integrating Bioinformatics and Clinicopathological Research of Gastrointestinal Stromal Tumors: Identification of Aurora Kinase A as a Poor Risk Marker

Abstract: By integrating bioinformatics and clinicopathological studies, AURKA was identified as a marker for high-risk GIST.

Cited by 28 publications

References 30 publications

Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel

Cytotoxic mechanism of PLK1 inhibitor GSK461364 against osteosarcoma: Mitotic arrest, apoptosis, cellular senescence, and synergistic effect with paclitaxel

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

Prognostic value of Aurora kinase A (AURKA) expression among solid tumor patients: a systematic review and meta-analysis

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