Aurora kinase A is a biomarker for bladder cancer detection and contributes to its aggressive behavior

Aaron Mobley; Shizhen Zhang; Jolanta Bondaruk; Yan Wang; Tadeusz Majewski; Nancy P. Caraway; Li Huang; Einav Shoshan; Guermarie Velazquez-Torres; Giovanni Nitti; Sangkyou Lee; June Goo Lee; Enrique Fuentes-Mattei; Daniel Willis; Li Zhang; Charles C. Guo; Hui Yao; Keith Baggerly; Yair Lotan; Seth P. Lerner; Colin Dinney; David McConkey; Menashe Bar-Eli; Bogdan Czerniak

doi:10.1038/srep40714

Aurora kinase A is a biomarker for bladder cancer detection and contributes to its aggressive behavior

Aaron Mobley, Shizhen Zhang, Jolanta Bondaruk, Yan Wang, Tadeusz Majewski, Nancy P. Caraway, Li Huang, Einav Shoshan, Guermarie Velazquez-Torres, Giovanni Nitti, Sangkyou Lee, June Goo Lee, Enrique Fuentes-Mattei, Daniel Willis, Li Zhang, Charles C. Guo, Hui Yao, Keith Baggerly, Yair Lotan, Seth P. LernerColin Dinney, David McConkey, Menashe Bar-Eli, Bogdan Czerniak

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Abstract

The effects of AURKA overexpression associated with poor clinical outcomes have been attributed to increased cell cycle progression and the development of genomic instability with aneuploidy. We used RNA interference to examine the effects of AURKA overexpression in human bladder cancer cells. Knockdown had minimal effects on cell proliferation but blocked tumor cell invasion. Whole genome mRNA expression profiling identified nicotinamide N-methyltransferase (NNMT) as a downstream target that was repressed by AURKA. Chromatin immunoprecipitation and NNMT promoter luciferase assays revealed that AURKA's effects on NNMT were caused by PAX3-mediated transcriptional repression and overexpression of NNMT blocked tumor cell invasion in vitro. Overexpression of AURKA and activation of its downstream pathway was enriched in the basal subtype in primary human tumors and was associated with poor clinical outcomes. We also show that the FISH test for the AURKA gene copy number in urine yielded a specificity of 79.7% (95% confidence interval [CI] = 74.2% to 84.1%), and a sensitivity of 79.6% (95% CI = 74.2% to 84.1%) with an AUC of 0.901 (95% CI = 0.872 to 0.928; P < 0.001). These results implicate AURKA as an effective biomarker for bladder cancer detection as well as therapeutic target especially for its basal type.

Original language	English (US)
Article number	40714
Journal	Scientific reports
Volume	7
DOIs	https://doi.org/10.1038/srep40714
State	Published - Jan 19 2017

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Mobley, A., Zhang, S., Bondaruk, J., Wang, Y., Majewski, T., Caraway, N. P., Huang, L., Shoshan, E., Velazquez-Torres, G., Nitti, G., Lee, S., Lee, J. G., Fuentes-Mattei, E., Willis, D., Zhang, L., Guo, C. C., Yao, H., Baggerly, K., Lotan, Y., ... Czerniak, B. (2017). Aurora kinase A is a biomarker for bladder cancer detection and contributes to its aggressive behavior. Scientific reports, 7, Article 40714. https://doi.org/10.1038/srep40714

Mobley, A, Zhang, S, Bondaruk, J, Wang, Y, Majewski, T, Caraway, NP, Huang, L, Shoshan, E, Velazquez-Torres, G, Nitti, G, Lee, S , Lee, JG, Fuentes-Mattei, E, Willis, D, Zhang, L, Guo, CC, Yao, H, Baggerly, K, Lotan, Y, Lerner, SP, Dinney, C, McConkey, D, Bar-Eli, M & Czerniak, B 2017, 'Aurora kinase A is a biomarker for bladder cancer detection and contributes to its aggressive behavior', Scientific reports, vol. 7, 40714. https://doi.org/10.1038/srep40714

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title = "Aurora kinase A is a biomarker for bladder cancer detection and contributes to its aggressive behavior",

abstract = "The effects of AURKA overexpression associated with poor clinical outcomes have been attributed to increased cell cycle progression and the development of genomic instability with aneuploidy. We used RNA interference to examine the effects of AURKA overexpression in human bladder cancer cells. Knockdown had minimal effects on cell proliferation but blocked tumor cell invasion. Whole genome mRNA expression profiling identified nicotinamide N-methyltransferase (NNMT) as a downstream target that was repressed by AURKA. Chromatin immunoprecipitation and NNMT promoter luciferase assays revealed that AURKA's effects on NNMT were caused by PAX3-mediated transcriptional repression and overexpression of NNMT blocked tumor cell invasion in vitro. Overexpression of AURKA and activation of its downstream pathway was enriched in the basal subtype in primary human tumors and was associated with poor clinical outcomes. We also show that the FISH test for the AURKA gene copy number in urine yielded a specificity of 79.7% (95% confidence interval [CI] = 74.2% to 84.1%), and a sensitivity of 79.6% (95% CI = 74.2% to 84.1%) with an AUC of 0.901 (95% CI = 0.872 to 0.928; P < 0.001). These results implicate AURKA as an effective biomarker for bladder cancer detection as well as therapeutic target especially for its basal type.",

author = "Aaron Mobley and Shizhen Zhang and Jolanta Bondaruk and Yan Wang and Tadeusz Majewski and Caraway, {Nancy P.} and Li Huang and Einav Shoshan and Guermarie Velazquez-Torres and Giovanni Nitti and Sangkyou Lee and Lee, {June Goo} and Enrique Fuentes-Mattei and Daniel Willis and Li Zhang and Guo, {Charles C.} and Hui Yao and Keith Baggerly and Yair Lotan and Lerner, {Seth P.} and Colin Dinney and David McConkey and Menashe Bar-Eli and Bogdan Czerniak",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = jan,

day = "19",

doi = "10.1038/srep40714",

language = "English (US)",

volume = "7",

journal = "Scientific reports",

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T1 - Aurora kinase A is a biomarker for bladder cancer detection and contributes to its aggressive behavior

AU - Mobley, Aaron

AU - Zhang, Shizhen

AU - Bondaruk, Jolanta

AU - Wang, Yan

AU - Majewski, Tadeusz

AU - Caraway, Nancy P.

AU - Huang, Li

AU - Shoshan, Einav

AU - Velazquez-Torres, Guermarie

AU - Nitti, Giovanni

AU - Lee, Sangkyou

AU - Lee, June Goo

AU - Fuentes-Mattei, Enrique

AU - Willis, Daniel

AU - Zhang, Li

AU - Guo, Charles C.

AU - Yao, Hui

AU - Baggerly, Keith

AU - Lotan, Yair

AU - Lerner, Seth P.

AU - Dinney, Colin

AU - McConkey, David

AU - Bar-Eli, Menashe

AU - Czerniak, Bogdan

PY - 2017/1/19

Y1 - 2017/1/19

N2 - The effects of AURKA overexpression associated with poor clinical outcomes have been attributed to increased cell cycle progression and the development of genomic instability with aneuploidy. We used RNA interference to examine the effects of AURKA overexpression in human bladder cancer cells. Knockdown had minimal effects on cell proliferation but blocked tumor cell invasion. Whole genome mRNA expression profiling identified nicotinamide N-methyltransferase (NNMT) as a downstream target that was repressed by AURKA. Chromatin immunoprecipitation and NNMT promoter luciferase assays revealed that AURKA's effects on NNMT were caused by PAX3-mediated transcriptional repression and overexpression of NNMT blocked tumor cell invasion in vitro. Overexpression of AURKA and activation of its downstream pathway was enriched in the basal subtype in primary human tumors and was associated with poor clinical outcomes. We also show that the FISH test for the AURKA gene copy number in urine yielded a specificity of 79.7% (95% confidence interval [CI] = 74.2% to 84.1%), and a sensitivity of 79.6% (95% CI = 74.2% to 84.1%) with an AUC of 0.901 (95% CI = 0.872 to 0.928; P < 0.001). These results implicate AURKA as an effective biomarker for bladder cancer detection as well as therapeutic target especially for its basal type.

AB - The effects of AURKA overexpression associated with poor clinical outcomes have been attributed to increased cell cycle progression and the development of genomic instability with aneuploidy. We used RNA interference to examine the effects of AURKA overexpression in human bladder cancer cells. Knockdown had minimal effects on cell proliferation but blocked tumor cell invasion. Whole genome mRNA expression profiling identified nicotinamide N-methyltransferase (NNMT) as a downstream target that was repressed by AURKA. Chromatin immunoprecipitation and NNMT promoter luciferase assays revealed that AURKA's effects on NNMT were caused by PAX3-mediated transcriptional repression and overexpression of NNMT blocked tumor cell invasion in vitro. Overexpression of AURKA and activation of its downstream pathway was enriched in the basal subtype in primary human tumors and was associated with poor clinical outcomes. We also show that the FISH test for the AURKA gene copy number in urine yielded a specificity of 79.7% (95% confidence interval [CI] = 74.2% to 84.1%), and a sensitivity of 79.6% (95% CI = 74.2% to 84.1%) with an AUC of 0.901 (95% CI = 0.872 to 0.928; P < 0.001). These results implicate AURKA as an effective biomarker for bladder cancer detection as well as therapeutic target especially for its basal type.

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Aurora kinase A is a biomarker for bladder cancer detection and contributes to its aggressive behavior

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