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.

Activation of S6 signaling is associated with cell survival and multinucleation in hyperplastic skin after epidermal loss of AURORA-A Kinase

“…AUR-A has diverse roles in regulating cell division that include promoting the entry into mitosis and bipolar spindle assembly [18]. AUR-A is a cancer-susceptibility gene that is frequently amplified or overexpressed in epithelial tumors, including skin cancers [19][20][21][22]. AUR-A transforms immortalized cells and promotes the malignant conversion of chemically induced skin cancers, resulting in metastasis-prone tumors that are characterized by centrosome amplification and genomic instability [20,23].…”

The Clinical Kinase Index: Prioritizing Understudied Kinases as Targets for the Treatment of Cancer

“…AURKA and AURKB also consistently scored high across every cancer cohort, as did other cell-cycle and mitoses related kinases ( BUB1B, BUB1, CDK1 ). Despite Aurora kinases being priority targets for cancer drug development, clinical trials have, thus far, showed limited efficacy in solid tumors [26, 50].…”

Detection of Bladder Cancer in Urine Sediments by a Novel Multicolor Fluorescence In Situ Hybridization (Quartet) Test

“…Voided urine specimens (approximately 200 ml) were collected and prepared for FISH analysis as previously described [15,16]. In brief, the…”

“…AURKA copy numbers have also been used as effective biomarkers for bladder cancer detection in voided urine. AURKA copy numbers and other multicolor fluorescence in situ hybridization (FISH) tests assessing chromosomal copy numbers (based predominantly on assays of centromeric probes) in exfoliated cells of voided urine samples have been used in clinical practice as noninvasive detection tests for bladder cancer, as has urine cytology [15][16][17][18][19]. They have also been applied to monitor the recurrence and progression of patients with nonmuscle-invasive bladder tumors.…”