High proliferation index, as determined by immunohistochemical expression of Aurora kinase B and geminin, indicates poor prognosis in neuroblastomas

Abstract

Expression profile analysis of cell cycle biomarkers provides a powerful index of the proliferative state of tumors, which is linked to disease aggressiveness. We investigated the impact of the biomarkers of S-G2-M phases of cell cycle, Aurora kinase B (AURKB) and geminin (GMNN), on disease progression in neuroblastomas. The expression of AURKB and GMNN was studied by immunostaining 84 neuroblastomas. A proliferation index (PI) was obtained on scanned immunostained slides using image analysis software. The median PI was 8.5 % for AURKB- and 16.8 % for GMNN-stained slides with a high correlation between the two (r s = 0.72, P < 0.001). The PI for both markers was significantly higher in neuroblastomas from patients with unfavorable clinical (high-risk group, advanced stage, age ≥18 months at presentation, primary abdominal compared to extra-abdominal sites), biological (MYCN amplification, 1p deletion, 17q gain), and pathological (undifferentiated or poorly differentiated status, high mitosis-karyorrhexis index, [MKI], unfavorable histology) factors. Using Cox regression models, a higher-than-median AURKB and GMNN PI was associated with a significantly shorter overall survival (OS) and event-free survival (EFS) in univariable analysis. In multivariable analysis, a high AURKB PI was associated with significantly shorter OS and EFS, independent of MYCN amplification, and significantly shorter EFS, independent of MKI. High GMNN PI was also associated with significantly shorter OS and EFS after adjusting for MYCN amplification but failed to reach statistical significance after adjusting for MKI. Our study shows that in neuroblastomas, AURKB- or GMNN-based PI provides valuable prognostic information and high PI indicates aggressive disease.

<p><em>AURKB</em> Promotes the Metastasis of Gastric Cancer, Possibly by Inducing EMT</p>

“…Our results were similar to previous studies, which found that AURKB was closely correlated with the prognosis, invasiveness, chemoresistance of various tumors. [7][8][9][10][11] Based on these results, we considered that AURKB could function as a novel oncogene and become a potential therapeutic target in GC.…”

“… 6 Overexpression or amplification of AURKB is usually detected in human cancers, including breast cancer, 7 ovarian cancer, 8 gastric/gastrointestinal cancer and other tumors, 9 , 10 and is proved to be related to poor prognosis. 11 Therefore, AURKB has become a promising therapeutic target in tumors. Some researchers found that high expression of AURKB was associated with the improved overall survival in GC, 12 however, others considered that inhibition of AURKB reduced GC cell viability and increased the sensitivity of resistant GC cell to cisplatin.…”

Aurora kinases: novel therapy targets in cancers

“…Loss of AURKB activity could override spindle assembly checkpoint (SAC) through premature removal of SAC proteins from the kinetochore [7], which leads to defect of chromosome segregation and conformation of polyploidy. Overexpression or amplification of Aurora kinases is generally detected in amount of human cancers, such as breast cancer [8–11], ovarian cancer [12–14], gastric/gastrointestinal cancer [15, 16] and other tumors [11, 17–33] (Table 1) and is associated with the poor prognosis [8, 34, 35]. Thus, Aurora kinases become promising therapeutic targets and numerous AKIs have been developed.…”

APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model

“…Abnormal Aurora A expression also contributes to esophageal cancer development and cisplatin resistance [ 30 , 31 ]. The scientific literature indicates that high levels of Aurora A kinase are associated with advanced clinical stage and poor prognosis in several cancers [ 32 – 36 ]. Additionally, Aurora B overexpression is associated with acute myeloid leukemia [ 37 ] and colorectal cancer [ 38 ].…”