Frequent overexpression of Aurora Kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions

Abstract

BACKGROUNDUpper gastrointestinal adenocarcinomas are a common cause of cancer‐related deaths. In this study, the authors investigated the prevalence and biological significance of Aurora Kinase A (AURKA) overexpression in upper gastrointestinal adenocarcinomas.METHODSQuantitative real‐time polymerase chain reaction (qRT‐PCR) and immunohistochemical staining on tumor tissue microarrays (TMA) were used to study the expression of AURKA in upper gastrointestinal adenocarcinomas. To investigate the biological and signaling impact of AURKA, the authors used multiple in vitro assays that included 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide (MTT), TUNEL (terminal deoxynucleotidyl transferase–mediated nick‐end labeling), cytochrome C release, flow cytometry, luciferase reporter, and Western blot analysis.RESULTSFrequent overexpression of AURKA transcript in upper gastrointestinal adenocarcinomas was detected compared with normal samples (47%; P = .001). The immunohistochemical analysis of 130 tumors demonstrated moderate‐to‐strong immunostaining of AURKA in >50% of upper gastrointestinal adenocarcinomas. By using camptothecin as a drug‐induced apoptosis in vitro model, the authors demonstrated that the expression of AURKA provided protection against apoptosis to gastrointestinal cancer cells (AGS and RKO) (P = .006) and RIE‐1 primary intestinal epithelial cells (P = .001). The AURKA overexpression mediated an increase in phosphorylation of AKTSer473 with an increase in HDM2 level. The shRNA‐knockdown of AKT in AURKA‐overexpressing cells reversed this effect and showed a significant increase in the p53 protein level, indicating a possible nexus of AURKA/AKT/p53. Indeed, overexpression of AURKA led to a remarkable reduction in the transcription activity of p53, with subsequent reductions in transcript and protein levels of its downstream proapoptotic transcription targets (p21, BAX, NOXA, and PUMA).CONCLUSIONSStudy results indicated that AURKA provides potent antiapoptotic properties to gastrointestinal cells by regulating levels of p53 through the AKT/HDM2 axis. Cancer 2008. ©2008 American Cancer Society.

Aurora kinase A (AURKA) and never in mitosis gene A-related kinase 6 (NEK6) genes are upregulated in erosive esophagitis and esophageal adenocarcinoma

“…This overexpression was more prevalent in gastroesophageal junction adenocarcinomas and lower in esophageal, Barrett-related adenocarcinomas (BAS) than in antrum and body gastric adenocarcinomas. They also found that the expression of AURKA caused an anti-apoptotic effect in gastrointestinal cancer cells with drug-induced apoptosis in an in vitro model (27). Rugge et al found that AURKA immunostaining increased significantly along with the Barrett's carcinogenesis, from Barrett's mucosa even without metaplasia towards Barrett's adenocarcinoma (24).…”

“…AURKA protein levels and kinase activity are low in the G1/S phase; accumulate during G2/M and decrease rapidly following mitosis (25). AURKA is an important kinase-encoding gene involved in centrosome duplication and distribution; its overexpression leads to centrosome amplification, chromosomal instability and aneuploidy in several cancer types (26,27). AURKA overexpression has been found in numerous tumor cells and tissues including gastric cancer, breast cancer, colorectal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer and esophageal squamous-cell carcinoma, esophageal adenocarcinoma and Barrett's esophagus (27,28).…”

“…AURKA is an important kinase-encoding gene involved in centrosome duplication and distribution; its overexpression leads to centrosome amplification, chromosomal instability and aneuploidy in several cancer types (26,27). AURKA overexpression has been found in numerous tumor cells and tissues including gastric cancer, breast cancer, colorectal cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer and esophageal squamous-cell carcinoma, esophageal adenocarcinoma and Barrett's esophagus (27,28). Dar et al demonstrated overexpression of mitotic kinase encoding gene in upper gastrointestinal adenocarcinomas through the immunohistochemical analysis of 130 tumors.…”

Detection of kinase amplifications in gastric adenocarcinomas

“…Of the samples, 70.0% (14/21) with AURK A amplification were poorly differentiated tumors and there was a statistically significant association between increased copy number of AURK A and tumor stages. Moreover, it is necessary to analyze AURK A amplification and its relation with expression levels in tumor samples because recent evidence (42) has shown the antiapoptotic potential of AURK A to gastrointestinal cells by regulating levels of P53 through the AKT/HDM2 pathway, and AURK A kinase inhibitors might be a therapeutic option for patients with AURK A-positive expression. An experimental study has shown that deletion of AURK A by AURK A-specific small interference RNA could be a potential therapeutic method in the treatment of gastric cancers (43).…”

Aurora-A as an independent molecular prognostic marker in gastric cancer

“…Moreover, several studies reported that there was a close association between Aurora-A overexpression and malignant biological behavior of cancer progression (9,16,(33)(34)(35). Additionally, Aurora-A overexpression was observed to be associated with egFr activation and overexpression (36,37).…”