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Aurora-A enhances malignant development of esophageal squamous cell carcinoma (ESCC) by phosphorylating ?-catenin.

ABSTRACT: The Aurora-A gene encodes a serine/threonine protein kinase that is frequently overexpressed in several types of human tumors. The overexpression of Aurora-A has been observed to associate with the grades of differentiation, invasive capability and distant lymph node metastasis of esophageal squamous cell carcinoma (ESCC). However, the molecular mechanism by which Aurora-A promotes malignant development of ESCC is still largely unknown. In this study, we show that Aurora-A overexpression enhances tumor cell invasion and metastatic potential in vitro and in vivo. Furthermore, Aurora-A overexpression inhibits the degradation of ?-catenin, promotes its dissociation from cell-cell contacts and increases its nuclear translocation. We also demonstrate for the first time that Aurora-A directly interacts with ?-catenin and phosphorylates ?-catenin at Ser552 and Ser675. Substitutions of serine residue with alanine at single or both positions substantially attenuate Aurora-A-mediated stabilization of ?-catenin, abolish its cytosolic and nuclear localization as well as transcriptional activity. In addition, Aurora-A overexpression is significantly correlated with increased cytoplasmic ?-catenin expression in ESCC tissues. In view of our results, we propose that Aurora-A-mediated phosphorylation of ?-catenin is a novel mechanism of malignancy development of tumor.

SUBMITTER: Jin S

PROVIDER: S-EPMC5528673 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Project description:MicroRNAs (miRNAs) are an endogenous conserved class of non-coding 20–22 nt small RNAs that regulate gene expression at post-transcriptional level by mostly binding to 3′-UTR of target mRNAs, leading to mRNA degradation or translation inhibition. Recent reports demonstrate a role for miRNA expression in the disease progression and outcome. By now, many researcher focusing on miRNA expression profiles in Barrett's esophagus and esophageal adenocarcinoma have been reported. Nevertheless, there is still a little information available about specific miRNA expression pattern and their roles in ESCC. To develop novel diagnostic and therapeutic targets for esophageal squamous cancer, we first investigated the expression profile of miRNA in three pairs of ESCC clinical samples. Tissues of ESCC and the matched normal counterparts were obtained from surgical specimens immediately after resection from patients undergoing primary surgical treatment of esophageal carcinoma from the Department of Tumor Surgery of Shantou Central Hospital, China. RNA labeling and hybridization were completed by KangChen Bio-tech Inc. (Shanghai, China) according to the manufacturer's instructions. Briefly, total RNA from three pairs of esophageal carcinoma and matched normal tissues were isolated by Trizol (Invitrogen, USA) and purified by RNeasy mini kit (QIAGEN, German). The concentration and quality of total RNA were measured by NanoDrop ND-1000 at 260 and 280 nm (A260/280) and checked by gel electrophoresis. Each RNA sample from three pairs of ESCC was separately labeled either using the miRCURY Hy3/Hy5 labeling kit and hybridized on the six miRCURYTM locked nucleic acid (LNA) array version 11.0 (Exiqon, Denmark), which contains probes for 1700 mature miRNA. Scans were quantified by using GenePix software (Molecular Devices). The data were exported to Microsoft Excel worksheets, log2 transformed, normalized using global Lowess (Locally Weighted Scatter plot Smoothing) regression algorithm (MIDAS, TIGR Microarray Data Analysis System).

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Aurora-A enhances malignant development of esophageal squamous cell carcinoma (ESCC) by phosphorylating ?-catenin.

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