Studio dei differenti livelli di espressione del gene Aurora A in pazienti con esofago di Barrett

Background: The development of oesophageal adenocarcinoma is generally closely associated with the presence of a specialised intestinal-type epithelium such as that found in Barrett’s oesophagus (BO). A particular histological condition is when the distal oesophagus showing cardiac and/or fundic mucosa without intestinal metaplasia cannot be defined as Barrett’s mucosa [condition that we call columnar-lined oesophagus (CLO)] and up till now, there has been no agreement in literature about the management of this condition. Aurora-A overexpression leads to centrosome amplification, chromosomal instability and aneuploidy in mammalian cells. Patients and methods: A prospective study was carried out on 28 consecutive patients who presented columnar mucosa above the gastro-oesophageal junction (GOJ) at endoscopy. As controls, two more biopsies were obtained, one on the normal-appearing squamous oesophagus above the GOJ, as far as possible from the columnar mucosa (controls A), and one taken 1 cm below the GOJ (controls B). The Aurora-A and p53 expression levels were analysed respectively by Quantitative Real Time PCR and immunohistochemistry.

In recent years, there has been an estimation in North America and Europe of a 40-fold increase in the risk of developing invasive adenocarcinoma of the oesophagus[1]. The proposed model of histological progression of this kind of tumour is a stepwise progression recognised as a metaplasia-dysplasiaadenocarcinoma sequence (MCS) [2]. Moreover, the development of oesophageal adenocarcinoma (OA) is generally closely associated with the presence of a specialised intestinal-type epithelium such as that found in Barrett’s oesophagus (BO) [3, 4]. BO occurs in 10%–12% of patients with chronic gastro-oesophageal reflux. Over a period of time, the presence of this stressful agent results in replacement of the normal squamous epithelium by the more acid-resistant columnar epithelium [5]. For this reason, Barrett’s mucosa is defined as the endoscopic presence of a metaplastic mucosa with goblet cells in the oesophagus, regardless of the length of the segment [6]. A particular histological condition is when the distal oesophagus showing cardiac and/or fundic mucosa without intestinal metaplasia (IM) cannot be defined as Barrett’s mucosa [7] and up till now, there has been no agreement in literature about the management of this condition. Hereafter, we refer to this condition as columnar-lined oesophagus (CLO). As in the molecular model proposed for colorectal cancer progression [8], several genetic alterations have been reported in the MCS [9]. In particular, p53 alterations have been reported in 5%–10% of cases with indeterminate dysplasia, in 65% of those with low-grade dysplasia, in 75% of cases with high-grade dysplasia and in 50%–90% of OA [10–12]. The p53 gene codifies for a nuclear phosphoprotein acting as a transcriptional regulator which prevents proliferation of damaged cells, in some cases inducing them to apoptosis [13]. In most normal tissues, the wild-type p53 protein is constitutively expressed at low levels because of a short half-life [14] due to rapid degradation, but it may accumulate in the cell as a result of several types of stress, such as DNA damage,hypoxia, loss of normal growth and survival signals, acidity and inflammatory processes [15], which may occur in different physiological or pathological situations, including tumorigenesis. In response to these situations of stress, p53 becomes stabilised and accumulates mostly in the nucleus. By regulating the expression of a number of genes, p53 then induces cell cycle arrest and/or apoptosis [16]. In Barrett’s mucosa, as a consequence of oxidative DNA damage caused by gastro-oesophageal reflux, there is an increased percentage of cells unable to carry out DNA repair; this is sometimes sequentially followed by p53 gene mutation and protein accumulation, DNA aneuploidy, dysplasia and carcinoma [17]. A new important gene correlated to cancer progression is Aurora-A also known as serine threonine kinase 15 (STK15), BTAK, Aurora kinase A, Aurora-2 or AIKI. This gene is a member of the Aurora/Ip11p family and is located in chromosome 20q13. Aurora-A is an important kinase-encoding gene involved in centrosome duplication and distribution; its overexpression leads to centrosome amplification, chromosomal instability and aneuploidy in mammalian cells [18]. Moreover, Aurora-A appears to be regulated by both phosphorylation and dephosporylation [19]. Aurora-A overexpression has been found in many tumour cells and tissues including breast cancer [20], gastric cancer [21], colorectal cancer [22], bladder cancer [23], pancreatic cancer [24], ovarian cancer [25], prostate cancer [26] and oesophageal squamous-cell carcinoma [27]. Up till now, however, there have not been any studies regarding Aurora-A expression alterations in precancerous forms such as BO or CLO, a condition probably preceding BO. Finally, recent studies have reported that Aurora-A and p53 activities mi