High Beclin 1 expression defines a poor prognosis in endometrial adenocarcinomas
Highlights
► Beclin 1, a marker of autophagic activity, was highly expressed in 18% of endometrioid adenocarcinomas and down-regulated in 52%. ► A high Beclin 1 expression was associated with high tumor grade, deep myometrial invasion and a poor 5-year survival. ► HIF1α and Beclin 1 proteins were significantly co-expressed, suggesting a link between beclin 1 expression and intratumoral hypoxia.
Introduction
Autophagy is an intracellular homeostatic mechanism, most important for the recycling of long-lived cytoplasmic proteins and defective organelles [1]. The formation of autophagosomes, that is double membrane vacuoles engulfing cytoplasmic components, is the first step in the autophagic process. These are, subsequently, fused with lysosomes (autolysosomes) and the sequestered material is degraded by lysosomal enzymes. Thus, the intracellular accumulation of waste constituents is prevented and, at the same time, complex molecules are converted to simpler for cell metabolism.
Given that various stress conditions, such as hypoxia and high acidity, accentuate the autophagic machinery, it is possible that, under these circumstances, autophagy may assume a dominant role in cancer cell survival and growth [2], [3].
Beclin 1 (BECN1), a mammalian orthologue of the yeast Apg6/Vps30 gene [4], functions as a scaffold for the formation of the PI3K complex, which is one of the first components recruited during the development of autophagosomes. It has, therefore, an important role in autophagy. Furthermore, Beclin 1 is present in intra-cytoplasmic organelles, including the trans-Golgi network, the endoplasmic reticulum, the mitochondria and the perinuclear membrane [4], [5].
In a previous study [6], we have shown that the LC3A protein, an essential component of the autophagic vacuoles, is highly expressed in a proportion of endometrial carcinomas and that a specific pattern reflecting excessive autophagic activity, namely the ‘stone-like’ structures (SLS), are linked with poor prognosis. In this study, we investigate the expression of Beclin 1 in a series of 155 endometrial adenocarcinomas of the endometrioid cell type in order to examine its clinico-pathological and prognostic role in malignant endometrial disease.
Section snippets
Materials and methods
The material comprised 155 endometrial adenocarcinomas of the endometrioid cell type, and 20 normally cycling endometria. The tissues, which were drawn from the files of the Department of Pathology, Democritus University of Thrace, Alexandroupolis, Greece, had been routinely fixed in 10% formol-saline.
All cancer patients in the series had been treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Their age ranged from 47 to 80 years (median 63). Patients with myometrial
Beclin 1 reactivity in endometrial tumor cells
Endometrial tumor cells expressed high Beclin 1 reactivity in 18.1% (28/155) of the cases studied (Fig. 1b); reactivity was intermediate in 29.7% (46/155), and low in 52.2% (81/155).
Beclin 1 reactivity in the normal endometrium
All normally cycling endometria, whether proliferating or secretory, demonstrated a high Beclin 1 reactivity in glandular epithelial cells, while stromal cells were unreactive.
Association with histological variables and HIF-1α
The association of Beclin 1 with the various histopathological parameters studied is shown in Table 1. High Beclin 1 expression was
Discussion
Beclin 1 is an essential protein for the initiation of autophagosome formation [4]. It resides in the trans-Golgi network, the endoplasmic reticulum and the mitochondria [4], [5], and a cytoplasmic reactivity, after immunohistochemical stain, was not, therefore, unexpected in both normal and malignant endometrial tissues.
Indeed, Beclin 1 was expressed strongly in the normally cycling endometrium, compared to stromal and myometrial cells, suggesting a role of the autophagic machinery in the
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
The authors thank Professor K.C. Catter, University of Oxford, Oxford, UK for kindly providing the monoclonal antibody HIF1α. They also thank Mrs. Kyriaki Devetzi for excellent technical assistance.
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