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Beclin-1 and LC3A expression in cutaneous malignant melanomas: a biphasic survival pattern for beclin-1

Sivridis, Efthimiosa; Koukourakis, Michael I.b; Mendrinos, Savvas E.d; Karpouzis, Antoniosc; Fiska, Alikia; Kouskoukis, Constantinosc; Giatromanolaki, Alexandraa

doi: 10.1097/CMR.0b013e328346612c
ORIGINAL ARTICLES: Basic research
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Autophagy is an intracellular pathway for the degradation of long-lived proteins and damaged organelles. It is, in essence, a recycling process allowing cells to survive oxygen and nutrient depletion. The expression of two autophagy-related proteins, beclin 1 and light chain 3A (LC3A) was investigated in 79 nodular cutaneous melanomas. The results were correlated with histopathological factors, vascular density, and hypoxia-related proteins [hypoxia-inducible factors (HIF1α and HIF2α) and lactate dehydrogenase 5]. The reactivity of both autophagy-related proteins was uniformly cytoplasmically diffused. High beclin 1 and LC3A reactivity was related to tumor hypoxia, as this was inferred from the intense expression of HIF1α and lactate dehydrogenase 5, whereas low beclin 1 and LC3A expression was linked with an increased vascular density. In addition, beclin 1 was related to disease-specific survival which, however, exposed a biphasic pattern. A strong beclin 1 expression extending over a tumor area of more than 50% (high) was associated with an increased rate of early deaths, whereas a similarly strong, but less-extensive cytoplasmic reactivity (<10% tumor area; low) defined a sharp fall in the survival 5 years after surgery. Furthermore, the low beclin 1 expression was associated with high Breslow's depth, high Clark's level, and ulceration. Low LC3A expression was also related to ulceration, but not to other histopathological features nor prognosis. In multivariate analysis, beclin 1 was an independent prognostic variable. It is concluded that extensive autophagic activity is generated by tumor hypoxia and anaerobic glycolysis, whereas angiogenesis maintains low autophagic activity. Atg6/beclin 1 was proved to be capable of deciphering the prognosis in cutaneous malignant melanoma, but the matter requires further investigation.

aDepartments of Pathology

bRadiotherapy/Oncology

cDermatology, Democritus University of Thrace Medical School, and University General Hospital of Alexandroupolis, Alexandroupolis, Greece

dDepartment of Pathology, New York University School of Medicine, Langone Medical Center, New York, USA

Correspondence to Alexandra Giatromanolaki, MD, Department of Pathology, Democritus University of Thrace Medical School, and University General Hospital of Alexandroupolis, PO Box 12, Alexandroupolis 68100, Greece Tel: +30 25510 75117; fax: +30 25510 30440; e-mail: agiatrom@med.duth.gr

Received December 9, 2010

Accepted March 3, 2011

© 2011 Lippincott Williams & Wilkins, Inc.