title: Autophagy patterns and prognosis in uveal melanomas.
abstract: Autophagy is a self-degradation mechanism by which cells recycle their own cytoplasmic constituents. It has been claimed that, under certain conditions, such a process may be associated with tumor progression. In this study, the autophagic activity was investigated in a series of 99 uveal melanomas after immunohistochemical staining for the autophagy-associated proteins MAP1LC3A and BECN1, most commonly known as LC3A and Beclin 1, respectively. These were assessed in parallel with the hypoxia-inducible factor 1α (HIF1A) and its downstream protein lactate dehydrogenase 5 (composed by five LDHA subunits). Increased autophagic reactivity, detected by MAP1LC3A or BECN1, was associated with intense pigmentation and tumor hypoxia. Uveal melanomas with extensive overexpression of BECN1 or those with underexpression of this protein were associated with the worst prognosis, but the former manifested metastases much earlier than the latter; only 58% of patients with extensive BECN1 overexpression were alive at 4 years, compared with 80% of patients with underexpressed patterns. It is concluded that autophagy is commonly upregulated in uveal melanomas, and may be associated with hypoxia and intense pigmentation. There is a strong association between extensive BECN1 overexpression and early metastases/poor prognosis, and between underexpression of this protein and late metastases/better prognosis.
authors.affiliation: Department of Pathology, Democritus University of Thrace Medical School, Alexandroupolis, Greece. agiatrom@med.duth.gr
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Giatromanolaki
authors.forename: Georgios St
authors.initials: GS
authors.lastname: Charitoudis
authors.forename: Nikolaos E
authors.initials: NE
authors.lastname: Bechrakis
authors.forename: Vassilios P
authors.initials: VP
authors.lastname: Kozobolis
authors.forename: Michael I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: Michael H
authors.initials: MH
authors.lastname: Foerster
authors.forename: Efthimios L
authors.initials: EL
authors.lastname: Sivridis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D015153:Blotting, Western; D015687:Cell Hypoxia; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D000080864:Lactate Dehydrogenase 5; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D008875:Middle Aged; D011379:Prognosis; D014604:Uveal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D000098943:Uveal Melanoma
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5