Autophagic activity in uveal melanomas

AbstractPurpose Autophagy is a self‐degradation mechanism by which cells recycle their own cytoplasmic constituents and organelles. Experimental data suggest that autophagy is up‐regulated by hypoxia in human neoplasia.Methods The autophagic activity was investigated in a series of 73 uveal melanomas after immunohistochemical staining for the autophagy‐associated proteins LC3A and Beclin1. This was assessed in parallel with the hypoxia inducible factor 1α (HIF1α) and its downstream protein lactate degydrogenase 5 (LDH5).Results Two patterns of LC3A expression were readily made out – diffuse cytoplasmic and cytoplasmic/juxta‐nuclear. The former was detected in 37/73 (50.7%) melanomas; the latter in 22/73 (30.1%) tumors. Beclin1 expression was invariably diffuse cytoplasmic and occurred in 37/73 (50.7%) uveal melanomas. LC3A and Beclin1, when highly expressed, were associated with intense pigmentation of the lesion, but only Beclin1 was associated with tumor necrosis (p<0.05) and a larger tumor size (p<0.05). It is of interest that Beclin1 and perinuclear LC3A expression were significantly related (p<0.02). In linear regression analysis, the LC3A juxta‐nuclear/perinuclear pattern and the Beclin1 expression were connected with the hypoxia‐related proteins HIF1α (p<0.02) and LDH5 (p<0.0001).Conclusion Autophagy is commonly up‐regulated in uveal melanomas, and may be associated with necrosis and large tumor size. There is a connection between Beclin1 and LC3A juxta‐nuclear/perinuclear pattern, and a strong link between autophagy and hypoxia as this is inferred by the intimate relationship of LC3A and Beclin1 with HIF1α and LDH5, the major LDH isoenzyme involved in anaerobic metabolism.