Expression and effect of inhibition of the ubiquitin-conjugating enzyme E2C on esophageal adenocarcinoma

Ubiquitin-dependent proteolysis of cyclins plays a criti-cal role in cell cycle progression and tumorigenesis. We examined the expression of ubiquitin-conjugating enzymeE2C (UBE2C) during progression fromBarrett’s metaplasia to esophageal adenocarcinoma (EA) and the effects of targeting this enzyme on EA-derived cell lines. Using oligonucleotide microarrays UBE2C ex-pression was elevated in 73 % (11 of 15) of EAs relative to Barrett’s metaplasia. Tissue microarray showed elevated UBE2C in 70 % (7 of 10) of dysplastic samples and in 87 % (58 of 67) of tumors relative to metaplastic samples. Transfection of dominant-negative UBE2C into Seg-1 cells decreased proliferation (P =.04) and increased mitotic arrest compared to vector controls (63.5 % vs 6.8%; P <.001). Transfection of UBE2C small interfering RNA also caused inhibiton of cell prolifer-ation and distortion of the cell cycle, with maximal in-crease of G2 cells (155 % of mock cells) at 72 hours and of S-phase cells (308 % of mock cells) at 24 hours. Treatment of Seg-1 cells with the proteasome inhibitor MG-262 (1 nM–1 MM) showed decreased proliferation (P =.02). EA-derived cells expressing UBE2C are sensitive to treatment with MG-262 and to silencing of UBE2C, suggesting that patients with EAs over-expressing UBE2C may benefit from agents targeting this ubiquitin-conjugating enzyme