Expression and effect of inhibition of the ubiquitin-conjugating enzyme E2C on esophageal adenocarcinoma.
Ubiquitin-dependent proteolysis of cyclins plays a critical role in cell cycle progression and tumorigenesis. We examined the expression of ubiquitin-conjugating enzyme E2C (UBE2C) during progression from Barrett's metaplasia to esophageal adenocarcinoma (EA) and the effects of targeting this enzyme on EA-derived cell lines. Using oligonucleotide microarrays UBE2C expression 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 proliferation and distortion of the cell cycle, with maximal increase of G(2) 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 microM) 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 overexpressing UBE2C may benefit from agents targeting this ubiquitin-conjugating enzyme.
Lin
Jules
J
Section of General Thoracic Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Raoof
Duna A
DA
Wang
Zhuwen
Z
Lin
Mu-Yen
MY
Thomas
Dafydd G
DG
Greenson
Joel K
JK
Giordano
Thomas J
TJ
Orringer
Mark B
MB
Chang
Andrew C
AC
Beer
David G
DG
Lin
Lin
L
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D008938:Mitosis / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D001897:Boronic Acids; D006131:Growth Inhibitors; C423917:MG 262; D011480:Protease Inhibitors; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes