肝细胞癌
E2F1
癌症研究
细胞周期蛋白
细胞周期蛋白D1
细胞生长
周期素
医学
细胞周期蛋白
细胞周期蛋白E1
细胞周期蛋白A2
细胞周期
肝细胞
细胞周期蛋白D
细胞周期蛋白B1
生物
癌症
内科学
生物化学
细胞周期蛋白依赖激酶1
体外
作者
Rossella Farra,Barbara Dapas,Gabriele Pozzato,Bruna Scaggiante,Francesco Agostini,Cristina Zennaro,Mario Grassi,Natalia Rosso,Carlo Giansante,Nicola Fiotti,Gabriele Grassi
标识
DOI:10.1016/j.dld.2011.07.007
摘要
Background No effective therapy is available for hepatocellular carcinoma. To identify novel therapeutic strategies, we explored the effects of the depletion of E2F1, cyclin E1–E2 whose inter-relationships in hepatocellular carcinoma cell proliferation have never been defined. Methods siRNA-mediated depletion of the targets was studied in the hepatocellular carcinoma cells HepG2, HuH7 and JHH6 characterized by high, medium and low hepatocyte differentiation grade, respectively; a model of normal human hepatocytes was also considered. Results The depletion of each target mRNA reduced the levels of the other two mRNAs, thus demonstrating a close regulatory control, also confirmed by over-expression experiments. At the protein level, an exception to this trend was observed for cyclinE1 whose amount increased upon cyclin E2 (HepG2, HuH7, JHH6) and E2F1 (HepG2) depletion. In HepG2, reduced cyclinE1 proteolysis accounted for this observation. Additionally, cyclin E1–E2–E2F1 targeting decreased the levels of cyclin A2 mRNA and of the hyper-phosphorylated form of pRb thus leading to an S-phase cell decrease; migration was impaired as well. Finally, the model of human hepatocytes used was clearly less affected by target mRNAs depletion than hepatocellular carcinoma cells. Conclusion Our data provide novel mutual relationships amongst cyclin E1–E2–E2F1 and indicate their role in sustaining hepatocellular carcinoma cell proliferation/migration, validating the concept of an anti-cyclin E1–E2–E2F1 therapeutic approach for hepatocellular carcinoma.
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