Cell cycle regulation and hepatocarcinogenesis

Greenbaum, Linda E.

doi:10.4161/cbt.3.12.1392

Cited by 56 publications

(42 citation statements)

References 84 publications

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“…Ectopic expression of Bax induces apoptosis with apoptosis-associated morphologic alterations, caspase activation, and subsequent substrate proteolysis (33,34). Increased cell turnover results in the selection of monoclonal hepatocyte populations that subsequently undergo genomic alterations that lead to the development of HCC (35). However, p53 showed no difference between the liver of wild-type and Cyp2e1-null mice treated with diethylnitrosamine (data not shown).…”

Section: Discussionmentioning

confidence: 75%

Role of CYP2E1 in Diethylnitrosamine-Induced Hepatocarcinogenesis In vivo

et al. 2007

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CYP2E1 metabolizes many low-molecular weight toxins and carcinogens. Some in vitro experiments suggest that CYP2E1 may be involved in the metabolic activation of diethylnitrosamine. However, there has been no direct evidence demonstrating a role for CYP2E1 in diethylnitrosamine-mediated carcinogenesis in vivo. To clarify this, we carried out a diethylnitrosamine-induced hepatocarcinogenesis experiment using Cyp2e1-null mice. Male 14-day-old wild-type and Cyp2e1-null mice were treated with diethylnitrosamine (10 mg/kg of body weight) and killed at weeks 24 and 36 after diethylnitrosamine treatment for investigation of tumors and at 6, 24, and 48 h for examination of apoptosis and gene expression. Liver weights of Cyp2e1-null mice were significantly different at weeks 24 and 36 compared with wild-type mice (P < 0.01). Liver tumor incidences of Cyp2e1-null mice were significantly decreased at weeks 24 and 36 compared with wild-type mice (P < 0.01). Cyp2e1-null mice showed significant decrease in the multiplicities of hepatocellular adenoma at weeks 24 and 36 (P < 0.05 and P < 0.01, respectively), and of hepatocellular carcinoma at week 36 (P < 0.01) compared with wild-type mice. Apoptotic index and caspase-3 and/or Bax mRNA expression of Cyp2e1-null mice were significantly different at 6, 24, and 48 h after diethylnitrosamine treatment compared with wild-type mice (P < 0.05). We conclude that Cyp2e1-null mice show lower tumor incidence and multiplicity compared with wild-type mice in diethylnitrosamine-induced hepatocarcinogenesis. It is suggested that CYP2E1 completely participates in diethylnitrosamine-induced hepatocarcinogenesis, and high frequency of tumors in wild-type mice could be associated with the increased apoptosis. [Cancer Res 2007;67(23):11141-6]

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Section: Discussionmentioning

confidence: 75%

Role of CYP2E1 in Diethylnitrosamine-Induced Hepatocarcinogenesis In vivo

et al. 2007

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“…One of the key factors contributing to hepatocellular carcinogenesis is the deregulation of cell cycle progression (Feng et al, 2011;Greenbaum, 2004). Cyclin-dependent kinase (Cdk) 10 is a Cdc2-related kinase, which was originally identified based on its homology to the Cdc2 PSTA1RE amino acid domain (Graña et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Clinical and biological significance of Cdk10 in hepatocellular carcinoma

Zhong

et al. 2012

Gene

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“…The overexpression of cyclins is generally associated with advanced-stage disease and poor prognosis in many types of cancers, including hepatocellular carcinoma (9)(10)(11)(12)(13). Although molecular agents targeting cyclin-dependent kinases (CDK) and other cell-cycle regulators have been extensively studied, their roles in cancer therapy were not established until recently, when the CDK inhibitor palbociclib was demonstrated to prolong the progression-free survival of breast cancer patients who received hormonal therapy (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Hsu

Lin

Cheng

et al. 2016

Clinical Cancer Research

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Purpose: To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclindependent kinase (CDK) inhibition in therapy.Experimental Design: The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenibsensitive (Huh-7 and HepG2, IC 50 5-6 mmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC 50 14-15 mmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosisrelated proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments. The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments.Results: Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect.Conclusions: The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma.

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Cell cycle regulation and hepatocarcinogenesis

Cited by 56 publications

References 84 publications

Role of CYP2E1 in Diethylnitrosamine-Induced Hepatocarcinogenesis In vivo

Role of CYP2E1 in Diethylnitrosamine-Induced Hepatocarcinogenesis In vivo

Clinical and biological significance of Cdk10 in hepatocellular carcinoma

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

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