Significance of hepatocellular proliferation in the development of hepatocellular carcinoma from anti-hepatitis C virus-positive cirrhotic patients

Tarao, Kazuo; Ohkawa, Shinichi; Shimizu, Akio; Harada, Masaoki; Nakamura, Yoshiyasu; Lto, Yoshihiko; Tamai, Setsuo; Hoshino, Hiroshi; Lnoue, Tohru; Kanisawa, Masayoshi

doi:10.1002/1097-0142(19940215)73:4<1149::aid-cncr2820730405>3.0.co;2-9

Cited by 94 publications

(52 citation statements)

References 20 publications

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“…For example, if combinations of specific amino acids maximize cyclin D1 expression and hepatocyte proliferation, these might promote adaptive liver regeneration in patients with rapidly progressing liver disease. On the other hand, enhanced cyclin D1 expression (through several mechanisms) and increased hepatocyte proliferation in the cirrhotic liver are associated with hepatocellular carcinoma (38,39). The current studies suggest that selective amino acid deficiency may override mitogenic signaling in hepatocytes.…”

Section: Discussionmentioning

confidence: 70%

Amino Acids Regulate Hepatocyte Proliferation through Modulation of Cyclin D1 Expression

Nelsen

Rickheim

Tucker

et al. 2003

Journal of Biological Chemistry

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The mechanisms by which amino acids regulate the cell cycle are not well characterized. In this study, we examined the control of hepatocyte proliferation by amino acids and protein intake. In short-term culture, hepatocytes demonstrated normal entry into S phase and cell cycle protein expression in the absence of essential amino acids. However, deprivation of a set of nonessential amino acids (NEAA) potently inhibited cell cycle progression and selectively down-regulated the expression of proliferation-control proteins. Notably, NEAA withdrawal after the mitogen restriction point still inhibited entry into S phase, suggesting that these amino acids regulate a distinct checkpoint. Cyclin D1, an important mediator of hepatocyte proliferation, was markedly inhibited at the transcriptional level by NEAA deprivation, and transfection with cyclin D1 (but not cyclin E) overcame the cell cycle arrest. As previously shown, protein-deprived mice demonstrated impaired hepatocyte proliferation in vivo after 70% partial hepatectomy. The expression of cyclin D1 and downstream cell cycle proteins after partial hepatectomy was inhibited in these mice. Transfection with cyclin D1 in vivo triggered hepatocyte DNA synthesis and the expression of S phase proteins in the absence of dietary protein. Cyclin D1 also induced global protein synthesis in NEAA-deprived hepatocytes and promoted liver growth in vivo in the setting of protein deprivation. These results indicate that cyclin D1 is a key target of amino acid signaling in hepatocytes.In addition to providing the substrates for protein synthesis, amino acids serve as regulatory molecules that modulate numerous cellular functions (1). It has long been recognized that the availability of amino acids controls growth and proliferation in cell culture systems, but the mechanisms have not been well defined (2, 3). A substantial body of literature indicates that amino acids regulate overall protein synthesis, an essential component of growth and proliferation, through several pathways that control the translational apparatus (4, 5). However, the downstream elements that link amino acids to the cell cycle remain to be determined. In yeast systems, nutrient insufficiency inhibits the expression of G 1 cyclins, which are required for normal entry into S phase (6 -9). However, a similar mechanism has not been clearly established in mammalian cells.In the normal adult liver, hepatocytes rarely replicate, but these cells rapidly enter the cell cycle following injuries that reduce functional liver mass (10). Hepatocyte proliferation is an important component of the adaptive response to liver diseases. In the best-studied model of hepatocyte proliferation in vivo, that of 70% partial hepatectomy (PH) 1 in rodents, most of the remaining hepatocytes enter the cell cycle in a relatively synchronous manner, and liver mass is restored within 1-2 weeks. In addition, primary hepatocytes in short-term culture proliferate readily in response to appropriate mitogens. Thus the hepatocyte culture and PH mo...

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Section: Discussionmentioning

confidence: 70%

Amino Acids Regulate Hepatocyte Proliferation through Modulation of Cyclin D1 Expression

Nelsen

Rickheim

Tucker

et al. 2003

Journal of Biological Chemistry

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“…Hepatocyte proliferation is also an important adaptive response in chronic liver diseases as hepatocytes destroyed by in¯ammation and other injuries are replaced to maintain adequate liver function. Enhanced hepatocyte proliferation in acute and chronic liver diseases is associated with an improved prognosis (Delhaye et al, 1996;Fang et al, 1994), but also may contribute to the development of hepatocellular carcinoma in the setting of cirrhosis (Tarao et al, 1994). The factors that regulate hepatocyte proliferation have not been completely identi®ed, but are thought to include growth factors and cytokines arising from both extrahepatic sites and the liver (Fausto, 2000;Michalopoulos and DeFrances, 1997).…”

Section: Introductionmentioning

confidence: 99%

Induction of hepatocyte proliferation and liver hyperplasia by the targeted expression of cyclin E and skp2

et al. 2001

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Cells in culture become competent to replicate in the absence of growth factor after progressing beyond the late G1 restriction point, suggesting that a set of genes expressed during G1 phase is su cient to trigger completion of the cell cycle. However, this has not been demonstrated in an in vivo system. In this study, we examined whether transfection of genes associated with the G1/S transition could trigger hepatocyte replication. Co-transfection of cyclin E and skp2 synergistically promoted cell cycle progression in cultured primary hepatocytes in the absence of mitogen or in the presence of growth inhibitors. Furthermore, transfection of hepatocytes in vivo with cyclin E and skp2 promoted abundant hepatocyte replication and hyperplasia of the liver. These studies con®rm that transfection with a small number of genes can trigger proliferation of quiescent hepatocytes in vivo, and suggest that therapies to enhance liver regeneration by targeting cell cycle control genes may be feasible. Oncogene (2001) 20, 1825 ± 1831.

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“…However, the predictive value of these assays was not fully appreciated because of insufficient study population, inadequate follow-up times, or failure to investigate all etiologic subsets of patients. [13][14][15][16][17] We therefore decided to assess the predictive power of the PCNA assay, which is based on detection of a highly conserved 36-kd acidic nuclear protein, in cirrhotic patients at risk for developing HCC. PCNA accumulates in the nuclei during the S-phase of the cell-cycle, i.e., proliferating cells, 18,19 and can semiquantitatively be measured by immunostaining in formalin-fixed, paraffin-embedded specimens.…”

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confidence: 99%

“…Conversely, assessment of liver cell proliferation, which is a critical step in cancer development, 11,12 might help to better estimate HCC risk at the individual level. Bromodeoxyuridine uptake assay, 13 silver staining of nucleolar organizer region proteins (AgNOR), 14,15 immunostaining of Ki67, 16 and proliferating cell nuclear antigen (PCNA) 17 have been employed for assessing liver cell proliferation in patients with chronic liver diseases, because these assays are applicable to archival specimens. However, the predictive value of these assays was not fully appreciated because of insufficient study population, inadequate follow-up times, or failure to investigate all etiologic subsets of patients.…”

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confidence: 99%

High rates of hepatocellular carcinoma in cirrhotic patients with high liver cell proliferative activity

et al. 2001

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The prevalence, risk factors, and clinical significance of high liver cell proliferative activity were investigated in 208 well-compensated cirrhotic patients (150 men; 50 years; 135 with chronic hepatitis C) who had been under prospective surveillance for hepatocellular carcinoma (HCC) with annual abdominal ultrasound (US) and serum ␣-fetoprotein (AFP) determination. Immunostaining for proliferating cell nuclear antigen (PCNA) was employed to assess liver cell proliferative activity in formalin-fixed, paraffin-embedded liver specimens. The percentage of reactive nuclei was calculated by a computer-assisted image analysis system. The overall PCNA labeling index (LI) ranged from 0.1% to 12.5% (mean, 2.1%), being significantly higher in the 50 patients who developed HCC during 88 ؎ 42 months of follow-up than in the 158 patients who remained cancer-free (3.6% ؎ 2.4% vs. 1.6% ؎ 1.5%; P < .0001). By receiver operating curve (ROC), a 2.0% cut-off value of PCNA-LI discriminated between patients at high and low risk for developing cancer. By multivariate analysis, high histologic grading scores and gender were associated to PCNA LI >2.0%. The yearly incidence of HCC was 5.2% for the 80 patients with PCNA-LI >2.0% compared with 1.1% for the 128 with low PCNA-LI (relative risk, 4.90; 95% CI, 2.63-9.55). By multivariate analysis, PCNA-LI >2.0% was the strongest independent predictor of cancer (hazard ratio, 5.49; 95% CI, 2.90-10.37). Overall, survival was significantly lower in patients with high liver cell proliferative activity rates than in those with low proliferative rates (10% vs. 75%; P < .0001). In conclusion, development of HCC in patients with compensated cirrhosis seems to be reliably predicted by liver cell proliferation status. (HEPATOLOGY 2001;34:523-528.)Cirrhosis is the dominant risk factor for hepatocellular carcinoma (HCC), worldwide. 1 Prospective surveillance programs based on repeat ultrasound (US) examinations of the liver have shown that HCC risk is particularly high in cirrhotic men older than age 50 who have either advanced liver disease or increased serum ␣-fetoprotein (AFP) levels. [2][3][4][5][6][7][8] To improve the effectiveness and cost-benefit ratio of HCC surveillance programs, close monitoring focused on patients with cirrhosis who have this particularly high risk for developing HCC has been considered. 9,10 However, the use of epidemiologic and clinical predictors for the selection of patients to be surveyed would result in an inappropriate loss of target population, because each of these predictors identifies nonoverlapping HCC risk groups. Conversely, assessment of liver cell proliferation, which is a critical step in cancer development, 11,12 might help to better estimate HCC risk at the individual level. Bromodeoxyuridine uptake assay, 13 silver staining of nucleolar organizer region proteins (AgNOR), 14,15 immunostaining of Ki67, 16 and proliferating cell nuclear antigen (PCNA) 17 have been employed for assessing liver cell proliferation in patients with chronic liver diseases, beca...

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Significance of hepatocellular proliferation in the development of hepatocellular carcinoma from anti-hepatitis C virus-positive cirrhotic patients

Cited by 94 publications

References 20 publications

Amino Acids Regulate Hepatocyte Proliferation through Modulation of Cyclin D1 Expression

Amino Acids Regulate Hepatocyte Proliferation through Modulation of Cyclin D1 Expression

Induction of hepatocyte proliferation and liver hyperplasia by the targeted expression of cyclin E and skp2

High rates of hepatocellular carcinoma in cirrhotic patients with high liver cell proliferative activity

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