Expression of cyclin-dependent kinase inhibitor p21 in human liver

Abstract

The p21 protein is a universal inhibitor of cyclindependent kinases and of cell-cycle progression and is involved in numerous growth-inhibitory pathways in cell culture systems. Recent studies suggest that p21 regulates hepatocyte cell cycle progression in models of liver regeneration. The present study was designed to investigate the possible involvement of p21 in the control of hepatocyte proliferation in human liver diseases. To examine that, the expression of p21 in clinical liver biopsy specimens was determined by immunohistochemistry. This was correlated with hepatocyte Ki-67 immunostaining (a marker of hepatocyte proliferation in vivo) as well as histologic features. Little p21 or Ki-67 expression was detected in normal human liver or in specimens of nonalcoholic steatohepatitis. In patients with alcoholic hepatitis, increased expression of p21, but not of Ki-67, was observed. In specimens with chronic hepatitis C, hepatocyte p21 expression was significantly correlated with Ki-67 immunostaining, as well as with the degree of inflammation and fibrosis. These results indicate that hepatocyte p21 expression is upregulated in response to hepatic injury and correlates with histologic markers of proliferation and disease activity. This study provides evidence that p21 plays a role in the regulation of hepatocyte proliferation in human liver diseases. (HEPATOLOGY 1998;28:738-743.) Cell proliferation is controlled by protein kinase complexes consisting of cyclins and cyclin-dependent kinases (CDKs) which regulate distinct phases of the cell cycle. Extracellular signals control cell-cycle progression by influencing the activity of cyclin/CDK kinase complexes; the dysregulation of these complexes contributes to the development of neoplasia.

Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice

“…3,45,46 The factors mediating the fate of progenitors after oxidative damage to mature hepatocytes remain poorly understood. To investigate this, we employed two well-accepted mouse models of oxidative liver injury, chronic NASH and acute ethionine-induced hepatotoxicity.…”

Pluripotent plasticity of stem cells and liver repopulation

“…[35][36][37][38]42,60 In rodent models for hepatocarcinogenesis, small oval cells that express both hepatocyte and cholangiocyte markers accumulate in the liver before cancerous nodules develop. 70,72,73,75 Similar oval cell(s) accumulation has also been described in human liver, close to hepatitis Bassociated hepatocellular carcinoma, 74 in hepatoblastoma, 76 in regenerating liver, 77 and in cholestatic liver diseases. 78 The putative progenitor cells accumulation in the livers of patients with chronic hepatitis C appears to be an acknowledged risk factor for hepatocellular carcinoma.…”

“…69,70 The replicative activity of mature hepatocytes is also known to be inhibited in patients with alcoholic hepatitis, 71 rodents with alcohol-induced fatty livers 72 and in some animal models of NAFLD. 73,74 Although the combination of oxidative liver damage and inhibited hepatocyte proliferation provides a strong stimulus for oval cell accumulation in the liver, whether or not this cell population is expanded in FLD has never been studied. 28 During viral-and steatosis-induced liver disease the contribution of BM cells to hepatocytes, either via oval cells or by independent mechanisms, is minimal and the majority of oval cells responding to this injury are sourced from the liver.…”

Hepatotropic growth factors protect hepatocytes during inflammation by upregulation of antioxidative systems

“…Intracellular antioxidative systems, e.g. p38-mitogen activated protein kinase or p21 may protect the cells, but they also decrease the hepatocyte proliferation rate by inhibiting hepatic DNA synthesis during the late G1 phase [39,40] . Other intracellular antioxidative systems include upregulation of enzymes e.g.…”