Background & Aims Ischemia and reperfusion injury are common causes of oxidative tissue damage associated with many liver diseases and hepatic surgery. The Wnt–β-catenin signaling pathway is an important regulator of hepatic development, regeneration, and carcinogenesis. However, the role of Wnt signaling in the hepatocellular response to ischemia–reperfusion (I/R) injury has not been determined. Methods Hepatic injury following ischemia or I/R was investigated in hepatocyte-specific, β-catenin–deficient mice, as well as Wnt1 overexpressing and wild-type (control) mice. Results Wnt–β-catenin signaling was affected by the cellular redox balance in hepatocytes. Following ischemia or I/R, mice with β-catenin–deficient hepatocytes were significantly more susceptible to liver injury. Conversely, mice that overexpressed Wnt1 in hepatocytes were resistant to hepatic I/R injury. Hypoxia inducible factor (HIF)-1α signaling was reduced in β-catenin–deficient liver but increased in hepatocytes that overexpressed Wnt1 under hypoxia and following I/R, indicating an interaction between β-catenin and HIF-1α signaling in the liver. The mechanism by which Wnt signaling protects against liver injury involves β-catenin’s role as a transcriptional co-activator of HIF-1α signaling, which promotes hepatocyte survival under hypoxic conditions. Conclusion Cellular redox balance affects Wnt–β-catenin signaling, which protects against hypoxia and I/R injury. These findings might be used to develop strategies for protection of hepatocytes, regeneration of liver, and inhibition of carcinogenesis.

The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.

Family with sequence similarity 83, member h (FAM83H) was identified, from a genome-wide search, as having the genetic etiology of human autosomal dominant hypocalcified amelogenesis imperfecta 1 . Thereafter, various mutations of FAM83H have been detected in amelogenesis imperfecta 1-5 and FAM83H-associated amelogenesis imperfecta is reported to be the most prevalent form of amelogenesis imperfecta 3,6 . Therefore, studies on FAM83H have typically been focused on tooth development. However, the cytoplasmic localization of FAM83H protein suggests that FAM83H might be involved in other cellular processes, including tumorigenesis 2, 5 . Increased expression of FAM83H in cancer tissue compared with normal tissue has been presented in recent microarray data 7 . In colorectal cancer, FAM83H contributes to the progression of cancer via regulating keratin cytoskeleton organization [8][9][10] . FAM83H overexpression along with aberrant localization of CK-1α could contribute to the progression of colorectal cancer through keratin cytoskeleton organization 8 . Another study showed that FAM83H could be an important molecule that can cause androgen independent prostate cancer progression 11 .

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Background-Keratins 8 and 18 (K8/K18) are important hepatoprotective proteins. Animals expressing K8/K18 mutants exhibit a marked susceptibility to acute/subacute liver injury. K8/K18 variants predispose to human end-stage liver disease and associate with fibrosis progression during chronic hepatitis C infection.

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Ordered cell cycle progression requires the expression and activation of several cyclins and cyclin-dependent kinases (Cdks). Hyperosmotic stress causes growth arrest possibly via proteasome-mediated degradation of cyclin D1. We studied the effect of hyposmotic conditions on three colonic (Caco2, HRT18, HT29) and two pancreatic (AsPC-1 and PaCa-2) cell lines. Hyposmosis caused reversible cell growth arrest of the five cell lines in a cell cycle-independent fashion, although some cell lines accumulated at the G 1 /S interface. Growth arrest was followed by apoptosis or by formation of multinucleated giant cells, which is consistent with cell cycle catastrophe. Hyposmosis dramatically decreased Cdc2, Cdk2, Cdk4, cyclin B1, and cyclin D3 expression in a time-dependent fashion, in association with an overall decrease in cellular protein synthesis. However, some protein levels remained unaltered, including cyclin E and keratin 8. Selective proteasome inhibition prevented Cdk and cyclin degradation and reversed hyposmotic stress-induced growth arrest, whereas calpain and lysosome enzyme inhibitors had no measurable effect on cell cycle protein degradation. Therefore, hyposmotic stress inhibits cell growth and, depending on the cell type, causes cell cycle catastrophe with or without apoptosis. The growth arrest is due to decreased protein synthesis and proteasome activation, with subsequent degradation of several cyclins and Cdks.The cell cycle involves a meticulously ordered series of events that control defined cell cycle stage check points and ultimate cell division. These events are tightly regulated by the expression and degradation, activation and inactivation, and subcellular localization of cyclins and cyclin-dependent kinases (Cdks) 1 (1-3). Cyclins associate with, and activate, Cdks and are periodically synthesized then degraded during cell cycle progression, whereas cellular Cdk levels tend to remain in excess throughout the normal cell cycle (1-5). In mammalian cells, Cdk4 and Cdk6 associate with D-type cyclins and regulate G 1 cell cycle phase progression. Cdk2 associates with the Eand A-type cyclins, and the respective complexes control G 1 /S transition and S phase progression, respectively (1-5). Cdc2 (also termed Cdk1) and the B-type cyclin form a cytoplasmic complex at the G 2 /M phase checkpoint, which translocates to the nucleus just prior to nuclear envelope breakdown during prophase. Abnormal sequestering of cyclin B1/Cdc2 complexes in the cytoplasm leads to perturbation of cell cycle progression (6 -8).Most mammalian cells have developed compensatory mechanisms to respond to changes in the osmolarity of the surrounding medium, which allow them to re-establish homeostasis of osmotically disturbed aspects of cell structure and function (9, 10). These mechanisms are necessary, because osmotic stress may severely compromise eukaryotic cell function due to the importance of maintaining homeostasis of inorganic ions as a prerequisite for normal progression of metabolic processes. Disruption of such me...

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