BackgroundCaveolin-1 is the main component of caveolae membrane structures and has different roles during tumorigenesis in different cancer types with varying expression profiles, indicating that the role of caveolin-1 varies according to tumor type. In this study, we investigated the role and expression of caveolin-1 in hepatocellular carcinogenesis.MethodsWe analyzed the expression of Caveolin-1 in 96 hepatocellular carcinoma (HCC), 29 cirrhosis, 20 normal liver tissues and 9 HCC cell lines by immunostaining and western blotting, respectively. After caveolin-1 was stably transfected to HepG2 and Huh7 cells, the effects of Caveolin-1 on the cellular motility, matrix invasion and anchorage-independent growth were studied. Also, caveolae structure was disrupted in endogenously caveolin expressing cells, SNU 449 and SNU 475 by addition of methyl-β-cyclodextrin and analyzed cellular motility and invasion.ResultsIn HCC cell lines, Caveolin-1 expression is correlated to differentiation and basal motility status of these cells. The percentage of Caveolin-1 positivity was found extremely low in normal liver tissue (5%) while it was increased in cirrhosis (45%) and in HCC (66%) (p = 0.002 and p = 0.001 respectively). Cav-1 expression in poorly differentiated HCC samples has been found significantly higher than well differentiated ones (p = 0.001). The caveolin-1 expression was found significantly higher in tumor cells than its peritumoral cirrhotic tissues in HCC samples (p < 0.001). Additionally, the patients with positive staining for Caveolin-1 had significantly higher portal vein invasion than those with negative staining (p = 0.02). Caveolin-1 overexpression increased motility and invasion of HepG2 and Huh7 cells. And disruption of caveolae results in a dramatic decline in both motility and invasion abilities in SNU-449 and SNU-475 cells. Furthermore, caveolin-1 overexpression resulted in down-regulation of E-cadherin while up-regulation of Vimentin. Also, it increased secreted MMP-2 and expression levels of MMP-9 and MT1-MMP. There was no significant difference in colony formation in soft agar between stable clones and parental ones.ConclusionIn conclusion, stepwise increase in Cav-1 expression in neoplastic stage with respect to pre-neoplastic stage during hepatocellular carcinogenesis and its ability to stimulate HCC cell motility and invasiveness indicate that this protein plays a crucial role in tumor progression.

End-stage liver disease secondary to alcoholic cirrhosis conThe prediction of abstinence from ethanol may be tinues to be a significant cause of death. 1 Most alcoholics with crucial to the optimal selection of liver transplantation end-stage liver disease do not have significant extrahepatic candidates with alcoholism. Of 84 consecutive end-stage complications of ethanol abuse. 2 Therefore, these patients are alcoholic patients who underwent transplantation not usually excluded because of other terminal medical condi-(1986-1994) at our institution, we analyzed 63 long-surtions, and many times will die shortly without transplantaviving recipients for pretransplantation variables to tion intervention. 2 Furthermore, excellent survival following predict posttransplantation abstinence (follow-up: 49.3 liver transplantation is noted with alcoholic recipients. [3][4][5][6][7][8][9][10][11] Be-{ 21 mo). Thirty-three pretransplantation variables cause these patients usually have liver disease solely because were reviewed from our transplantation data base and of the intake of a toxin (ie, ethanol), abstinence from this supplemented and confirmed with interviews with retoxin usually predicts minimal problems with liver disease cipients. The psycho-social inclusion criteria included following liver transplantation. The appropriate allocation of the following: patient recognition of alcoholism, a domiliver transplantation to specific alcoholic patients is made cile, an occupation, and at least one close personal relamore difficult by the large number of patients with end-stage tionship. The incidence of abstinence from ethanol was alcoholic cirrhosis and the intense demand for donor organs (50/63) 79%. A logistic regression of the 33 variables in for other end-stage liver diseases in which disease recurrence conjunction with our above inclusion criteria accurately may be less likely or more predictable. 12-14 Herein lies the predicted abstinence (90% accuracy, x 2 model, P õ problem that besets transplantation physicians: the appro-.00001) based on the absence of previous history of any priate selection of alcoholics with end-stage liver disease for illicit drug use (Drug Use: yes Å 1/no Å 0), the presence transplantation based on the prediction of long-term abstiof an active, personal life insurance policy (Life Ins: yes nence from alcohol. number of alcoholic sisters (ETOH-SIS), andThe aims of this study are to describe the following: 1) the the length of pretransplantation abstinence (PREresults of liver transplantation for patients with alcoholic TRANS-ABS, mos): Prob. of abstinence Å 1/1 / e 0F , F Å end-stage liver disease (survival, the incidence of abstinence, 00.33 / 0.89 (DRUG USE) 01.02 (LIFE INS) 01.68 (ETOHand pattern of recidivism); and 2) an analysis of pretrans-SIS) /0.24 (PRE-TRANS-ABS). In contrast, receiver-opplantation variables that may predict abstinence from alcohol erating characteristic curve analysis found that 7 and 9 following transplantation. months of pretransplantation abstinence were the be...

BackgroundHepatocyte growth factor (HGF) induced c-Met activation is known as the main stimulus for hepatocyte proliferation and is essential for liver development and regeneration. Activation of HGF/c-Met signaling has been correlated with aggressive phenotype and poor prognosis in hepatocellular carcinoma (HCC). MUC1 is a transmembrane mucin, whose over-expression is reported in most cancers. Many of the oncogenic effects of MUC1 are believed to occur through the interaction of MUC1 with signaling molecules. To clarify the role of MUC1 in HGF/c-Met signaling, we determined whether MUC1 and c-Met interact cooperatively and what their role(s) is in hepatocarcinogenesis.ResultsMUC1 and c-Met over-expression levels were determined in highly motile and invasive, mesenchymal-like HCC cell lines, and in serial sections of cirrhotic and HCC tissues, and these levels were compared to those in normal liver tissues. Co-expression of both c-Met and MUC1 was found to be associated with the differentiation status of HCC. We further demonstrated an interaction between c-Met and MUC1 in HCC cells. HGF-induced c-Met phosphorylation decreased this interaction, and down-regulated MUC1 expression. Inhibition of c-Met activation restored HGF-mediated MUC1 down-regulation, and decreased the migratory and invasive abilities of HCC cells via inhibition of β-catenin activation and c-Myc expression. In contrast, siRNA silencing of MUC1 increased HGF-induced c-Met activation and HGF-induced cell motility and invasion.ConclusionsThese findings indicate that the crosstalk between MUC1 and c-Met in HCC could provide an advantage for invasion to HCC cells through the β-catenin/c-Myc pathway. Thus, MUC1 and c-Met could serve as potential therapeutic targets in HCC.

Our results suggest that duration of symptoms longer than 6 h was an important factor for determining the need for resection. The use of non-absorbable mesh for acutely incarcerated groin hernia repair is effective and may be used with an acceptable incidence of wound infection and recurrence even when intestinal necrosis was present.

Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become “immortal”) by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene hepatocellular immortality signature test that discriminated HCC from cirrhosis with high accuracy. Our findings demonstrate that senescence bypass plays a central role in hepatocellular carcinogenesis engendering systematic changes in the transcription of genes regulating DNA repair, proliferation, differentiation and metabolism.