Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression data from the LEC rat model with naturally occuring and oxidative stress induced liver tumorigenesis

ABSTRACT: To elucidate the fundamental molecular mechanisms responsible for multistep hepatotumorigenesis, this study investigated genes that were upregulated in a stepwise manner from the naïve liver condition through to chronic oxidative stress-induced hepatitis and liver tumor by time-series microarray analysis. The time-dependent gene expression profile should reflect the multistep process of hepatotumorigenesis, and might identify genes that function specifically in hepatotumorigenesis. We reduced several clinicopathological variables by using the Long-Evans Cinnamon rat, a model with naturally occurring and oxidative stress-induced hepatotumorigenesis. Gene expression patterns were analyzed serially by profiling liver tissue from naïve status (4 weeks old) rats through to those with chronic hepatitis (26 and 39 weeks old) to tumor development (67 weeks old). This study represents a normal versus diseased comparison with different time points of spontaneously developed liver tumor and normal liver tissue. In the first series of experiments, equivalent amounts of RNA from 2 pairs randomly selected from 8 paired liver tumor and adjacent nontumor tissue specimens were mixed and analyzed in order to normalize variations among mice. Average gene expression levels for tumor and non-tumor tissue samples were calculated using the 4 Affymetrix microarray datasets, respectively. In the following experiments, a mixture of equivalent amounts of RNA isolated from LEC rats at 4, 26, and 39 weeks of age and controls, respectively, was exploited as an RNA pool for Affymetrix microarray analyses. A total of 12 samples (4 sets of tumor-non-tumor pairs and a normal control, and 3 serial samples) were hybridized to Affymetrix Rat Expression 230 2.0 Arrays.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Akihito Tsubota

PROVIDER: E-GEOD-17384 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

IQGAP1 and vimentin are key regulator genes in naturally occurring hepatotumorigenesis induced by oxidative stress.

Tsubota Akihito A Matsumoto Kenji K Mogushi Kaoru K Nariai Koichi K Namiki Yoshihisa Y Hoshina Sadayori S Hano Hiroshi H Tanaka Hiroshi H Saito Hirohisa H Tada Norio N

Carcinogenesis 20091216 3

To identify key genes involved in the complex multistep process of hepatotumorigenesis, we reduced multivariate clinicopathological variables by using the Long-Evans Cinnamon rat, a model with naturally occurring and oxidative stress-induced hepatotumorigenesis. Gene expression patterns were analyzed serially by profiling liver tissues from rats of a naive status (4 weeks old), through to those with chronic hepatitis (26 and 39 weeks old) to tumor development (67 weeks old). Of 31 099 probe sets ...[more]

PMID: 20015863

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Project description:Reprinted from http://www.haltctrial.org/ Purpose The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C virus with previous interferon treatment. Study Hypotheses <ol> <li>In patients with chronic hepatitis C and bridging fibrosis who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can prevent progression to cirrhosis.</li> <li>In patients with cirrhosis secondary to chronic hepatitis C who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can reduce the risks of hepatic decompensation or of hepatocellular carcinoma.</li> </ol> Study Design 1145 patients with chronic HCV and advanced hepatic fibrosis (Ishak stage 3-6) who failed to respond to previous treatment with interferon were enrolled at 10 clinical centers and entered into a Lead-in phase. They were treated with a combination of pegylated interferon (Pegasys®, Hoffmann-La Roche) 180 µg/week and ribavirin (1000-1200 mg/day) for 24 weeks. Patients who had no detectable HCV-RNA at week 20 continued on combination therapy until week 48. 662 patients who did not clear virus were randomly assigned at week 24 to either continue treatment with pegylated interferon alone (90 µg/week) for an additional 42 months, or to have treatment discontinued. All patients were followed at 3-month intervals following randomization. Liver biopsy was performed at baseline and after 1.5 and 3.5 years of treatment. Because of slower than expected enrollment and the approval by the FDA of peginterferon alfa-2b after the start of the trial, we modified the study protocol in three ways. First, criteria for admission to the trial were liberalized to allow patients to enter the trial with lower platelet and white blood cell counts than had been initially considered safe or tolerable. Second, 151 Lead-in patients and those continuing on therapy after 24 weeks who demonstrated return of viremia during or after their 48-week treatment period (called "Breakthrough" or "Relapse" patients, respectively) were allowed to return to enter the randomized trial. Third, 237 patients treated with peginterferon alfa-2b (or with peginterferon alfa-2a in licensing trials) outside the HALT-C Trial who in other respects met all study criteria, having received the equivalent of Trial Lead-in period therapy, were allowed to enter the long-term trial as "Express" patients. A total 1050 patients were randomized. Those patients who completed Month 48 were offered an "extended follow-up (observation only)" until October 2009. These visits will primarily be to identify outcome events, and to provide information to patients concerning the current status of the trial. Some questionnaires, blood tests, and an ultrasonogram will be performed. Quarterly (every 3 months) <ul> <li>Interval history of complications, adverse events</li> <li>Current medications</li> <li>Brief physical examination</li> <li>Laboratory tests: liver panel, CBC, INR, AFP</li> <li>Child-Pugh Score</li> <li>Stored serum</li> </ul> Annual <ul> <li>Complete physical examination</li> <li>Ultrasound of liver</li> </ul> 1.5 years (M24 visit, middle of study) <ul> <li>Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients)</li> </ul> 3.5 years (M48, end of study) <ul> <li>Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients)</li> <li>Endoscopy: evaluate esophageal varices and portal hypertension</li> </ul> After Month 48 <ul> <li>Observation only (no treatment) to determine clinical outcomes</li> <li>Clinic visit every 6 months with current medications, brief PE, liver panel, CBC, AFP, stored</li> <li>Serum</li> <li>Ultrasound of liver every 6 months</li> </ul> Outcome Variables Primary outcome variables to be assessed in the two groups of patients include: <ul> <li>Development of cirrhosis on liver biopsy (progression of Ishak fibrosis score by 2 points or more)</li> <li>Development of hepatic decompensation, as shown by:</li> <ul> <li>Sustained increase in the Child-Turcotte-Pugh score to 7 points or higher</li> <li>Variceal hemorrhage</li> <li>Ascites</li> <li>Spontaneous bacterial peritonitis</li> <li>Hepatic encephalopathy</li> <li>Development of hepatocellular carcinoma</li> <li>Death</li> </ul> </ul> Secondary outcomes include quality of life, serious adverse events, events requiring dose reductions, and development of presumed hepatocellular carcinoma.

Dataset Information

Gene expression data from the LEC rat model with naturally occuring and oxidative stress induced liver tumorigenesis

Publications

IQGAP1 and vimentin are key regulator genes in naturally occurring hepatotumorigenesis induced by oxidative stress.

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