Project description:Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and it is necessary to elucidate the mechanism of hepatocarcinogenesis. Hepatocellular carcinoma (HCC) has a high mortality rate and develops based on the chronic inflammatory hepatic disease. Therefore, novel prophylactic or therapeutic strategies are required to improve outcome. In this study, influence of diethylnitrosamine (DEN) and retinoic acid (ATRA) on hepatocarcinogenesis was investigated in mouse. These results suggest that the control of NF-M-NM-:B signaling during the early stage of HCC development is important for the prevention of malignant transformation in hepatocytes. Genes induced by the following treatments in mice liver were investigated at 2 days or 7 days after treatment; DEN: diethylnitrosamine (treatment of DEN (drinking water 80 mg/L)) ATRA: retinoic acid (treatment of ATRA (drinking water 30 mg/L)) G0s2 siRNA : G0s2 knockdown mouse liver (treatment of G0s2 siRNA) Control siRNA: treatment of scramble siRNA (negative control)
Project description:Hepatocellular carcinoma (HCC) initiation is characterized by the sequential stepwise accumulation of molecular alterations. However, the earliest events during the dynamic temporal trend of hepatocarcinogenesis are still unknown. Using a diethylnitrosamine (DEN)-induced rat HCC model, we report a comprehensive transcriptomic landscape of liver tissues at the stages of hepatitis, cirrhosis, and HCC.
Project description:Gene-expression profiles of rat hepatocellular carcinoma induced by diethylnitrosamine (DEN) and the effect of erlotinib Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level.
Project description:We used microarrays to detail the molecular mechanism underlying the HLF (hepatic leukemia factor)-triggered HCC (hepatocellular carcinoma) initiation We conducted transcriptome microarray analysis of DEN (diethylnitrosamine)-induced HCCs from HLF-deficient mice or WT (wild type) mice.
Project description:Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and it is necessary to elucidate the mechanism of hepatocarcinogenesis. Hepatocellular carcinoma (HCC) has a high mortality rate and develops based on the chronic inflammatory hepatic disease. Therefore, novel prophylactic or therapeutic strategies are required to improve outcome. In this study, influence of diethylnitrosamine (DEN) and retinoic acid (ATRA) on hepatocarcinogenesis was investigated in mouse. These results suggest that the control of NF-κB signaling during the early stage of HCC development is important for the prevention of malignant transformation in hepatocytes.
Project description:Gene-expression profiles of rat hepatocellular carcinoma induced by diethylnitrosamine (DEN) and the effect of erlotinib Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level. Animals received humane care according to the criteria outlined in the M-bM-^@M-^\Guide for the Care and Use of Laboratory AnimalsM-bM-^@M-^] of the National Academy of Sciences. All animals were maintained in accordance with the institutional guidelines of the Massachusetts General Hospital Subcommittee on Research Animal Care. Male Wistar rats received weekly IP injections of diethylnitrosamine (DEN) at 50 mg/kg, 100mg/kg, or vehicle control (PBS) for 18 weeks. A subset of rats received either daily (5X a week) IP injections of 2 mg/kg erlotinib or vehicle control during weeks 13 - 18. In a separate study, the erlotinib dose was lowered to 0.5 mg/kg. The vehicle groups from the two studies were not significantly different so they were combined together for analysis. Rats were weighed at the end of each week. Animals were sacrificed at 9, 13 and 19 weeks after a one-week washout period to eliminate acute effects of DEN. At the time of sacrifice, the non-tumor liver tissues were collected in RNase-free tubes and snap-frozen in liquid nitrogen. Frozen tissues were stored at -80M-BM-0C until RNA extraction.
Project description:The expression of NRF2 was activated in human hepatocellular carcinoma. In current study, we observed that in hepatic carcinogen diethylnitrosamine induced liver tumor mouse model, NRF2 knockout mouse developed less liver tumor incidence than wild type mouse. To reveal the detailed mechanism, RNA-seq experiment was conducted to compare gene transcriptome profiles of NRF2 WT and KO mice during HCC progression.
Project description:In our current study, we observed that in hepatic carcinogen diethylnitrosamine (DEN)-induced liver tumor mouse model, diphthamide-deficient mouse developed less liver tumor incidence than control mouse. To explore the detailed mechanism, RNA-seq experiment was conducted to compare gene transcriptome profiles of control and diphthamide-deficient livers during HCC progression.
Project description:Mice developing diethylnitrosamine (DEN)-induced hepatocellular carcinoma were transfected in vivo with Gas1 by hydrodynamic gene delivery. The treatment significantly (p < 0.05) reduced the number of large tumors (more than 2 mm diameter) and histological analyses revealed that the number of carcinoma foci in liver was reduced in favor of less malignant lesions, such as hyperplastic areas, and that the number of lung metastases was also diminished. To study the effects of DEN and the subsequent transfection with Gas1, an expression microarray experiment was designed in which the transcription of 20758 genes in liver was determined. A triangular analysis of microarray data shows that transfection with Gas1 restores the level of transcription level of 182 out of the 698 genes, whose expression was affected by DEN. Therefore, transfection of liver tumor-bearing animals with Gas1 significantly reduces the size and proliferative activity of tumors and restores the transcriptional profile of the liver. Here we studied effects of diethylnitrosamine treatment of mice on the transcription of 20758 liver genes and the consequences of transfecting the livers with Gas1.