Hepatocellular carcinoma (HCC) is a high incidence cancer and a major health concern worldwide. Among the many molecular signaling pathways that are dysregulated in HCC, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK) signaling pathway has gained renewed attention from basic and clinical researchers. Mutations in Ras and Raf genes which are known to activate the Ras/Raf/MAPK signaling pathway have been infrequently detected in human HCC; however, the Ras/Raf/MAPK signaling pathway is activated in more than 50% of HCC cases, suggesting an alternative mechanism for the activation of the signaling pathway. Kinase suppressor of Ras acts as a molecular scaffold for facilitating the assembly of Ras/Raf/MAPK signaling pathway components and has been implicated in the regulation of this signaling pathway. In this review, we provide important insights into the cellular and molecular mechanisms involved in the activation of the Ras/Raf/MAPK signaling pathway and discuss potential therapeutic strategies for HCC.

Hepatocellular carcinoma (HCC) is a high incidence cancer and a major health concern worldwide. Among the many molecular signaling pathways that are dysregulated in HCC, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK) signaling pathway has gained renewed attention from basic and clinical researchers. Mutations in Ras and Raf genes which are known to activate the Ras/Raf/MAPK signaling pathway have been infrequently detected in human HCC; however, the Ras/Raf/MAPK signaling pathway is activated in more than 50% of HCC cases, suggesting an alternative mechanism for the activation of the signaling pathway. Kinase suppressor of Ras acts as a molecular scaffold for facilitating the assembly of Ras/Raf/MAPK signaling pathway components and has been implicated in the regulation of this signaling pathway. In this review, we provide important insights into the cellular and molecular mechanisms involved in the activation of the Ras/Raf/MAPK signaling pathway and discuss potential therapeutic strategies for HCC.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCC develops in various causes – Viral hepatitis infection, toxins, or other liver conditions - by activation of oncogenes and/or inactivation of tumor suppressors. Understanding of signal pathways and protein-protein interactions critical in tumor development may lead to novel treatment strategy. To evaluate the progression of HCC and effects of potential therapies, various animal models have been established. Experimental models of HCC provide valuable tools to investigate the risk factors, new treatment modalities and biologic characteristics. Subcutaneous xenograft models have been widely used in the past. However, with the advancement of in vivo imaging technology, investigators are more concerned with the orthotopic models nowadays. Genetically engineered mouse models have greatly facilitated studies of gene function in HCC development. Lately, a novel approach for stable gene expression in mouse hepatocytes by hydrodynamic injection has been developed. Each model has its own advantages and disadvantages. Therefore, selecting the optimal models based on study objectives is necessary. In this review, we highlight both the frequently used mouse models and some emerging ones with emphasis on their merits or defects, and give advices for investigators to choose a “best-fit” animal model in HCC research.
Animals* ; Carcinoma, Hepatocellular ; Gene Expression ; Hepatitis ; Hepatocytes ; Heterografts ; Humans ; Hydrodynamics ; Liver Neoplasms* ; Liver* ; Mice ; Models, Animal* ; Models, Theoretical ; Oncogenes ; Population Characteristics ; Research Personnel ; Risk Factors ; Signal Transduction

Purpose: We investigate whether low-dose rapamycin is effective in preventing hepatocellular carcinoma (HCC) growth and treating HCC after tumor development in transgenic mice. Materials and Methods: We established transgenic mice with HCC induced by activated HrasG12V and p53 suppression. Transgenic mice were randomly assigned to five experimental groups: negative control, positive control, tacrolimus only, rapamycin only, and tacrolimus plus rapamycin. The mice were further divided into two groups according to time to commencement of immunosuppressant treatment: de novo treatment and post-tumor development. Results: In the de novo treatment group, marked suppression of tumor growth was observed in the rapamycin only group. In the post-tumor development group, the rapamycin only group displayed no significant suppression of tumor growth, compared to the positive control group. In T lymphocyte subset analysis, the numbers of CD4+ effector T cells and CD4+ regulatory T cells were significantly lower in the positive control, tacrolimus only, and tacrolimus plus rapamycin groups than the negative control group.Immunohistochemical analysis revealed significantly higher expression of phosphorylated-mTOR, 4E-BP1, and S6K1 in the positive control group than in the rapamycin only group. Conclusion Low-dose rapamycin might be effective to prevent HCC growth, but may be ineffective as a treatment option after HCC development.

Purpose: We investigate whether low-dose rapamycin is effective in preventing hepatocellular carcinoma (HCC) growth and treating HCC after tumor development in transgenic mice. Materials and Methods: We established transgenic mice with HCC induced by activated HrasG12V and p53 suppression. Transgenic mice were randomly assigned to five experimental groups: negative control, positive control, tacrolimus only, rapamycin only, and tacrolimus plus rapamycin. The mice were further divided into two groups according to time to commencement of immunosuppressant treatment: de novo treatment and post-tumor development. Results: In the de novo treatment group, marked suppression of tumor growth was observed in the rapamycin only group. In the post-tumor development group, the rapamycin only group displayed no significant suppression of tumor growth, compared to the positive control group. In T lymphocyte subset analysis, the numbers of CD4+ effector T cells and CD4+ regulatory T cells were significantly lower in the positive control, tacrolimus only, and tacrolimus plus rapamycin groups than the negative control group.Immunohistochemical analysis revealed significantly higher expression of phosphorylated-mTOR, 4E-BP1, and S6K1 in the positive control group than in the rapamycin only group. Conclusion Low-dose rapamycin might be effective to prevent HCC growth, but may be ineffective as a treatment option after HCC development.