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Impairment of pre-mRNA splicing in liver disease: Mechanisms and consequences

World Journal of Gastroenterology 2010年第25期16卷 3091-3102页

作者： carmen berasain Saioa Gońi Josefa Castillo Maria Ujue Latasa Jesús Prieto Matias A Avila Division of Hepatologyand Gene Therapy CIMA University of Navarra Pamplona31008 Spain

Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention ofintronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulatepre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies.

关键词： Cell signalling Hepatocarcinogenesis PremRNA splicing Splicing factors Targeted anticancer therapy

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Immunotherapy and immunoescape in colorectal cancer

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World Journal of Gastroenterology 2007年第44期13卷 5822-5831页

作者： Guillermo Mazzolini Oihana Murillo Catalina Atorrasagasti Juan Dubrot Iigo Tirapu Miguel Rizzo Ainhoa Arina Carlos Alfaro Arantza Azpilicueta carmen berasain José L Perez-Gracia Alvaro Gonzalez Ignacio Melero Liver Unit Facultad de Ciencias Biomédicas Universidad Austral Presidente Perón 1500 (1635) Derqui-Pilar Buenos Aires Argentina Centro de Investigación Médica Aplicada and Clínica Universitaria Universidad de Navarra Pamplona Spain

Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNγ in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma.

关键词：结肠癌免疫疗法基因疗法白介素

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