Two Step Forward Genetic Screen in Mice Identifies the Ral Pathway as a Central Drug Target in Hepatocellular Carcinoma.
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 Aof hepatocellular carcinoma (HCC) will be crucial to developing new therapies aimed at selected targets. Given the sparse treatment options of advanced HCC, such progress is needed urgently for this highly prevalent cancer. However, even though the full genomes of roughly 500 HCC samples are now fully available from diverse sequencing efforts and public databases, the genetics of HCC remains challenging. This is mostly owing to the significant heterogeneity of these tumors and the experimental/diagnostic problem of a lack of disease free control liver tissue. Thus, novel approaches investigating HCC genetics from a different perspective are needed. In this issue of Gastroenterology, Kodama et al present a forward genetics approach to identify novel aspects in HCC biology. In contrast with conventional reverse genetic approaches investigating the effects of altering particular genes, the forward genetic approach begins with a particular biological phenomenon and aims to identify the genetic changes responsible for the development of this specific phenotype. A forward genetic approach has the advantage of providing an unbiased selection of genes associated with the phenotype of interest, such as HCC development. The authors used the sleeping beauty transposon system (SB) Generally, transposable elements are capable of moving from 1 location on the genome to another. Among the diverse known and developed transposon systems the SB system functions through a DNA cut and paste mechanism. This process is catalyzed by the active enzyme transposase. The enzyme binds to the transposable DNA element (transposon) at its bindings sites within terminal inverted repeats at both ends. After formation of a synaptic complex, the transposable element is excised from its original location and reintegrated at a novel target site, exclusively TA dinucleotide sites. Since the Noble Prize winning discovery of transposable elements in maize plants by Barbara McClintock in 1983, these genetic elements have been identified in multiple organisms among them mouse and man. Their identification changed the perception of genes and chromosomes as an all time stable composite, toward a flexible organization of genetic information in our cells. To apply transposon technology to vertebrate model organisms or even gene therapy, the Tc1/mariner type, an active vertebrate element
Gastroenterology