Establishment of a conditional knock out mouse to investigate the function of C4.4A in liver diseases

The human homolog of a rat metastasis-associated molecule, hC4.4 A, is a glycolipid-anchored membrane protein with structural homology to the urokinase-type plasminogen activator receptor (uPAR). Although C4.4A expression is rather restricted in non-transformed tissues, it has been observed in tumours derived from brain, lung, liver, kidney, stomach and colon. C4.4A is expressed in over 80% of primary colorectal cancer and liver metastasis with negligible expression in adjacent colonic mucosa, inflamed colonic tissue and liver. In addition, mC4.4A expression is strongly up-regulated in migrating keratinocytes during wound healing and in malignant melanoma. Because of the direct interaction with the adhesion proteins laminin-1, laminin-5, galectin-3 and the identification as a substrate for the metalloproteases ADAM 10 and -17, C4.4A was previously proposed to be involved in the regulation of cell–cell or cell–matrix contacts during malignant tissue remodeling. We generated a C4.4A mouse in which Exon2 of the C4.4A gene is flanked by loxP sites. Liver specific gene inactivation can be achieved by mating the C4.4A loxP mice with a tamoxifen inducible albumin-Cre mouse strain. Administration of tamoxifen at the desired time point in embryonic development or adult life will induce hepatocyte specific Cre gene expression. The recombinase activity results in the excision of the floxed Exon2 and the time and tissue specific knockout of C4.4A. The loxP C4.4A mouse will be suitable to investigate its function in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCC), liver metastases, cirrhosis and hepatitis.

C4.4A - cholangiocarcinoma - cirrhosis - hepatitis - hepatocellular carcinoma - knock out mouse - liver metastases