Cancer of liver cells (hepatocellular carcinoma) is often diagnosed late as it may grow slowly and for unnoticed for years; consequently most patients present with advanced disease, the outlook for which is currently very poor. The process of epithelial to mesenchymal transition (EMT), which is required for many cancers to undergo metastasis and set up secondary tumours in other organs and tissues, occurs in advanced disease and in the case of liver cancer very little is known about EMT.
A recent study published in the journal Oncogene shows that a molecule that is normally involved in holding epithelial cells together in tissues, Claudin 1, can in fact promote EMT and allow cancer cells to become more invasive. Increased levels of Claudin 1 in liver cancer cells causes promotion of genes involved in EMT through up-regulation of key transcription factors ZEB1 and SLUG. Another important EMT transcription factor, SNAIL, was shown to not be involved, but interestingly a protein called c-Abl was found to be very important for this process.
c-Abl, is best known for being part of a mutation that occurs commonly in a form of leukaemia called CML and a number of drugs targeting c-Abl have been developed to treat CML. For example, Imatinib (Glivec) is an inhibitor that blocks the BCR-Abl fusion oncogene product which has been very useful for doctors treating CML. In this present study, the group showed that by silencing the protein c-Abl in cells that have Claudin 1 over-expressed, they could reverse the up-regulation of ZEB1 and SLUG and prevent the invasiveness conveyed by EMT. This study demonstrates that in the future when doctors look at hepatocellular carcinoma they could look for increased levels of Claudin 1 as a possible indicator of the invasiveness of the cancer. With more work, this marker could be validated and possibly even exploited as a druggable target for the treatment of liver cancer.
Suh Y, Yoon CH, Kim RK, Lim EJ, Oh YS, Hwang SG, An S, Yoon G, Gye MC, Yi JM, Kim MJ, Lee SJ.
Claudin-1 inducesepithelial-mesenchymal transition through activation of the c-Abl-ERK signalingpathway in human liver cells.
Oncogene. 2013 Oct 10;32(41):4873-4882. doi: 10.1038/onc.2012.505.