Worldwide, primary hepatocellular carcinoma is the fifth most commonly diagnosed solid cancer and the third most common cause of cancer related death. Because of its constantly increasing incidence in developed countries and its poor prognosis, HCC represents a major health problem. Diagnostic markers for early-stage HCC are of great need but still lacking due to the high complexity and heterogeneity of HCC. The purpose of this study was to examine Wisp1 expression in different liver tumor stages and its functional role in epithelial- and fibroblastoid-type HCC cell lines. By immunohistochemical staining of HCC patient samples, we demonstrated that Wisp1 expression is enhanced in well- and moderately differentiated HCC and is associated with inflammation and steatosis, but is absent in poorly differentiated HCC. Furthermore, we found that Wisp1 is expressed and secreted in HCC cell lines(FLC4, HLF). Treatment of the epithelial-type HCC cell lines with human recombinant Wisp1 led to an increase in proliferation, while fibroblastoid-type HCC cell lines showed an increase in migration. Interestingly, both types of cell lines displayed the activation of the same phosphokinases upon Wisp1 stimulation. Knockdown of Wisp1 with shRNA in the epithelial-type HCC cell line consequently decreased proliferation and, more importantly, led to apoptosis. Our study thus identified Wisp1 as a novel immunohistochemical marker for the detection of well differentiated, early-stage HCC as well as a regulator of proliferation in the epithelial-type HCC cell line and a regulator of migration in the fibroblastoidtype HCC cell lines via activation of distinct HCC related phosphokinases. These results pose Wisp1 as a possible diagnostic marker for HCC for which currently only poor therapies are available.
|Supervisor:||Zawatzky, Prof. Dr Rainer|
|Date of thesis defense:||16 October 2012|
|Date Deposited:||27 Feb 2013 11:14|
|Faculties / Institutes:||The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences|
|Controlled Keywords:||Wisp1, CCN, HCC|