The pathogenesis of
polycystic liver disease is not well understood. The putative function of the associated
proteins, hepatocystin and Sec63p, do not give insight in their role in cystogenesis and their tissue-wide expression does not fit with the liver-specific phenotype of the disease. We designed this study with the specific aim to dissect whether pathways involved in
polycystic kidney diseases are also implicated in
polycystic liver disease. Therefore, we immunohistochemically stained
cyst tissue specimen with
antibodies directed against markers for apoptosis, proliferation, growth receptors, signaling and adhesion. We analyzed genotyped
polycystic liver disease cyst tissue (n=21) compared with normal liver tissue (n=13). None of the
cysts showed proliferation of epithelial cells. In addition, anti-apoptosis marker Bcl-2 revealed slight increase in expression, with variable increase of apoptosis marker active
caspase 3.
Growth factor receptors, EGFR and c-erbB-2, were overexpressed and mislocalized. We found EGFR staining in the nuclei of
cyst epithelial cells regardless of mutational state of the patient. Further, in hepatocystin-mutant
polycystic liver disease patients, apical membranous staining of c-erbB-2 and adhesion markers, MUC1 and CEA, was lost and the
proteins appeared to be retained in cytoplasm of
cyst epithelia. Finally, we found loss of adhesion molecules
E-cadherin and
Ep-CAM in
cyst epithelium of all patients. Nevertheless, we observed normal
beta-catenin expression. Our results show that
polycystic liver disease cystogenesis is different from renal cystogenesis.
Polycystic liver disease involves overexpression of
growth factor receptors and loss of adhesion. In contrast, proliferation or deregulated apoptosis do not seem to be implicated. Moreover differential findings for PRKCSH- and SEC63-associated
polycystic liver disease suggest a divergent mechanism for cystogenesis in these two groups.