Disrupted cell adhesion but not proliferation mediates cyst formation in polycystic liver disease

Abstract

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 ¼ 21) compared with normal liver tissue (n ¼ 13). None of the cysts showed proliferation of epithelial cells. In addition, anti-apoptosis marker Bcl-2 revealed a 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 the 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 b-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.

Congenital disorders of glycosylation in hepatology: The example of polycystic liver disease

“…Complete loss of PRKCSH from the cyst epithelium is expected to affect the function of glucosidase II and as a consequence glycosylation and protein folding in these cells. This seems to be confirmed by the finding that in cyst epithelial cells, specific membrane proteins are retained in the ER whereas these proteins are normally distributed in hepatocystin expressing biliary cells [56].…”

“…The glycoprotein quality control system depends on proper functioning of the glucosidase II complex. Incomplete glucose cleavage results in reduced rates of protein folding, accelerated protein degradation, reduced expression of cell-surface proteins and defects in protein secretion [50,[56][57][58]. Some proteins depend heavily on the folding machinery of the ER and cannot obtain their native conformation without glucosidase II cleavage and subsequent interaction with the ER chaperones [59,60].…”

PRKCSH Genetic Mutation Was Not Found in Taiwanese Patients with Polycystic Liver Disease

“…PRKCSH mutation results in lack of hepatocystin in biliary epithelia [18], causing disrupted cell adhesion and cyst formation [19]. Also, another gene, SEC63, which encodes a component of the protein translocation machinery in ER, was found to be responsible for a small part of PCLD [7].…”

Functions and pathologies of BiP and its interaction partners

“…The result is uncontrolled proliferation of the respective liver cells and, thus, cyst formation. We note that this concept was recently challenged on the basis of novel data that were obtained for patients with a mutation in the SEC63 gene [121], and additional new results may suggest a divergent mechanism for cystogenesis in patients with mutations in the PRKCSH gene versus the SEC63 gene [122]. In the case of mutations in the PRKCSH gene, it was concluded that the lack of hepatocystin does not result in proliferation but in disrupted cell adhesion.…”