In situ expression patterns of melanoma inhibitory activity 2 in healthy and diseased livers.
Recently we identified a novel gene of the MIA gene family, melanoma inhibitory activity 2 (MIA2) and found that MIA2 mRNA is selectively expressed in hepatocytes. Here, we analyzed the in situ expression of MIA2 protein and mRNA in healthy and diseased livers to get first insights into the function of MIA2.


METHODS
We analyzed liver tissue of patients with chronic hepatitis C (HepC) infection and hepatocellular carcinoma (HCC) as well as a human multi-tissue array, primary human hepatocytes and the hepatoma cell-lines HepG2, Hep3B and PLC by immunohistochemical staining and quantitative RT-PCR. In addition to MIA2, the expression of alpha-smooth muscle actin (alpha-sma), a marker for activated hepatic stellate cells (HSCs)/myofibroblast, was analyzed.


RESULTS
Hepatocytes were confirmed as the exclusive cellular source of MIA2 expression, with a granular, cytoplasmatic staining pattern without enhancement at the cell membrane. In contrast, only low MIA2 expression levels were detected in most HCC and hepatoma cell lines. Only in HCC that contained fibrous stroma or thick hyalinized bundles, adjacent atypical hepatocytes revealed strong staining. In accordance, MIA2 expression was also upregulated in non-tumorous livers of patients with HepC and correlated with the staging of fibrosis. Interestingly, both in HCC and liver tissues of patients with HepC we found a correlation of MIA2 and alpha-sma expression.


CONCLUSIONS
We define for the first time in situ expression patterns of MIA2 in healthy and diseased livers. Our data raise the hypothesis that activation of HSCs/myofibroblasts has influence on MIA2 expression in vivo, consistent with our previous in vitro findings. Since the staining pattern and the protein structure highly suggests that MIA2 is a secreted protein, it may possibly serve as a marker of hepatic fibrosis.
Hellerbrand
Claus
C
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
Bataille
Frauke
F
Schlegel
Jacqueline
J
Hartmann
Arndt
A
Mühlbauer
Marcus
M
Schölmerich
Jürgen
J
Büttner
Reinhard
R
Hofstädter
Ferdinand
F
Bosserhoff
Anja-Katrin
AK
D000328:Adult; D001483:Base Sequence; D015415:Biomarkers / Q000032:analysis; D001707:Biopsy, Needle; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000473:pathology*; D016022:Case-Control Studies; D016326:Extracellular Matrix Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006521:Hepatitis, Chronic / Q000097:blood / Q000473:pathology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000097:blood / Q000473:pathology*; D008113:Liver Neoplasms / Q000097:blood / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012334:RNA, Neoplasm / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D046509:Tissue Culture Techniques
D015415:Biomarkers; D016326:Extracellular Matrix Proteins; C090059:MIA protein, human; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012367:RNA, Viral