title: Liver regeneration associated protein (ALR) exhibits antimetastatic potential in hepatocellular carcinoma.
abstract: Augmenter of liver regeneration (ALR), which is critically important in liver regeneration and hepatocyte proliferation, is highly expressed in cirrhotic livers and hepatocellular carcinomas (HCC). In the current study, the functional role of ALR in hepatocancerogenesis was analyzed in more detail. HepG2 cells, in which the cytosolic 15 kDa ALR isoform was reexpressed stably, (HepG2-ALR) were used in migration and invasion assays using modified Boyden chambers. Epithelial-mesenchymal transition (EMT) markers were determined in HepG2-ALR cells in vitro and in HepG2-ALR tumors grown in nude mice. ALR protein was quantified in HCC and nontumorous tissues by immunohistochemistry. HepG2-ALR, compared with HepG2 cells, demonstrated reduced cell motility and increased expression of the epithelial cell markers E-cadherin and Zona occludens-1 (ZO-1), whereas SNAIL, a negative regulator of E-cadherin, was diminished. Matrix metalloproteinase MMP1 and MMP3 mRNA expression and activity were reduced. HepG2-ALR cell-derived subcutaneously grown tumors displayed fewer necrotic areas, more epithelial-like cell growth and fewer polymorphisms and atypical mitotic figures than tumors derived from HepG2 cells. Analysis of tumor tissues of 53 patients with HCC demonstrated an inverse correlation of ALR protein with histological angioinvasion and grading. The 15 kDa ALR isoform was found mainly in HCC tissues without histological angioinvasion 0. In summary the present data indicate that cytosolic ALR reduces hepatoma cell migration, augments epithelial growth and, therefore, may act as an antimetastatic and EMT reversing protein.
authors.affiliation: Center for Liver Cell Research, University Medical Center Regensburg, Germany.
authors.forename: Rania
authors.initials: R
authors.lastname: Dayoub
authors.forename: Hannah
authors.initials: H
authors.lastname: Wagner
authors.forename: Frauke
authors.initials: F
authors.lastname: Bataille
authors.forename: Oliver
authors.initials: O
authors.lastname: Stöltzing
authors.forename: Thilo
authors.initials: T
authors.lastname: Spruss
authors.forename: Christa
authors.initials: C
authors.lastname: Buechler
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D002465:Cell Movement; D002478:Cells, Cultured; D003579:Cytochrome Reductases / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014183:Transplantation, Heterologous; D062826:Zonula Occludens-1 Protein
chemical_list: D015820:Cadherins; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D003579:Cytochrome Reductases; C500897:GFER protein, human; D050862:Oxidoreductases Acting on Sulfur Group Donors; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1