Claudins and tricellulin in fibrolamellar hepatocellular carcinoma
Fibrolamellar hepatocellular carcinoma is a subtype of hepatocellular carcinoma occurring in non-cirrhotic liver at a younger age. The tumor expresses both hepatocellular and cholangiocellular markers. Previously, our group described overexpression of tight junction protein claudin 4 in cholangiocellular carcinoma in contrast to hepatocellular carcinoma. In the present study, tight junction protein expressions were studied to possibly clarify bipotential lineage of fibrolamellar hepatocellular carcinoma. Eleven fibrolamellar hepatocellular carcinomas were compared with seven “conventional” hepatocellular carcinomas, seven cholangiocellular carcinomas, and five normal liver samples. By immunohistochemistry, all fibrolamellar hepatocellular carcinomas were positive for HepPar1 and cytokeratins 7, 8, and 18, but negative for cytokeratin 19. Glypican-3 gave weak staining in two cases. Expression of claudin 1 was lower, while that of claudin 2 was higher in fibrolamellar hepatocellular carcinomas than in other tumors. Claudins 3, 4, and 7 were not detectable in fibrolamellar hepatocellular carcinomas as in the majority of “conventional” hepatocellular carcinomas, contrary to high expression observed in cholangiocellular carcinomas. Focal or diffuse claudin 5 expression was detected in nine of 11 fibrolamellar hepatocellular carcinomas contrary to other tumors. Tricellulin was significantly downregulated in all tumors compared with normal liver. Our findings showed claudins to exhibit specific expression patterns in fibrolamellar hepatocellular carcinomas not observed in other primary liver tumors, with unique claudin 5 expression and pattern features similar to common hepatocellular carcinoma, but different from cholangiocellular carcinoma. This is the first report describing the loss of tricellulin expression in human hepatic tumors.
KeywordsFibrolamellar hepatocellular carcinoma Tight junction proteins Claudins Hepatocellular carcinoma Cholangiocellular carcinoma Tricellulin
This work was supported by grants ETT-089/2009 by the Hungarian Ministry of Health and OTKA T 75468 by the Hungarian National Scientific Research Fund.
Conflict of interest
The authors have no financial relationship with the organizations that sponsored the research. The authors declare that they have no conflict of interest.
- 2.Ishak KG, Goodman ZD, Stocker JT (2001) Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, Third Series, Fascicle 31. Armed Forces Institute of Pathology, Washington, DCGoogle Scholar
- 13.Lapis K, Zs S, Kopper L, Karácsonyi S, Ormos J (1990) Fibrolamellar carcinomas of the liver. Zentralbl Allg Pathol Pathol Anat 136:135–149Google Scholar
- 14.Malouf G, Falissard B, Azoulay D, Callea F, Ferrell LD, Goodman ZD, Hayashi Y, Hsu HC, Hubscher SG, Kojiro M, Ng IO, Paterson AC, Reynes M, Zafrani ES, Emile JF (2009) Is histological diagnosis of primary liver carcinomas with fibrous stroma reproducible among experts? J Clin Pathol 62:519–524PubMedCrossRefGoogle Scholar
- 15.Lee J-S, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A, Roberts LR, Demetris AJ, Sun Z, Nevens F, Roskams T, Thorgeirsson SS (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12:410–416PubMedCrossRefGoogle Scholar
- 16.Kakar S, Chen X, Ho C, Burgart LJ, Sahai V, Dachrut S, Yabes A, Jain D, Ferrell LD (2009) Chromosomal changes in fibrolamellar hepatocellular carcinoma detected by array comparative genomic hybridization. Hum Pathol 22:134–141Google Scholar
- 18.Libbrecht L, Severi T, Cassiman D, Vander Borght S, Pirenne J, Nevens F, Verslype C, van Pelt J, Roskams T (2006) Glypican-3 expression distinguishes small hepatocellular carcinomas from cirrhosis, dysplastic nodules, and focal nodular hyperplasia-like nodules. Am J Surg Pathol 30:1405–1411PubMedCrossRefGoogle Scholar
- 20.Zs N, Szász AM, Tátrai P, Németh J, Gyorffy H, Somorácz A, Szíjártó A, Kupcsulik P, Kiss A, Schaff Z (2009) Claudin-1, -2, -3, -4, -7, -8, and -10 protein expression in biliary tract cancers. J Histochem Cytochem 57:113–121Google Scholar
- 40.Dos Reis PP, Bharadwaj RR, Machado J, Macmillan C, Pintilie M, Sukhai MA, Perez-Ordonez B, Gullane P, Irish J, Kamel-Reid S (2008) Claudin 1 overexpression increases invasion and is associated with aggressive histological features in oral squamous cell carcinoma. Cancer 113:3169–3180PubMedCrossRefGoogle Scholar
- 53.Comper F, Antonello D, Beghelli S, Gobbo S, Montagna L, Pederzoli P, Chilosi M, Scarpa A (2009) Expression pattern of claudins 5 and 7 distinguishes solid-pseudopapillary from pancreatoblastoma, acinar cell and endocrine tumors of the pancreas. Am J Surg Pathol 33:768–774PubMedCrossRefGoogle Scholar
- 57.Krug SM, Amasheh S, Richter JF, Milatz S, Günzel D, Westphal JK, Huber O, Schulzke JD, Fromm M (2009) Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol 20:3713–3724Google Scholar