Tricellulin Expression and its Prognostic Significance in Primary Liver Carcinomas.

Numerous data suggest that altered expression of tight junction proteins such as occludin and claudins plays important role in carcinogenesis. However, little is known about tricellulin, a transmembrane tight junction protein concentrated where three epithelial cells meet. We aimed to characterize tricellulin expression in normal and cirrhotic liver in comparison to primary hepatic neoplasms. Tricellulin expression of 20 control livers, 12 cirrhotic livers, 32 hepatocellular carcinomas (HCC), and 20 intrahepatic cholangiocarcinomas (iCCC) was investigated by immunohistochemistry and Western blotting. Co-localization of tricellulin with claudin-1, -4, and MRP2 was studied using double immunofluorescence. Scattered tricellulin immunopositivity was restricted to biliary pole of hepatocytes confirmed by co-localization with MRP2. Moreover, spotted-like reaction was observed between bile duct epithelial cells. In 40 % of HCCs marked tricellulin overexpression was measured regardless of tumor grades. In iCCCs, however, tricellulin expression decreased parallel with dedifferentiation. In HCCs high tricellulin expression, in iCCCs low tricellulin expression correlated with poor prognosis. Co-localization with MRP2 might substantiate that tricellulin plays role in blood-biliary barrier. Overexpressed tricellulin in a subset of HCCs correlated with unfavorable prognosis. Similar to ductal pancreatic adenocarcinoma, higher grades of iCCCs were associated with decreased tricellulin expression correlating with poor prognosis

Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma

Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation