Abstract
The differentiation status of tumor cells, defined by histomorphological criteria, is a prognostic factor for survival of patients affected with intrahepatic cholangiocarcinoma (ICC). To strengthen the value of morphological differentiation criteria, we wished to correlate histopathological differentiation grade with expression of molecular biliary differentiation markers and of microRNAs previously shown to be dysregulated in ICC. We analysed a series of tumors that were histologically classified as well, moderately or poorly differentiated, and investigated the expression of cytokeratin 7, 19 and 903 (CK7, CK19, CK903), SRY-related HMG box transcription factors 4 and 9 (SOX4, SOX9), osteopontin (OPN), Hepatocyte Nuclear Factor-1 beta (HNF1β), Yes-associated protein (YAP), Epithelial cell adhesion molecule (EPCAM), Mucin 1 (MUC1) and N-cadherin (NCAD) by qRT-PCR and immunostaining, and of miR-31, miR-135b, miR-132, miR-200c, miR-221 and miR-222. Unexpectedly, except for subcellular location of SOX9 and OPN, no correlation was found between the expression levels of these molecular markers and histopathological differentiation grade. Therefore, our data point toward necessary caution when investigating the evolution and prognosis of ICC on the basis of cell differentiation criteria.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary tumor of the liver
We selected tumors areas in which CK7-positive cells represented more than 50% of the tumor surface (Fig 1D–1F), in order to reduce the contamination of epithelial cancer cells by non-epithelial cells during the RNA extraction procedure
All our carcinoma express low levels of these markers irrespective of the tumor differentiation grade (Figs 2 to 4), thereby suggesting that the epithelial cells are undergoing a dedifferentiation process, at least at the molecular level. In line with this observation, Mazur and coworkers previously proposed that SRY-related HMG box transcription factor 9 (SOX9) expression decreases in the early step of ICC development [7]. These results raise the question of the real differentiation status of the tumors, and may explain why some differentiation markers are associated with good or poor prognosis in distinct studies (e.g. SOX9; [7, 11]), and why some other differentiation markers such as HNF1β are not associated with prognosis [7, 13]
Summary
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary tumor of the liver. It represents less than 10% of cholangiocarcinoma cases, but in contrast to perihilar and distal cholangiocarcinoma, its incidence and mortality rates are rising [1,2,3]. These include tumor size, surgical strategy, serum markers, TNM staging, histological features, mutational profiles, gene expression signatures (mRNA, microRNA, lncRNA), or expression of individual genes at the PLOS ONE | DOI:10.1371/journal.pone.0157140. These include tumor size, surgical strategy, serum markers, TNM staging, histological features, mutational profiles, gene expression signatures (mRNA, microRNA, lncRNA), or expression of individual genes at the PLOS ONE | DOI:10.1371/journal.pone.0157140 June 9, 2016
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