Abstract
Accumulating evidence has shown that dysregulation of tight junctions (TJs) is involved in tumor development and progression. In this study, we investigated the expression and subcellular distribution of tricellulin, which constitutes tricellular TJs, using human pancreatic adenocarcinomas. In well-differentiated pancreatic adenocarcinoma tissues, tricellulin immunostaining was prominent in the cytoplasm and the plasma membrane. In contrast, in poorly differentiated tissues, its immunostaining was predominantly observed in the nuclei and was almost absent in the plasma membrane. The distinct immunostaining of tricellulin successfully distinguished poorly differentiated adenocarcinoma from moderately and well-differentiated adenocarcinomas with high levels of sensitivity and specificity. Nuclear tricellulin expression significantly correlated with lymph node metastasis, lymphatic invasion and poor survival. In pancreatic cancer cell lines, tricellulin localization shifted from the membrane to nucleus with decreasing differentiation status. Nuclear localization of tricellulin promoted cell proliferation and invasiveness possibly in association with MAPK and PKC pathways in pancreatic cancers. Our results provide new insights into the function of tricellulin, and its nuclear localization may become a new prognostic factor for pancreatic cancers.
Highlights
Accumulating evidence has shown that dysregulation of tight junctions (TJs) is involved in tumor development and progression
Tricellulin immunoreactivities were more prominent than in normal regions, and the subcellular distribution of tricellulin varied depending on the degree of differentiation (Fig. 1a): In well-differentiated carcinoma components, localization of tricellulin was prominent in the cytoplasm and the plasma membrane
We found that nuclear localization of tricellulin is significantly associated with clinicopathological parameters such as lymph node metastasis and shorter survival time
Summary
Accumulating evidence has shown that dysregulation of tight junctions (TJs) is involved in tumor development and progression. We investigated the expression and subcellular distribution of tricellulin, which constitutes tricellular TJs, using human pancreatic adenocarcinomas. Nuclear localization of tricellulin promoted cell proliferation and invasiveness possibly in association with MAPK and PKC pathways in pancreatic cancers. Tight junctions (TJs) are the apicalmost components of intercellular junctional complexes in epithelial and endothelial cells They primarily inhibit solute and water flow through the paracellular space[4,5]. We examined tricellulin expression in human pancreatic cancers in association with its subcellular localization, and we evaluated possible correlations with several clinicopathological variables. We investigated whether tricellulin expression and its subcellular localization are responsible for the aggressive behaviors of cancer cells such as proliferation and invasiveness. Our results suggest that aberrant nuclear localization of tricellulin confers immature histology and oncogenic properties of pancreatic malignancy
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