Abstract
ABSTRACTThe inositol polyphosphate-4-phosphatase type II (INPP4B) has been mostly proposed to act as a tumor suppressor whose expression is frequently dysregulated in numerous human cancers. To date, little is unveiled about whether and how INPP4B will exert its tumor suppressive function on the turnover of cadherin-based cell-cell adhesion system in pancreatic ductal adenocarcinomas (PDACs) in vitro. Here we provide the evidence that INPP4B manipulates cadherin switch in certain PDAC cell lines through a phosphorylated AKT-inactivation manner. The knockdown of INPP4B in AsPC-1 results in a more invasive phenotype, and overexpression of it in PANC-1 leads to partial reversion of mesenchymal status and impediment of in vitro invasion but not migration. More importantly, E-cadherin (Ecad) is enriched in the early and sorting endosomes containing INPP4B by which its recycling rather than degradation is enabled. Immunohistochemical analysis of 39 operatively resected PDAC specimens reveals it is poorly differentiated, non-cohesive ones in which the INPP4B and Ecad are partially or completely compromised in expression. We therefore identify INPP4B as an tumor suppressor in PDAC which attenuates AKT activation and participates in preservation of Ecad in endocytic pool and cellular membrane.
Highlights
Epithelial-mesenchymal transition (EMT) is a developmental progress that endows epithelial cell with partial loss of epithelial features and gain of mesenchymal phenotype due to being transcriptionally reprogrammed
Knockdown of target gene in AsPC-1 significantly decreased the Vim (1.75-fold reduction of transcript and 1.52-fold reduction of protein; P < 0.05) and Ecad (2.08-fold reduction of transcript and 1.61-fold reduction of protein; P < 0.05), with elevated Ncad level (4.12-fold increase of transcript and 3.31-fold increase of protein; P < 0.05) relative to the control (Figure 1(e,f), Figure S1B). These findings were further supported by the varying intensities of target protein staining when INPP4B expression was modified in immunofluorescence analysis (Figure 1(g))
Cytoplasmic expression of Ncad was detected when cadherin switch was evident in transduced cells, few membranous expression was obviously observed, and perhaps the lack of mature cell-cell junctions could account for this phenomenon
Summary
Epithelial-mesenchymal transition (EMT) is a developmental progress that endows epithelial cell with partial loss of epithelial features and gain of mesenchymal phenotype due to being transcriptionally reprogrammed. The classical event frequently seen in cancer-associated EMT is characterized by the cadherin switch between E- and N-cadherin (Ecad, Ncad), under certain circumstances, together with the varying levels of vimentin (Vim) [1]. This mesenchymal state facilitates destabilization of cellcell adhesion complex and change of cell polarity, resulting in increased invasiveness of tumor cells [2]. Signaling transduced by PI(3,4)P2 can be modulated by inositol polyphosphate 4-phosphastases type II (INPP4B), which preferentially hydrolyzes PI(3,4)P2 to phosphatidylinositol-3-phosphate (PI(3)P) [5] This dephosphorylation compromises the activation of AKT, which unveils the tumor-suppressing function of INPP4B in the context of some malignancies [6,7]. We hypothesize that INPP4B could play a role in modulating the turnover of cadherins, thereby inducing stabilization of cell-cell contact and suppression of cell invasion
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