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Inositol polyphosphate-4-phosphatase type II plays critical roles in the modulation of cadherin-mediated adhesion dynamics of pancreatic ductal adenocarcinomas.
Cell Adhesion & Migration ( IF 3.2 ) Pub Date : 2018-06-29 , DOI: 10.1080/19336918.2018.1491496
Bin Zhang 1 , Weidong Wang 2 , Chonghui Li 3 , Rong Liu 1
Affiliation  

The 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.

中文翻译:

II型肌醇多磷酸-4-磷酸酶在调节钙粘蛋白介导的胰腺导管腺癌的黏附动力学中起着关键作用。

II型肌醇多磷酸-4-磷酸酶(INPP4B)主要被提议作为一种肿瘤抑制因子,其表达在许多人类癌症中经常失调。迄今为止,关于胰管性腺癌(PDAC)体外INPP4B是否以及如何在基于钙粘蛋白的细胞粘附系统的更新中发挥其抑癌功能的报道很少。在这里,我们提供了证据,表明INPP4B通过磷酸化AKT灭活方式来操纵某些PDAC细胞系中的钙黏着蛋白开关。在AsPC-1中敲低INPP4B会导致更具侵袭性的表型,在PANC-1中过表达会导致间充质状态的部分逆转,并阻碍体外侵袭而不是迁移。更重要的是,E-cadherin(Ecad)在包含INPP4B的早期和分选内体中富集,从而可以再循环而不降解。对39个手术切除的PDAC标本进行的免疫组织化学分析显示,该标本分化差,无内聚性,其中INPP4B和Ecad的表达部分或完全受损。因此,我们确定INPP4B作为PDAC中的一种肿瘤抑制因子,可减弱AKT激活并参与内吞池和细胞膜中Ecad的保存。
更新日期:2019-11-01
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