Low PIP4K2B expression in human breast tumors correlates with reduced patient survival: A role for PIP4K2B in the regulation of E-cadherin expression.
Low PIP4K2B expression in human breast tumors correlates with reduced patient survival: A role for PIP4K2B in the regulation of E-cadherin expression.
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DOI：
10.1158/0008-5472.can-13-0424
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发表时间：
2013-12-01
期刊：
影响因子：
11.2
通讯作者：
Divecha N
中科院分区：
文献类型：
--
作者：
Keune WJ;Sims AH;Jones DR;Bultsma Y;Lynch JT;Jirström K;Landberg G;Divecha N
磷脂酰肌醇-5-磷酸（PtdIns 5 P）4-激酶β（PIP 4K 2B）直接调节两种重要的磷酸肌醇（PI）第二信使PtdIns 5 P和磷脂酰肌醇-（4，5）-二磷酸（PtdIns（4，5）P2）的水平。PIP 4K 2B与基因转录、TP 53和AKT活化的调节以及细胞活性氧积累的调节有关。然而，它在人类肿瘤发展和患者生存中的作用尚不清楚。在这里，我们使用IHC染色并通过对2999例乳腺肿瘤的基因表达谱进行荟萃分析，在一组（489例）乳腺肿瘤患者中询问了PIP 4K 2B的表达，两者均具有相关的临床结果数据。PIP 4 K2 B低表达与肿瘤大小增加、高诺丁汉组织学分级（NHG）、Ki 67表达和远处转移相关，而PIP 4 K2 B高表达与ERBB 2表达强烈相关。Kaplan Meier曲线显示，与中等表达相比，高表达和低表达的PIP 4K 2B均与较差的患者生存相关。在正常（MCF 10A）和肿瘤（MCF 7）乳腺上皮细胞系中，使用sh-RNAi介导的敲低，模拟低PIP 4K 2B表达，导致肿瘤抑制蛋白E-钙粘蛋白（CDH 1）的转录和表达减少。在MCF 10A细胞中，PIP 4K 2B的敲除还增强了TGFβ诱导的上皮向间质转化（EMT），这是转移发展期间所需的过程。基因表达数据集的分析证实了低PIP 4K 2B和低CDH 1表达之间的关联。CDH 1表达降低和PIP 4K 2B表达降低导致TGFβ诱导的EMT增强可能部分解释了PIP 4K 2B低表达与患者生存率差之间的相关性。
Phosphatidylinositol-5-phosphate (PtdIns5P) 4-kinase beta (PIP4K2B) directly regulates the levels of two important phosphoinositide (PI) second messengers PtdIns5P and phosphatidylinositol-(4,5)-bisphosphate (PtdIns(4,5)P2). PIP4K2B has been linked to the regulation of gene transcription, TP53 and AKT activation and to the regulation of cellular reactive oxygen accumulation. However its role in human tumour development and on patient survival is not known. Here we have interrogated the expression of PIP4K2B in a cohort (489) of breast tumour patients using IHC staining and by a meta-analysis of gene expression profiles from 2999 breast tumours, both with associated clinical outcome data. Low PIP4K2B expression was associated with increased tumour size, high Nottingham histological grade (NHG), Ki67 expression and distant metastasis, while high PIP4K2B expression strongly associated with ERBB2 expression. Kaplan Meier curves showed that both high and low PIP4K2B expression correlated with poorer patient survival compared to intermediate expression. In normal (MCF10A) and tumour (MCF7) breast epithelial cell lines, mimicking low PIP4K2B expression, using sh-RNAi mediated knockdown, led to a decrease in the transcription and expression of the tumour suppressor protein E-cadherin (CDH1). In MCF10A cells knockdown of PIP4K2B also enhanced TGFβ induced epithelial to mesenchymal transition (EMT), a process required during the development of metastasis. Analysis of gene expression datasets confirmed the association between low PIP4K2B and low CDH1expression. Decreased CDH1 expression and enhancement of TGFβ-induced EMT by reduced PIP4K2B expression might in part explain the association between low PIP4K2B expression and poor patient survival.