INPP4B suppresses prostate cancer cell invasion.
INPP4B suppresses prostate cancer cell invasion.
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DOI：
10.1186/s12964-014-0061-y
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发表时间：
2014-09-25
期刊：
影响因子：
--
通讯作者：
Agoulnik IU
中科院分区：
文献类型：
--
作者：
Hodgson MC;Deryugina EI;Suarez E;Lopez SM;Lin D;Xue H;Gorlov IP;Wang Y;Agoulnik IU
INPP 4 B和PTEN双特异性磷酸酶在前列腺癌进展为转移性疾病期间经常丢失。我们和其他人先前已经表明，INPP 4 B表达的缺失与多种恶性肿瘤的预后不良和前列腺癌的转移扩散相关。我们证明了INPP 4 B在高度侵袭性的人前列腺癌PC-3细胞中的从头表达抑制了它们在体外和体内的侵袭。使用全局基因表达分析，我们发现INPP 4 B调节许多与细胞粘附、细胞外基质和细胞骨架相关的基因。重要的是，从头表达的INPP 4 B抑制促炎趋化因子IL-8并诱导PAK 6。在独立衍生的INPP 4 B阳性LNCaP前列腺癌细胞系中，这些基因在INPP 4 B下调后以相互的方式调节。在PC-3和LNCaP细胞中均高度活跃的PI 3 K/Akt途径的抑制在任一细胞类型中均不再现INPP 4 B介导的IL-8 mRNA表达的抑制。相比之下，PKC信号传导的抑制在任一前列腺癌细胞系中表型模仿INPP 4 B介导的对IL-8的抑制作用。在PC-3细胞中，INPP 4 B过表达导致转移相关的BIRC 5蛋白水平、PKC磷酸化水平以及共同的PKC和IL-8下游靶点考克斯-2的表达下降。相反，内源性INPP 4 B耗竭后，LNCaP细胞中考克斯-2表达增加。总之，我们发现INPP 4 B是一种新的致癌PKC信号转导抑制剂，进一步强调了INPP 4 B在维持前列腺上皮正常生理和抑制前列腺肿瘤转移潜能中的作用。本文的在线版本（doi：10.1186/s12964-014-0061-y）包含补充材料，可供授权用户使用。
INPP4B and PTEN dual specificity phosphatases are frequently lost during progression of prostate cancer to metastatic disease. We and others have previously shown that loss of INPP4B expression correlates with poor prognosis in multiple malignancies and with metastatic spread in prostate cancer. We demonstrate that de novo expression of INPP4B in highly invasive human prostate carcinoma PC-3 cells suppresses their invasion both in vitro and in vivo. Using global gene expression analysis, we found that INPP4B regulates a number of genes associated with cell adhesion, the extracellular matrix, and the cytoskeleton. Importantly, de novo expressed INPP4B suppressed the proinflammatory chemokine IL-8 and induced PAK6. These genes were regulated in a reciprocal manner following downregulation of INPP4B in the independently derived INPP4B-positive LNCaP prostate cancer cell line. Inhibition of PI3K/Akt pathway, which is highly active in both PC-3 and LNCaP cells, did not reproduce INPP4B mediated suppression of IL-8 mRNA expression in either cell type. In contrast, inhibition of PKC signaling phenocopied INPP4B-mediated inhibitory effect on IL-8 in either prostate cancer cell line. In PC-3 cells, INPP4B overexpression caused a decline in the level of metastases associated BIRC5 protein, phosphorylation of PKC, and expression of the common PKC and IL-8 downstream target, COX-2. Reciprocally, COX-2 expression was increased in LNCaP cells following depletion of endogenous INPP4B. Taken together, we discovered that INPP4B is a novel suppressor of oncogenic PKC signaling, further emphasizing the role of INPP4B in maintaining normal physiology of the prostate epithelium and suppressing metastatic potential of prostate tumors. The online version of this article (doi:10.1186/s12964-014-0061-y) contains supplementary material, which is available to authorized users.
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DOI：
10.1158/1078-0432.ccr-09-0911
发表时间：
2009-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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DOI：
10.4049/jimmunol.1201529
发表时间：
2012-10-01
期刊：
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