CUB Domain-Containing Protein 1, a Prognostic Factor for Human Pancreatic Cancers, Promotes Cell Migration and Extracellular Matrix Degradation
CUB Domain-Containing Protein 1, a Prognostic Factor for Human Pancreatic Cancers, Promotes Cell Migration and Extracellular Matrix Degradation
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DOI：
10.1158/0008-5472.can-10-0220
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发表时间：
2010-06-15
期刊：
影响因子：
11.2
通讯作者：
Sakai, Ryuichi
中科院分区：
文献类型：
--
作者：
Miyazawa, Yuri;Uekita, Takamasa;Sakai, Ryuichi
含CUB结构域蛋白1（CDCP 1）是一种在几种实体癌中高度表达的膜蛋白。我们以前报道过CDCP 1调节失巢凋亡抵抗以及癌细胞迁移和侵袭，尽管其潜在机制尚未阐明。在这项研究中，我们发现胰腺癌组织中CDCP 1的表达与总生存率显著相关，并且胰腺癌细胞系中CDCP 1的表达在实体瘤细胞系中相对较高。这些细胞中CDCP 1表达的减少通过抑制基质金属蛋白酶-9的分泌来抑制细胞外基质（ECM）降解。使用CDCP 1的Y 734 F突变体，它缺乏酪氨酸磷酸化位点，我们表明，CDCP 1调节细胞迁移，侵袭，和ECM降解的酪氨酸磷酸化依赖性的方式，这些CDCP 1相关的特性被抑制通过阻断CDCP 1和蛋白激酶C δ（PKC δ）的协会。CDCP 1通过将PKC δ募集到Src家族激酶中，通过PKC δ的酪氨酸磷酸化来调节PKC δ的酶活性。Corpine作为PKC δ的CDCP 1依赖性结合伴侣，在胰腺细胞的迁移和侵袭中发挥重要作用，但在ECM降解中不起作用。这些结果表明，CDCP 1表达可能通过促进侵袭和转移在胰腺癌的不良结局中起关键作用，并且阻断CDCP 1的表达、磷酸化或PKC δ结合位点的分子是潜在的治疗候选物。Cancer Res; 70（12）; 5136-46. (C)2010年AACR。
CUB domain-containing protein 1 (CDCP1) is a membrane protein that is highly expressed in several solid cancers. We reported previously that CDCP1 regulates anoikis resistance as well as cancer cell migration and invasion, although the underlying mechanisms have not been elucidated. In this study, we found that expression of CDCP1 in pancreatic cancer tissue was significantly correlated with overall survival and that CDCP1 expression in pancreatic cancer cell lines was relatively high among solid tumor cell lines. Reduction of CDCP1 expression in these cells suppressed extracellular matrix (ECM) degradation by inhibiting matrix metalloproteinase-9 secretion. Using the Y734F mutant of CDCP1, which lacks the tyrosine phosphorylation site, we showed that CDCP1 regulates cell migration, invasion, and ECM degradation in a tyrosine phosphorylation-dependent manner and that these CDCP1-associated characteristics were inhibited by blocking the association of CDCP1 and protein kinase C delta (PKC delta). CDCP1 modulates the enzymatic activity of PKC delta through the tyrosine phosphorylation of PKC delta by recruiting PKC delta to Src family kinases. Cortactin, which was detected as a CDCP1-dependent binding partner of PKC delta, played a significant role in migration and invasion but not in ECM degradation of pancreatic cells. These results suggest that CDCP1 expression might play a crucial role in poor outcome of pancreatic cancer through promotion of invasion and metastasis and that molecules blocking the expression, phosphorylation, or the PKC delta-binding site of CDCP1 are potential therapeutic candidates. Cancer Res; 70(12); 5136-46. (C) 2010 AACR.