NIDO, AMOP and vWD domains of MUC4 play synergic role in MUC4 mediated signaling.
NIDO, AMOP and vWD domains of MUC4 play synergic role in MUC4 mediated signaling.
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MUC4 的 NIDO、AMOP 和 vWD 结构域在 MUC4 介导的信号传导中发挥协同作用
DOI：
10.18632/oncotarget.14420
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发表时间：
2017-02-07
期刊：
影响因子：
--
通讯作者：
Miao Y
中科院分区：
文献类型：
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作者：
Zhu Y;Zhang JJ;Peng YP;Liu X;Xie KL;Tang J;Jiang KR;Gao WT;Tian L;Zhang K;Xu ZK;Miao Y
众所周知，MUC4 粘蛋白是克服胰腺癌的重要潜在靶点。三个作用不明确的独特结构域（NIDO、AMOP 和 vWD）仅存在于 MUC4 中，但在其他膜结合粘蛋白中未发现。我们前期的研究首次报道其剪接变体MUC4/Y可以作为MUC4（MUC4基因片段超过30KB，太大而无法克隆和真核表达）在胰腺癌中的模型。更重要的是，基于具有适当长度基因序列的MUC4/Y，很容易构建MUC4/Y（MUC4）独特的结构域缺失模型进行研究。本研究重点通过一系列体外测定、基于序列的转录组分析、qRT-PCR和Western blot验证以及系统比较分析，研究独特的NIDO、AMOP和vWD结构域各自的作用或它们对MUC4(MUC4/Y)介导的功能和机制的协同作用。我们的结果表明：1) NIDO、AMOP 和 vWD 结构域或它们的协同作用分别对 MUC4/Y 介导的胰腺癌恶性功能、分子机制下游，特别是 MUC4/Y 触发的恶性肿瘤相关正反馈环发挥重要作用。 2）三个独特结构域对MUC4/Y介导的功能和机制的协同作用比各自的结构域更加突出，因为三个结构域的协同作用对MUC4/Y介导的信号中枢发挥更显着的作用。因此，改善结构域缺失的逆转效应并打破结构域的协同作用将有助于阻断MUC4/Y(MUC4)触发各种致癌信号通路。
MUC4 mucin is well known as an important potential target to overcome pancreatic cancer. Three unique domains (NIDO, AMOP, and vWD) with unclear roles only present in MUC4 but are not found in other membrane-bound mucins. Our previous studies first reported that its splice variant, MUC4/Y can be a model of MUC4 (MUC4 gene fragment is more than 30KB, too huge to clone and eukaryotic express) in pancreatic cancer. More importantly, based on MUC4/Y with the appropriate length of gene sequence, it is easy to construct the unique domain-lacking models of MUC4/Y (MUC4) for research. The present study focuses on investigation of the respective role of the unique NIDO, AMOP, and vWD domain or their synergistic effect on MUC4(MUC4/Y)-mediated functions and mechanisms by series of in vitro assays, sequence-based transcriptome analysis, validation of qRT-PCR & Western blot, and systematic comparative analysis. Our results demonstrate: 1) NIDO, AMOP, and vWD domain or their synergy play significant roles on MUC4/Y-mediated malignant function of pancreatic cancer, downstream of molecule mechanisms, particularly MUC4/Y-triggered malignancy-related positive feedback loops, respectively. 2) The synergistic roles of three unique domains on MUC4/Y-mediated functions and mechanisms are more prominent than the respective domain because the synergy of three domain plays the more remarkable effects on MUC4/Y-mediated signaling hub. Thus, to improve reversed effects of domain-lacking and break the synergism of domains will contribute to block MUC4/Y(MUC4) triggering various oncogenic signaling pathways.