The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways.
The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways.
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DOI：
10.1371/journal.pone.0032232
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Van Seuningen I
中科院分区：
文献类型：
--
作者：
Jonckheere N;Skrypek N;Merlin J;Dessein AF;Dumont P;Leteurtre E;Harris A;Desseyn JL;Susini C;Frénois F;Van Seuningen I
粘蛋白MUC 4及其膜伴侣ErbB 2致癌受体是人类胰腺肿瘤发展中潜在的相互作用伴侣。然而，它们的运作方式在很大程度上仍然是未知的。在这项工作中，我们的目的是确定的细胞机制和ErbB 2和MUC 4在人胰腺癌细胞系的控制下的细胞内信号通路。使用免疫共沉淀和GST下拉，我们表明，MUC 4和ErbB 2相互作用的人胰腺癌细胞系CAPAN-2通过表皮生长因子结构域MUC 4。产生稳定的细胞克隆，其中MUC 4或ErbB 2通过shRNA方法被敲低（KD）。然后在体外和体内研究这些细胞的生物学特性。我们的研究结果表明，ErbB 2-KD细胞更多的凋亡和较少的增殖（减少细胞周期蛋白D1和增加p27 kip 1的表达），而迁移和侵袭特性没有改变。MUC 4-KD克隆的增殖性较低，细胞周期蛋白D1表达降低，G1期细胞阻滞和ErbB 2/ErbB 3表达改变。它们的迁移性能降低，而侵入性能增加。重要的是，ErbB 2和MUC 4表达的抑制不会损害相同的信号传导途径（MUC 4表达的抑制影响JNK途径，而ErbB 2的抑制改变MAPK途径）。最后，ErbB 2-KD和MUC 4-KD细胞在体内显示出受损的肿瘤生长。我们的研究结果表明，ErbB 2和MUC 4，物理相互作用，激活不同的细胞内信号通路，以调节CAPAN-2胰腺癌细胞的生物学特性。
The mucin MUC4 and its membrane partner the ErbB2 oncogenic receptor are potential interacting partners in human pancreatic tumour development. However, the way they function is still largely unknown. In this work, we aimed to identify the cellular mechanisms and the intracellular signalling pathways under the control of both ErbB2 and MUC4 in a human pancreatic adenocarcinomatous cell line. Using co-immunoprecipitation and GST pull-down, we show that MUC4 and ErbB2 interact in the human pancreatic adenocarcinomatous cell line CAPAN-2 via the EGF domains of MUC4. Stable cell clones were generated in which either MUC4 or ErbB2 were knocked down (KD) by a shRNA approach. Biological properties of these cells were then studied in vitro and in vivo. Our results show that ErbB2-KD cells are more apoptotic and less proliferative (decreased cyclin D1 and increased p27kip1 expression) while migration and invasive properties were not altered. MUC4-KD clones were less proliferative with decreased cyclin D1 expression, G1 cell cycle arrest and altered ErbB2/ErbB3 expression. Their migration properties were reduced whereas invasive properties were increased. Importantly, inhibition of ErbB2 and MUC4 expression did not impair the same signalling pathways (inhibition of MUC4 expression affected the JNK pathway whereas that of ErbB2 altered the MAPK pathway). Finally, ErbB2-KD and MUC4-KD cells showed impaired tumour growth in vivo. Our results show that ErbB2 and MUC4, which interact physically, activate different intracellular signalling pathways to regulate biological properties of CAPAN-2 pancreatic cancer cells.
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影响因子：
6.4
作者：
Kielosto, Mari;Nummela, Pirjo;Hoelttae, Erkki
通讯作者：
Hoelttae, Erkki
影响因子：
8
作者：
Jonckheere, N;Perrais, M;Van Seuningen, I
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Van Seuningen, I
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作者：
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Hirakawa, Kosei
影响因子：
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作者：
Jonckheere N;Skrypek N;Van Seuningen I
通讯作者：
Van Seuningen I