Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells.
Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells.
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DOI：
10.18632/oncotarget.3308
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发表时间：
2015-03-20
期刊：
影响因子：
--
通讯作者：
Batra SK
中科院分区：
文献类型：
--
作者：
Das S;Rachagani S;Torres-Gonzalez MP;Lakshmanan I;Majhi PD;Smith LM;Wagner KU;Batra SK
MUC 16（CA 125）是一种I型跨膜糖蛋白，在包括胰腺癌（PC）在内的多种癌症中上调。然而，羧基末端MUC 16在PC中裂解后产生的存在和作用尚不清楚。我们之前的研究使用了系统的双表位标记的结构域删除羧基末端MUC 16的方法已经证明了17 kDa切割的MUC 16（MUC 16-Cter）的产生。在这里，我们使用MUC 16（F114 HA）的114个羧基末端残基的双表位标记版本（N-末端FLAG-和C-末端HA-标记）证明了MUC 16-Cter在PC中的功能意义。使用F114 HA转染的MiaPaCa-2和T3 M4细胞的体外分析显示，具有细胞凋亡抗性的G2/M期细胞的增殖、运动性和积累增加，这是与癌症干细胞（CSC）相关的特征。这得到了ALDH+ CSC的富集沿着增强的耐药性的支持。从机制上讲，我们证明了MUC 16-Cter的一种新功能，它促进JAK 2的核转位，导致组蛋白-3磷酸化上调干细胞特异性基因LMO 2和NANOG。使用Jak 2 +/+和Jak 2 −/−电池证明了Jak 2依赖性。使用eGFP-荧光素酶标记的细胞，我们证明了MUC 16-Cter在体内增强的致瘤性和转移潜力。综上所述，我们证明MUC 16-Cter介导的CSC富集是PC细胞的致瘤性、转移性和耐药性的部分原因。
MUC16 (CA125) is a type-I transmembrane glycoprotein that is up-regulated in multiple cancers including pancreatic cancer (PC). However, the existence and role of carboxyl-terminal MUC16 generated following its cleavage in PC is unknown. Our previous study using a systematic dual-epitope tagged domain deletion approach of carboxyl-terminal MUC16 has demonstrated the generation of a 17-kDa cleaved MUC16 (MUC16-Cter). Here, we demonstrate the functional significance of MUC16-Cter in PC using the dual-epitope tagged version (N-terminal FLAG- and C-terminal HA-tag) of 114 carboxyl-terminal residues of MUC16 (F114HA). In vitro analyses using F114HA transfected MiaPaCa-2 and T3M4 cells showed enhanced proliferation, motility and increased accumulation of cells in the G2/M phase with apoptosis resistance, a feature associated with cancer stem cells (CSCs). This was supported by enrichment of ALDH+ CSCs along with enhanced drug-resistance. Mechanistically, we demonstrate a novel function of MUC16-Cter that promotes nuclear translocation of JAK2 resulting in phosphorylation of Histone-3 up-regulating stemness-specific genes LMO2 and NANOG. Jak2 dependence was demonstrated using Jak2+/+ and Jak2−/− cells. Using eGFP-Luciferase labeled cells, we demonstrate enhanced tumorigenic and metastatic potential of MUC16-Cter in vivo. Taken together, we demonstrate that MUC16-Cter mediated enrichment of CSCs is partly responsible for tumorigenic, metastatic and drug-resistant properties of PC cells.
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影响因子：
3.8
作者：
Harper LJ;Costea DE;Gammon L;Fazil B;Biddle A;Mackenzie IC
通讯作者：
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影响因子：
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影响因子：
6.2
作者：
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通讯作者：
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