Involvement of Wnt/β-catenin signaling in the mesenchymal stem cells promote metastatic growth and chemoresistance of cholangiocarcinoma.
Involvement of Wnt/β-catenin signaling in the mesenchymal stem cells promote metastatic growth and chemoresistance of cholangiocarcinoma.
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间充质干细胞中 Wnt/β-连环蛋白信号传导的参与促进胆管癌的转移生长和化疗耐药。
DOI：
10.18632/oncotarget.5514
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发表时间：
2015-12-08
期刊：
影响因子：
--
通讯作者：
Song G
中科院分区：
文献类型：
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作者：
Wang W;Zhong W;Yuan J;Yan C;Hu S;Tong Y;Mao Y;Hu T;Zhang B;Song G
间充质干细胞 (MSC) 是多能祖细胞，能够分化成多种谱系，包括骨、软骨、脂肪和肌肉。最近的研究表明，间充质干细胞可以有效地募集到肿瘤部位，调节肿瘤的生长和转移。然而，潜在的分子机制尚未完全了解。在这里，我们首先证明，在异种移植肿瘤模型中，人脐带源间充质干细胞（hUC-MSC）与人胆管癌细胞系 QBC939 混合时，可显着增加癌细胞的增殖和转移能力。当将人参皂苷的主要肠道细菌代谢物化合物K（CK）作为抗癌药物给予异种移植肿瘤小鼠时，间充质干细胞及其条件培养基（MSC-CM）可以提高肿瘤的耐药性。此外，MSC大大增加了胆管癌细胞QBC939和Mz-ChA-1的集落形成和侵袭。胆管癌组织切片和裸鼠移植瘤的免疫化学研究表明，β-catenin的表达对于胆管癌的发生发展具有重要作用。我们进一步证明MSCs和MSCs-CM可以通过靶向Wnt/β-catenin信号通路促进胆管癌细胞的增殖和迁移。 hUC-MSCs或MSCs-CM通过促进β-连环蛋白的核转位来刺激Wnt活性，并上调Wnt靶基因MMPs家族、细胞周期蛋白D1和c-Myc。总之，我们的研究强调了 MSC 在癌症转移中的关键作用，并表明 MSC 通过激活 Wnt/β-catenin 信号传导促进胆管癌细胞的转移生长和化疗耐药。
Mesenchymal stem cells (MSCs) are multi-potent progenitor cells with ability to differentiate into multiple lineages, including bone, cartilage, fat, and muscles. Recent research indicates that MSCs can be efficiently recruited to tumor sites, modulating tumor growth and metastasis. However, the underlying molecular mechanisms are not fully understood. Here, we first demonstrated that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), when mixed with human cholangiocarcinoma cell lines QBC939 in a xenograft tumor model, significantly increased the cancer cells proliferation and metastatic potency. MSCs and their conditioned media (MSC-CM) could improve the drug resistance of tumor when the compound K (CK) as an anti-cancer drug, a major intestinal bacterial metabolite of panaxoside, was administered to xenograft tumor mice. Furthermore, MSCs greatly increased the colony formation and invasion of cholangiocarcinoma cells QBC939 and Mz-ChA-1. Immunochemistry studies of cholangiocarcinoma tissue chips and transplantation tumor from nude mice showed that the expression of β-catenin was important for cholangiocarcinoma development. We further demonstrated that MSCs and MSCs-CM could promote proliferation and migration of cholangiocarcinoma cells through targeting the Wnt/β-catenin signaling pathway. hUC-MSCs or MSCs-CM stimulated Wnt activity by promoting the nuclear translocation of β-catenin, and up-regulated Wnt target genes MMPs family, cyclin D1 and c-Myc. Together, our studies highlight a critical role for MSCs on cancer metastasis and indicate MSCs promote metastatic growth and chemoresistance of cholangiocarcinoma cells via activation of Wnt/β-catenin signaling.