U0126 inhibits pancreatic cancer progression via the KRAS signaling pathway in a zebrafish xenotransplantation model
U0126 inhibits pancreatic cancer progression via the KRAS signaling pathway in a zebrafish xenotransplantation model
复制标题
在斑马鱼异种移植模型中，U0126 通过 KRAS 信号通路抑制胰腺癌进展。
DOI：
10.3892/or.2015.4019
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发表时间：
2015-08-01
期刊：
影响因子：
4.2
通讯作者：
Wang, Xu
中科院分区：
文献类型：
--
作者：
Guo, Meng;Wei, Huanhuan;Wang, Xu
胰腺癌是最具侵袭性的人类癌症之一，其治疗的药物结果仍然令人失望。合适的动物模型将为新药的研究提供一个有效的平台，而斑马鱼已经成为癌症研究中最有前途和最全面的模型动物之一。本研究采用移植人胰腺癌细胞的斑马鱼异种移植模型，研究胰腺癌细胞的进展和转移，并测定新药U0126在体内的药理作用。我们首先将人胰腺癌细胞注射到斑马鱼幼虫和成年斑马鱼体内，建立了原发性胰腺癌异种移植模型，然后研究了cm - dii标记的人胰腺癌细胞的行为。随后，我们通过评估一种已知的靶向KRAS信号通路的小分子抑制剂U0126来测试该模型在药物筛选中的潜力。KRAS突变细胞表现出显著的增殖和迁移行为，并侵入斑马鱼的血管系统。U0126处理后，斑马鱼幼鱼体内Mia PaCa-2细胞的增殖和迁移受到明显抑制。这些结果表明，斑马鱼异种移植可以作为一种简单有效的工具来筛选和鉴定新的抗胰腺癌化合物。
Pancreatic cancer is one of the most aggressive human cancers, and the pharmaceutical outcomes for its treatment remain disappointing. Proper animal models will provide an efficient platform for investigating novel drugs, and the zebrafish has become one of the most promising and comprehensive model animal in cancer research. In the present study, we used a novel xenograft model in zebrafish by transplanting human pancreatic cancer cells to study the progression and metastasis of pancreatic cancer cells and to assay the pharmacological effects of new drug U0126 in vivo. We first established a primary xenograft model of pancreatic cancer by injecting human pancreatic cancer cells into both live larval and adult zebrafish, and then investigated the behaviors of CM-DiI-labeled human pancreatic cancer cells. Subsequently, we tested the potential of this model for drug screening by evaluating a known small-molecule inhibitor, U0126, which targets the KRAS signaling pathway. Cells with KRAS mutations exhibited significant proliferative and migratory behaviors and invaded the zebrafish vasculature system. In contrast, the proliferation and migration of Mia PaCa-2 cells in zebrafish larvae were substantially repressed following U0126 treatment. These results suggest that zebrafish xeno-transplantation can be used as a simple and efficient tool to screen and identify new anti-pancreatic cancer compounds.