Interaction with tumor-associated macrophages promotes PRL-3-induced invasion of colorectal cancer cells via MAPK pathway-induced EMT and NF-κB signaling-induced angiogenesis
Interaction with tumor-associated macrophages promotes PRL-3-induced invasion of colorectal cancer cells via MAPK pathway-induced EMT and NF-κB signaling-induced angiogenesis
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与肿瘤相关巨噬细胞的相互作用通过 MAPK 通路诱导的 EMT 和 NF-κ B 信号诱导的血管生成促进 PRL-3 诱导的结直肠癌细胞侵袭
DOI：
10.3892/or.2019.7049
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发表时间：
2019-05-01
期刊：
影响因子：
4.2
通讯作者：
Chu, Zhonghua
中科院分区：
文献类型：
--
作者：
Zhang, Tao;Liu, Lu;Chu, Zhonghua
再生肝蛋白磷酸酶-3（PRL-3）被认为是转移相关的磷酸酶，与预后不良有关。此外，肿瘤相关巨噬细胞（TAM）参与癌症进展。先前的研究表明PRL-3通过诱导TAM浸润促进侵袭和转移。然而，其潜在机制尚未阐明。在本研究中，蛋白质印迹分析，聚合酶链反应，免疫组化，ELISA，进行小鼠模型实验和功能实验以证实TAM和结肠直肠癌（CRC）细胞之间的相互作用通过激活TAM中的促分裂原活化蛋白激酶（MAPK）途径和上调白细胞介素（IL）-1的表达而诱导CRC细胞中的上皮-间质转化（EMT）相关特征。6和IL-8。IL-6和IL-8的中和作用降低了EMT以及CRC细胞的侵袭和迁移能力。因此，IL-6和IL-8被认为是EMT和CRC侵袭和转移的重要因素。此外，在TAM与过表达PRL-3的CRC细胞共培养后观察到血管生成增加。与大肠癌细胞共培养后，大肠癌细胞中血管内皮生长因子-A表达明显上调，核因子-κ B（NF-κ B）信号通路被激活。此外，注射具有高PRL-3表达水平的CRC细胞的裸鼠倾向于产生更大的异种移植物。过表达PRL-3的异种移植CRC细胞的免疫组织化学结果也证实了异种移植物中MAPK途径的激活。总体而言，这些发现表明PRL-3通过激活TAM中的MAPK通路以启动EMT来促进CRC细胞侵袭和转移，并且PRL-3通过激活CRC细胞中的NF-κ B通路来促进血管生成。
Protein phosphatase of regenerating liver-3 (PRL-3) is considered to be metastasis-associated phosphatase and is associated with a poor prognosis. Additionally, tumor-associated macrophages (TAMs) participate in cancer progression. A previous study demonstrated that PRL-3 promotes invasion and metastasis by inducing TAM infiltration. However, the underlying mechanism has not been elucidated. In the present study, western blot analysis, polymerase chain reaction, immunohistochemistry, ELISA, mouse model experiments and functional experiments were performed to confirm that the interaction between TAMs and colorectal cancer (CRC) cells induced epithelial-mesenchymal transition (EMT)-associated features in CRC cells by activating mitogen-activated protein kinase (MAPK) pathways in TAMs and upregulating the expression of interleukin (IL)-6 and IL-8. The neutralization of IL-6 and IL-8 reduced EMT and the invasive and migratory abilities of CRC cells. Therefore, IL-6 and IL-8 were considered important factors in EMT, and in CRC invasion and metastasis. In addition, increased angiogenesis was observed after TAMs were co-cultured with CRC cells that overexpress PRL-3. Vascular endothelial growth factor-A was significantly upregulated, and the nuclear factor-kappa B (NF-kappa B) signaling pathway was activated in CRC cells after co-culture. Moreover, nude mice injected with CRC cells with high PRL-3 expression levels tended to generate larger xenografts. Immunohistochemistry results from xenografted CRC cells overexpressing PRL-3 also confirmed the activation of MAPK pathways in xenografts. Overall, the findings indicate that PRL-3 promotes CRC cell invasion and metastasis by activating MAPK pathways in TAMs to initiate the EMT, and PRL-3 promotes angiogenesis by activating the NF-kappa B pathway in CRC cells.