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

Zhang,Tao; Liu,Lu; Lai,Wei; Zeng,Yujie; Xu,Heyang; Lan,Qiusheng; Su,Pengwei; Chu,Zhonghua

doi:10.3892/or.2019.7049

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

Authors:
- Tao Zhang
- Lu Liu
- Wei Lai
- Yujie Zeng
- Heyang Xu
- Qiusheng Lan
- Pengwei Su
- Zhonghua Chu
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Affiliations: Department of Gastrointestinal Surgery, Sun Yat‑Sen Memorial Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510120, P.R. China
Published online on: March 7, 2019 https://doi.org/10.3892/or.2019.7049
Pages: 2790-2802
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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‑κB (NF‑κB) 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‑κB pathway in CRC cells.

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