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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.

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.

SUBMITTER: Zhang T

PROVIDER: S-EPMC6448091 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common respiratory disease characterized by persistent hypoxemia and an uncontrolled inflammatory response. Valsartan, an angiotensin II type 1 receptor antagonist, is clinically used to treat hypertension and has anti-inflammatory and antioxidant effects on gefitinib-induced pneumonia in rats. However, the potential therapeutic effects of valsartan on lipopolysaccharide (LPS)-induced ALI remain unclear. This study investigated the protective role of valsartan in LPS-induced ALI and its underlying mechanisms. Methods: LPS-treated BEAS-2B cells and ALI mouse model were established. BEAS-2B cells were treated with LPS (10 μg/mL) for 24h, with or without valsartan (20, 40, and 80 µM). For ALI mouse models, LPS (5 mg/kg) was administered through intratracheal injection to treat the mice for 24h, and valsartan (10 or 30 mg/kg) was injected intraperitoneally twice 2 h before and 12 h after the LPS injection. Pulmonary functional parameters were examined by an EMKA pulmonary system. Hematoxylin and eosin staining, flow cytometry, CCK-8 assay, qRT-PCR, ELISA, immunofluorescence, Western blotting, and related commercial kits were used to assess the pathological damage to the lungs, neutrophil recruitment in the lung tissue and bronchoalveolar lavage fluid (BALF), cell viability, inflammation, oxidative activity, and mucus production, respectively. Potential mechanisms were further explored using network pharmacology and Western blotting. Results: Valsartan rescued LPS-reduced cell viability of BEAS-2B cells, improved the pulmonary function, ameliorated pathological lung injury in mice with ALI, ameliorated LPS-induced neutrophil recruitment in BALF and lung tissue of mice, attenuated oxidative stress by increasing the level of SOD and decreasing that of MDA and GSSG, inhibited LPS-induced MUC5AC overproduction, decreased the LPS-induced increase in expression of pro-inflammatory cytokines/chemokines including TNF-α, IL-6, IL-1β, CXCL-1 and CXCL-2, and restored the expression of anti-inflammatory IL-10. Mechanistic studies showed that valsartan inhibits LPS-induced phosphorylation of nuclear factor-kappa B (NF-κΒ) and mitogen-activated protein kinases (MAPKs) including P38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in both LPS-treated cells and the mouse model of ALI. Conclusion: Valsartan protects against LPS-induced ALI by attenuating oxidative stress, reducing MUC5AC production, and attenuating the inflammatory response that may involve MAPK and NF-κΒ pathways.

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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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