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Archive > Volume 15 Issue 1 > 2023,15(1):94-101. DOI:https://doi.org/10.1016/j.chmed.2022.08.004 Prev Next

紫檀芪通過調(diào)控NE/TSP-1信號(hào)抑制炎癥誘導(dǎo)的黑色素瘤轉(zhuǎn)移

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Pterostilbene supresses inflammation-induced melanoma metastasis by impeding neutrophil elastase-mediated thrombospondin-1 degradation

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    摘要:
    目的：慢性炎癥是促使腫瘤轉(zhuǎn)移的重要因素。紫檀芪（PTE）是白藜蘆醇的二甲基化衍生物，具有抗腫瘤和抗炎活性。本研究旨在探討PTE對(duì)炎癥誘導(dǎo)腫瘤轉(zhuǎn)移的抑制作用及其潛在機(jī)制。 方法：采用脂多糖（LPS）滴鼻和黑色素瘤細(xì)胞（B16）尾靜脈注射的方法建立肺部炎癥誘導(dǎo)腫瘤轉(zhuǎn)移的小鼠模型。PTE連續(xù)給藥4周后，考察小鼠肺指數(shù)、肺表面轉(zhuǎn)移結(jié)節(jié)數(shù)、組織病理以及肺部炎癥因子和中性粒細(xì)胞彈性蛋白酶（NE）的表達(dá)情況。同時(shí)通過體外劃痕實(shí)驗(yàn)和Transwell實(shí)驗(yàn)考察PTE對(duì)NE誘導(dǎo)B16細(xì)胞遷移的影響，采用western blot法檢測(cè)血栓反應(yīng)蛋白-1 （TSP-1）和上皮-間質(zhì)轉(zhuǎn)化（EMT）標(biāo)記物的表達(dá)情況。 結(jié)果：與模型組相比，PTE能顯著抑制肺部炎癥誘導(dǎo)的B16細(xì)胞轉(zhuǎn)移，主要表現(xiàn)為降低小鼠肺指數(shù)、減少肺表面轉(zhuǎn)移結(jié)節(jié)數(shù)，同時(shí)PTE還顯著減輕肺組織的炎細(xì)胞浸潤、下調(diào)炎癥因子TNF-α和IL-6的水平。此外，PTE還能顯著抑制肺組織內(nèi)NE的表達(dá)和酶活，繼而上調(diào)肺組織內(nèi)TSP-1的表達(dá)。體外實(shí)驗(yàn)結(jié)果顯示，PTE在對(duì)細(xì)胞增殖無影響的濃度下能顯著抑制NE誘導(dǎo)的B16細(xì)胞遷移，同時(shí)不僅能抑制NE對(duì)TSP-1的降解，還能逆轉(zhuǎn)NE誘導(dǎo)的vimentin、N-cadherin和E-cadherin的表達(dá)變化。 結(jié)論：PTE能夠阻止炎癥誘導(dǎo)的腫瘤轉(zhuǎn)移，其機(jī)制可能與抑制NE介導(dǎo)的TSP-1降解有關(guān)。

    Abstract:
    Objective: Chronic inflammation plays a fatal role in tumor metastasis. Pterostilbene (PTE) is a natural dimethylated analogue of resveratrol with anticancer and anti-inflammatory activities. This study aimed to investigate the inhibitory effect of PTE on inflammation-associated metastasis and explore the underlying mechanisms. Methods: Lipopolysaccharide (LPS)-induced lung inflammation and melanoma metastasis models were established in mice. After PTE treatment for four weeks, the organ index, histological changes, proinflammatory cytokines, and the expression and activity of neutrophil elastase (NE), a biomarker of neutrophil influx in the lungs, were analysed. Additionally, direct effects of PTE on NE-induced B16 cell migration were explored in wound healing and Transwell assays, and the expression of thrombospondin-1 (TSP-1) and epithelial-mesenchymal transition (EMT) markers were also detected. Results: PTE obviously attenuated the LPS-induced metastasis of circulatory B16 cells to lungs by reducing the number of metastatic nodules on the lung surfaces and the lung weight/body weight ratio. PTE treatment also significantly reduced LPS-activated increase levels of tumor necrosis factor (TNF)-a and interleukin (IL)-6 in the lungs of tumor-bearing mice. In addition, increased expression and enzyme activity of NE and decreased expression of TSP-1 were observed, and these were blocked by PTE. In vitro, PTE at concentrations without cytotoxicity also markedly suppressed NE-triggered B16 cell migration, prevented NE-induced TSP-1 proteolysis and reversed the expression of vimentin, N-cadherin and Ecadherin. Conclusion: PTE could block inflammation-enhanced tumor metastasis, and the underlying mechanism might be associated with the inhibition of NE-mediated TSP-1 degradation.

    關(guān)鍵詞:
    紫檀芪;炎癥;黑色素瘤;轉(zhuǎn)移;中性粒細(xì)胞彈性蛋白酶;血小板反應(yīng)蛋白-1

    Keywords:


    Project Supported:
    This work was supported by the Key Project of Health Commission of Changzhou (No. ZD201911), Applied Basic Research Program of Changzhou Municipal Science and Technology Burean (No. CJ20209014) and Program of Taizhou Municipal Bureau of Science and Technology (No. TZ201831).

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