MAPK4 facilitates angiogenesis by inhibiting the ERK pathway in non-small cell lung cancer

Cancer Innovation Pub Date : 2024-04-16 DOI:10.1002/cai2.117

Jing Chen, Jing Yang, Yufang Liu, Xu Zhao, Juanjuan Zhao, Lin Tang, Mengmeng Guo, Ya Zhou, Chao Chen, Dongmei Li, Zhenke Wen, Guiyou Liang, Lin Xu

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Abstract

Background

Angiogenesis plays an important role in the occurrence and development of non-small cell lung cancer (NSCLC). The atypical mitogen-activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear.

Methods

Adult male C57BL/6 wild-type mice were randomly divided into the control group and p-siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on.

Results

We found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c-Jun n-terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo.

Conclusion

Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC.

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MAPK4 通过抑制 ERK 通路促进非小细胞肺癌的血管生成

背景血管生成在非小细胞肺癌（NSCLC）的发生和发展中起着重要作用。非典型丝裂原活化蛋白激酶4（MAPK4）已被证明参与了多种疾病的发病机制。然而，MAPK4在NSCLC肿瘤血管生成中的潜在作用仍不清楚。方法将成年雄性 C57BL/6 野生型小鼠随机分为对照组和 p-siMAPK4 干预组。用流式细胞术和免疫荧光染色分析细胞增殖情况。用免疫荧光染色法分析瘤体的血管密度。通过 Western 印迹分析和免疫荧光染色等方法检测 MAPK4 及相关信号分子的表达。结果我们发现，主要在局部内皮细胞（ECs）中表达的 MAPK4 与 NSCLC 肿瘤血管生成相关。此外，沉默 MAPK4 可抑制人脐静脉内皮细胞（HUVECs）的增殖和迁移能力。全基因分析表明，沉默MAPK4改变了与细胞周期和血管生成通路相关的多个基因的表达，沉默MAPK4增加了细胞外调节蛋白激酶1/2（ERK1/2）通路的转导，但没有增加Akt和c-Jun n-末端激酶通路的转导。进一步分析表明，沉默 MAPK4 可抑制在肿瘤细胞上清液中培养的 HUVEC 的增殖和迁移能力，这与 ERK1/2 通路的转导增加有关。临床数据分析表明，MAPK4和CD34的高表达与NSCLC患者的不良预后有关。使用 CD34 启动子驱动的小干扰 RNA 靶向沉默 EC 中的 MAPK4 可有效抑制肿瘤血管生成和 NSCLC 在体内的生长。结论我们的研究结果表明，MAPK4 在 NSCLC 的血管生成和发展过程中发挥着重要作用。因此，MAPK4 可能是治疗 NSCLC 的一个新靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Innovation

CiteScore

0.70

自引率

0.00%

发文量