B7-H6 Promotes Cell Proliferation, Migration and Invasion of Non-Hodgkin Lymphoma via Ras/MEK/ERK Pathway Based on Quantitative Phosphoproteomics Data
B7-H6 Promotes Cell Proliferation, Migration and Invasion of Non-Hodgkin Lymphoma via Ras/MEK/ERK Pathway Based on Quantitative Phosphoproteomics Data
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基于定量磷酸化蛋白质组学数据 B7-H6 通过 Ras/MEK/ERK 通路促进非霍奇金淋巴瘤细胞增殖、迁移和侵袭
DOI：
10.2147/ott.s257512
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发表时间：
2020-06
影响因子：
4
通讯作者：
Xiaoyan Ke
中科院分区：
文献类型：
--
作者：
Siyuan Yang;Lei Yuan;Yanfang Wang;Mingxia Zhu;Jing Wang;Xiaoyan Ke
目的 B7 同源物 6 (B7-H6) 在多种癌细胞中被发现处于上调水平，并被确定与较差的临床特征呈正相关。然而，在非霍奇金淋巴瘤 (NHL) 中，B7-H6 的作用及其潜在作用机制仍不清楚。本研究旨在通过体内和体外实验探讨B7-H6在NHL中的调控机制，以提供可能应用于临床实践的新治疗策略。方法采用免疫组化方法比较B7-H6在T淋巴细胞淋巴瘤（TLBL）、弥漫性大B细胞淋巴瘤（DLBCL）和淋巴结反应性增生（LRH）组织中的表达情况。通过Western blot筛选了10个NHL细胞系，以评估B7-H6的表达。使用移植肿瘤小鼠模型在体内研究 B7-H6 敲低对 NHL 细胞的细胞增殖、迁移和侵袭的影响，并在体外通过细胞计数试剂盒-8 (CCK-8) 和 Transwell 测定进行研究。通过定量磷酸化蛋白质组学来鉴定 B7-H6 影响的蛋白质磷酸化及相关通路的变化。通过 B7-H6 过表达和通路抑制剂测定验证了 B7-H6 对 NHL 的影响。结果NHL细胞系、TLBL、DLBCL组织中B7-H6的表达水平较对照组显着升高。在敲除 B7-H6 的 Jurkat 和 Raji 细胞中观察到细胞增殖、迁移和侵袭受到抑制。通过体内实验进一步验证了B7-H6促进肿瘤发生的能力。此外，通过定量磷酸化蛋白质组学分析，B7-H6 显着影响 Ras 和 HIF-1 信号通路。 Western blot分析证实B7-H6敲除后Ras/MEK/ERK通路受到显着抑制。引人注目的是，MEK抑制剂AZD8330被发现能够充分抑制Ras/MEK/ERK通路，部分逆转细胞增殖并完全逆转B7-H6诱导的细胞迁移和侵袭。结论 B7-H6通过Ras/MEK/ERK通路促进NHL细胞增殖、迁移和侵袭。因此，B7-H6或Ras/MEK/ERK通路靶向可作为治疗NHL的潜在疗法。
Purpose B7 homologue 6 (B7-H6) has been found at an up-regulated level in multiple cancer cells and identified to be positively correlated with inferior clinical features. In non-Hodgkin lymphoma (NHL), however, the roles of B7-H6 and the underlying mechanism of action remain unclear. Through in vivo and in vitro experiments, the aim of this study was to explore the regulatory mechanism of B7-H6 in NHL in order to provide new therapeutic strategies that can potentially be applied in clinical practice. Methods The expression of B7-H6 in T-lymphoblastic lymphoma (TLBL), diffuse large B cell lymphoma (DLBCL) and lymph node reactive hyperplasia (LRH) tissues were compared by immunohistochemistry. A total of 10 NHL cell lines were screened by Western blot to evaluate the expression of B7-H6. The effects of B7-H6 knockdown on cell proliferation, migration and invasion of NHL cells were studied in vivo using a transplanted tumor mice model, and in vitro by Cell Counting Kit-8 (CCK-8) and Transwell assays. Quantitative phosphoproteomics was performed to identify the changes of protein phosphorylation and related pathways affected by B7-H6. The effects of B7-H6 on NHL were validated via B7-H6 overexpression and pathway inhibitor assays. Results The expression levels of B7-H6 in NHL cell lines, and TLBL and DLBCL tissues were significantly increased compared with those in the control groups. Inhibition of cell proliferation, migration and invasion was observed in Jurkat and Raji cells with B7-H6 knockdown. The ability of B7-H6 in promoting tumorigenesis was further validated by in vivo experiments. In addition, Ras and HIF-1 signaling pathways were shown to be significantly affected by B7-H6 through quantitative phosphorylation proteomics analysis. Ras/MEK/ERK pathway was verified to be significantly inhibited after B7-H6 knockdown by Western blot analysis. Strikingly, MEK inhibitor AZD8330 was found to have the ability to sufficiently inhibit Ras/MEK/ERK pathway, partially reverse cell proliferation and completely reverse cell migration and invasion induced by B7-H6. Conclusion B7-H6 promotes cell proliferation, migration and invasion in NHL via Ras/MEK/ERK pathway. Hence, B7-H6 or Ras/MEK/ERK pathway targeting may be used as potential therapeutics for treating NHL.
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细胞外调节的激酶：从RAS到ERK底物的信号传导以控制生物学结果。
影响因子：
--
作者：
Eblen ST
通讯作者：
Eblen ST
DOI：
10.1007/978-3-642-02202-9_346
发表时间：
2012
期刊：
--
影响因子：
--
作者：
H. S. Nicholson
通讯作者：
H. S. Nicholson
影响因子：
6.4
作者：
Specht, Elisa;Kaemmerer, Daniel;Lupp, Amelie
通讯作者：
Lupp, Amelie
影响因子：
4
作者：
SCHLESSINGER, J
通讯作者：
SCHLESSINGER, J
影响因子：
4.3
作者：
Matsuki E;Younes A
通讯作者：
Younes A