MYLK4 promotes tumor progression through the activation of epidermal growth factor receptor signaling in osteosarcoma.
MYLK4 promotes tumor progression through the activation of epidermal growth factor receptor signaling in osteosarcoma.
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MYLK4通过激活骨肉瘤中表皮生长因子受体信号传导促进肿瘤进展
DOI：
10.1186/s13046-021-01965-z
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发表时间：
2021-05-12
期刊：
影响因子：
--
通讯作者：
Sun W
中科院分区：
文献类型：
--
作者：
Yang M;Zhang T;Zhang Y;Ma X;Han J;Zeng K;Jiang Y;Wang Z;Wang Z;Xu J;Hua Y;Cai Z;Sun W
骨肉瘤(Osteosaroma，OS)是青少年最常见的原发骨癌，肺转移是OS患者的主要死亡原因。方法我们在靶点数据库中研究了肌球蛋白轻链激酶家族成员在转移和未转移患者中的表达情况，并确定只有肌球蛋白轻链激酶家族成员4(MYLK4)在转移性骨肉瘤患者中有较高的表达。用免疫组织化学(IHC)和Western blotting(WB)对结果进行验证。通过伤口愈合、Transwell和集落形成实验观察MYLK4对OS细胞转移和增殖的影响。通过质谱分析确定了MYLK4的新结合蛋白。组织芯片分析显示MYLK4与pEGFR(Y1068)之间存在相关性。结果肌球蛋白轻链激酶家族成员4(Myosin Light Chain Kinase Family 4，MYLK4)在人OS转移组织中显著上调。MYLK4过表达可促进OS的生长和转移，而沉默MYLK4则导致细胞生长和转移减少。从机制上讲，质谱学分析表明MYLK4与骨肉瘤细胞中的表皮生长因子受体(EGFR)相互作用，并通过EGFR信号通路促进生长和转移。组织芯片分析还显示，MYLK4的表达与pEGFR(Y1068)的表达呈正相关。此外，EGFR抑制剂吉非替尼可部分逆转MYLK4过表达对细胞增殖和转移的影响。结论MYLK4通过激活EGFR信号通路促进OS的生长和转移，有望成为治疗OS的新靶点。
BackgroundOsteosarcoma (OS) is the most common primary bone cancer in adolescents and lung metastasis is the leading cause of death in patients with OS. However, the molecular mechanisms that promote OS growth and metastasis remain unknown.MethodsWe investigated the expression of myosin light chain kinase family members between metastasis and non-metastasis patients in the TARGET database and ensured that only myosin light chain kinase family member 4 (MYLK4) had higher expression in metastatic osteosarcoma patients. Then we confirmed the results by immunohistochemistry (IHC) and Western blotting (WB) of OS tissues. The effect of MYLK4 on the metastasis and proliferation of OS cells was investigated by wound healing, Transwell and colony-formation assays. Mass spectrum analysis was used to ensure the new binding protein of MYLK4. Tissue microarrays analysis was used to show the correlation between MYLK4 and pEGFR (Y1068). A series of in vivo experiments were conducted to reveal the mechanisms by which MYLK4 modulated the metastasis and proliferation of OS.ResultsMyosin Light Chain Kinase Family Member 4 (MYLK4) was significantly upregulated in metastatic human OS tissues. Growth and metastasis of OS could be accelerated by MYLK4 overexpression, whereas silencing MYLK4 expression resulted in decreased cell growth and metastasis. Mechanistically, mass spectrum analysis showed that MYLK4 interacted with the epidermal growth factor receptor (EGFR) in osteosarcoma cells and promoted growth and metastasis via the EGFR signaling pathway. Tissue microarrays analysis also showed that MYLK4 expression had a positive correlation with the expression of pEGFR (Y1068). Moreover, the EGFR inhibitor gefitinib could partially reverse the effect of cell proliferation and metastasis caused by MYLK4 overexpression. Importantly, the combination of MYLK4 and EGFR inhibitors had synergistic effects on growth and metastasis of OS in vitro and in vivo.ConclusionOur results indicate that MYLK4 promotes OS growth and metastasis by activating the EGFR signaling pathway and can be a novel therapeutic target for the treatment of OS patients.
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