Maternal Embryonic Leucine Zipper Kinase Promotes Tumor Growth and Metastasis via Stimulating FOXM1 Signaling in Esophageal Squamous Cell Carcinoma
Maternal Embryonic Leucine Zipper Kinase Promotes Tumor Growth and Metastasis via Stimulating FOXM1 Signaling in Esophageal Squamous Cell Carcinoma
复制标题
母体胚胎亮氨酸拉链激酶通过刺激食管鳞状细胞癌中的 FOXM1 信号传导促进肿瘤生长和转移
DOI：
10.3389/fonc.2020.00010
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发表时间：
2020-01-28
影响因子：
4.7
通讯作者：
Xie, Songqiang
中科院分区：
文献类型：
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作者：
Chen, Liang;Wei, Qiuren;Xie, Songqiang
食管鳞状细胞癌是一种常见的胃肠道恶性肿瘤，是世界范围内癌症相关死亡的主要原因之一。然而，由于缺乏有价值的分子治疗靶点，目前尚无临床有效的食管鳞癌靶向治疗药物。本研究旨在探讨母胚亮氨酸拉链激酶（MELK）在食管鳞癌中的生物学功能及其分子机制。检测MELK mRNA和蛋白在食管鳞癌细胞系和临床标本中的表达。采用MTT法、集落形成法和软琼脂法检测细胞增殖和集落形成情况。伤口愈合和transwell实验用于评估肿瘤细胞迁移和侵袭的能力。采用裸鼠皮下移植瘤模型和肺转移模型研究MELK在食管鳞癌细胞致瘤性和转移中的作用。MELK在ESCC细胞系和人样本中观察到高表达，特别是在转移性肿瘤组织中。MELK过表达可促进ESCC细胞增殖、集落形成、迁移和侵袭，并增加MMP-2和MMP-9的表达和酶活性。更重要的是，MELK的增强表达大大加速了体内ESCC细胞的肿瘤生长和肺转移。相比之下，慢病毒shRNA敲低MELK在体外和动物模型中都产生了相反的效果。MELK促进FOXM 1的磷酸化，导致其下游靶点（PLK 1、Cyclin B1和Aurora B）的激活，从而促进ESCC细胞的肿瘤发生和转移。总之，MELK通过激活FOXM 1信号通路增强ESCC细胞的肿瘤发生、迁移、侵袭和转移，表明MELK是ESCC患者的潜在治疗靶点，即使是那些处于晚期的患者。
Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignancy and is one of the most important cause of cancer related mortalities in the world. However, there is no clinically effective targeted therapeutic drugs for ESCC due to lack of valuable molecular therapeutic targets. In the present study, we investigated the biological function and molecular mechanisms of maternal embryonic leucine zipper kinase (MELK) in ESCC. The expression of MELK mRNA and protein was determined in cell lines and clinical samples of ESCC. MTT, focus formation and soft agar assays were carried out to measure cell proliferation and colony formation. Wound healing and transwell assays were used to assess the capacity of tumor cell migration and invasion. Nude mice models of subcutaneous tumor growth and lung metastasis were performed to examine the function of MELK in tumorigenecity and metastasis of ESCC cells. High expression of MELK was observed in ESCC cell line and human samples, especially in the metastatic tumor tissues. Moreover, overexpression of MELK promoted cell proliferation, colony formation, migration and invasion, and increased the expression and enzyme activity of MMP-2 and MMP-9 in ESCC cells. More importantly, enhanced expression of MELK greatly accelerated tumor growth and lung metastasis of ESCC cells in vivo. In contrast, knockdown of MELK by lentiviral shRNA resulted in an opposite effect both in vitro and in animal models. Mechanistically, MELK facilitated the phosphorylation of FOXM1, leading to activation of its downstream targets (PLK1, Cyclin B1, and Aurora B), and thereby promoted tumorigenesis and metastasis of ESCC cells. In conclusion,MELK enhances tumorigenesis, migration, invasion and metastasis of ESCC cells via activation of FOXM1 signaling pathway, suggesting MELK is a potential therapeutic target for ESCC patients, even those in an advanced stage.