MUC1/KL-6 expression confers an aggressive phenotype upon myeloma cells
MUC1/KL-6 expression confers an aggressive phenotype upon myeloma cells
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DOI：
10.1016/j.bbrc.2018.11.016
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发表时间：
2018-12-09
影响因子：
3.1
通讯作者：
Okuno, Yutaka
中科院分区：
文献类型：
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作者：
Endo, Shinya;Nishimura, Nao;Okuno, Yutaka
已知唾液酸糖蛋白MUC 1参与各种类型癌症的发病机制。KL-6是MUC 1的表面抗原之一，也是间质性肺炎的标志物。一部分骨髓瘤患者（3.9%）血清KL-6水平升高，但无任何间质性肺炎证据，且其骨髓瘤细胞具有高MUC 1表达。我们建立了一个骨髓瘤细胞系命名为EMM 1从多发性骨髓瘤患者伴有血清KL-6升高。与其他骨髓瘤细胞系相比，EMM 1细胞表达高水平的MUC 1。在EMM 1细胞中，MUC 1的敲低诱导细胞周期停滞在S期和凋亡，表明MUC 1的表达参与EMM 1细胞的加速生长。RNA-seq分析表明MUC 1表达激活了EMM 1细胞中k-ras和TNF α诱导的NF κ B通路。我们将EMM 1细胞皮下注射到Rag 2（-/-）jak 3（-/-）Balb/c小鼠中以建立小鼠异种移植模型。这些小鼠具有侵袭性肿瘤生长，伴随着高血清KL-6水平。此外，在EMM 1细胞中MUC 1敲低导致肿瘤生长受到抑制。这些发现表明，MUC 1是开发用于治疗KL-6（+）骨髓瘤患者的药物的潜在靶点，而EMM 1细胞和EMM 1移植小鼠是开发此类新型药物的有用工具。(C)2018爱思唯尔公司All rights reserved.
The sialic glycoprotein, MUC1, is known to be involved in the pathogenesis of various types of cancers. KL-6 is one of the surface antigens of MUC1 and also a marker of interstitial pneumonitis. A fraction of patients with myeloma (3.9%) have elevated serum KL-6 levels without any evidence of interstitial pneumonitis and their myeloma cells have high MUC1 expression. We established a myeloma cell line designated EMM1 from a patient with multiple myeloma accompanied with elevated serum KL-6. EMM1 cells expressed high levels of MUC1 compared with other myeloma cell lines. Knockdown of MUC1 in EMM1 cells induced cell cycle arrest during S phase and apoptosis, suggesting that the MUC1 expression is involved in accelerated growth of EMM1 cells. RNA-seq analysis suggests that MUC1 expression activates k-ras and TNF alpha-induced NF kappa B pathways in EMM1 cells. We injected EMM1 cells subcutaneously into Rag2(-/-)jak3(-/- )Balb/c mice to establish a mouse xenograft model. These mice had aggressive tumor growth that was accompanied by high serum KL-6 levels. In addition, MUC1 knockdown in EMM1 cells led to inhibited tumor growth. These findings demonstrate that MUC1 serves as a potential target for developing drugs for treatment of patients with KL-6(+) myeloma, and EMM1 cells and EMM1-engrafted mice are useful tools for the development of such novel agents. (C) 2018 Elsevier Inc. All rights reserved.