Tumor necrosis factor-α and interferon-γ stimulate MUC16 (CA125) expression in breast, endometrial and ovarian cancers through NFκB.
Tumor necrosis factor-α and interferon-γ stimulate MUC16 (CA125) expression in breast, endometrial and ovarian cancers through NFκB.
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DOI：
10.18632/oncotarget.7652
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发表时间：
2016-03-22
期刊：
影响因子：
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通讯作者：
Carson DD
中科院分区：
文献类型：
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作者：
Morgado M;Sutton MN;Simmons M;Warren CR;Lu Z;Constantinou PE;Liu J;Francis LL;Conlan RS;Bast RC Jr;Carson DD
跨膜粘蛋白（Transmembrane mucins，TM）局限于正常上皮细胞的顶端表面。在肿瘤中，TM不仅过度表达，而且失去了极化分布。MUC 16/CA 125是携带CA 125表位的高分子量TM，CA 125表位是人类癌症的众所周知的分子标志物。当单独使用时，低浓度TNFα（2.5 ng/ml）或IFNγ（20 IU/ml）轻度刺激MUC 16 mRNA和蛋白表达;然而，两种细胞因子联合治疗导致多种癌细胞类型中MUC 16 mRNA和蛋白表达的中度（3倍或更少）至较大（> 10倍）刺激，表明这可能是一种全身反应。人类癌症组织微阵列分析表明，MUC 16表达与某些癌症中的TNFα和IFNγ染色强度直接相关。我们发现NFκB是MUC 16细胞因子刺激的重要介质，因为siRNA介导的NFκB/p65敲低大大降低了细胞因子的反应性。最后，我们证明了MUC 16的250 bp近端启动子区含有一个NFκB结合位点，该位点占TNFα应答的很大一部分。开发操纵MUC 16表达的方法可以提供治疗其生长或转移特征在于TM（包括MUC 16）水平升高的癌症的新方法。
Transmembrane mucins (TMs) are restricted to the apical surface of normal epithelia. In cancer, TMs not only are over-expressed, but also lose polarized distribution. MUC16/CA125 is a high molecular weight TM carrying the CA125 epitope, a well-known molecular marker for human cancers. MUC16 mRNA and protein expression was mildly stimulated by low concentrations of TNFα (2.5 ng/ml) or IFNγ (20 IU/ml) when used alone; however, combined treatment with both cytokines resulted in a moderate (3-fold or less) to large (> 10-fold) stimulation of MUC16 mRNA and protein expression in a variety of cancer cell types indicating that this may be a general response. Human cancer tissue microarray analysis indicated that MUC16 expression directly correlates with TNFα and IFNγ staining intensities in certain cancers. We show that NFκB is an important mediator of cytokine stimulation of MUC16 since siRNA-mediated knockdown of NFκB/p65 greatly reduced cytokine responsiveness. Finally, we demonstrate that the 250 bp proximal promoter region of MUC16 contains an NFκB binding site that accounts for a large portion of the TNFα response. Developing methods to manipulate MUC16 expression could provide new approaches to treating cancers whose growth or metastasis is characterized by elevated levels of TMs, including MUC16.