Upregulation of neutrophil gelatinase-associated lipocalin by ErbB2 through nuclear factor-kappaB activation.
Upregulation of neutrophil gelatinase-associated lipocalin by ErbB2 through nuclear factor-kappaB activation.
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DOI：
10.1158/0008-5472.can-09-2483
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Yu D
中科院分区：
文献类型：
--
作者：
Li SH;Hawthorne VS;Neal CL;Sanghera S;Xu J;Yang J;Guo H;Steeg PS;Yu D
ErbB2（HER2，neu）是一种受体酪氨酸激酶，在约 25% 的浸润性乳腺癌中过度表达。中性粒细胞明胶酶相关脂质运载蛋白 (NGAL) 是一种分泌型糖蛋白，在包括乳腺癌在内的多种癌症中表达。 NGAL 可以抑制红细胞生成，导致贫血。贫血通常发生在癌症患者中，并对生活质量产生负面影响。然而，目前癌症相关贫血的治疗存在潜在的并发症。尽管 ErbB2 和 NGAL 表达之间的关系尚不清楚，但 ErbB2、NGAL 和贫血均与乳腺癌患者转移增加和预后不良相关。在这里，我们使用体外乳腺癌细胞系和体内携带由小鼠乳腺肿瘤病毒（MMTV-neu）驱动的激活的c-neu癌基因的转基因小鼠，证明ErbB2过度表达导致NGAL上调，这依赖于核因子κB（NF-κB）活性。 MMTV-neu 转基因小鼠在肿瘤发生后出现贫血，并且 NF-κB 抑制剂和 ErbB2 靶向治疗可以部分阻止贫血进展。综上所述，ErbB2通过NF-κB激活上调NGAL参与癌症相关贫血，ErbB2、NF-κB、NGAL通路可能作为癌症相关贫血的潜在治疗靶点。
ErbB2 (HER2, neu) is a receptor tyrosine kinase overexpressed in about 25% of invasive breast carcinomas. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted glycoprotein expressed in a variety of cancers including breast carcinomas. NGAL can inhibit erythroid cell production leading to anemia. Anemia usually occurs in cancer patients and negatively impacts quality of life. However, current treatment for cancer-related anemia has potential complications. ErbB2, NGAL, and anemia have all been associated with increased metastasis and poor prognosis in breast cancer patients, although the relationship between ErbB2 and NGAL expression is not clear. Here, using breast cancer cell lines in vitro and transgenic mice carrying the activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV-neu) in vivo, we demonstrate that ErbB2 overexpression leads to NGAL upregulation, which is dependent on nuclear factor kappa B (NF-κB) activity. MMTV-neu transgenic mice developed anemia after tumor onset, and anemia progression could be partially arrested by an NF-κB inhibitor and an ErbB2-targeted therapy. Taken together, upregulation of NGAL by ErbB2 through NF-κB activation is involved in cancer-related anemia, and ErbB2, NF-κB, NGAL pathway may serve as potential therapeutic targets for cancer-related anemia.