HN1 contributes to migration, invasion, and tumorigenesis of breast cancer by enhancing MYC activity.
HN1 contributes to migration, invasion, and tumorigenesis of breast cancer by enhancing MYC activity.
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HN1通过增强MYC活性促进乳腺癌的迁移、侵袭和肿瘤发生
DOI：
10.1186/s12943-017-0656-1
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发表时间：
2017-05-11
期刊：
影响因子：
37.3
通讯作者：
Liu P
中科院分区：
文献类型：
--
作者：
Zhang C;Xu B;Lu S;Zhao Y;Liu P
研究背景HN1在许多肿瘤中表达上调，但HN1在乳腺癌发生发展中的作用及其调控机制尚未得到很好的了解。我们通过乳房形成试验、侧群分析、伤口愈合试验、Transwell试验、软琼脂形成试验和异种移植瘤模型来确定HN1对乳腺癌干细胞的扩增以及乳腺癌的迁移、侵袭和成瘤的影响。为了确定HN1是否调节MYC的表达，我们利用实时定量聚合酶链式反应和Western印迹分析来检测MYC及其靶基因的表达，以确定HN1过表达的乳腺癌细胞中MYC基因被敲除所引起的表型。HN1高表达患者的生存期明显短于HN1低表达患者。在乳腺癌细胞系中，HN1基因的异位过表达不仅促进了乳腺癌干细胞的扩增，而且促进了细胞的迁移、侵袭和肿瘤的发生，而HN1基因的敲除则减弱了这些作用。此外，MYC(也称为c-MYC)水平与HN1水平呈正相关，机制分析表明HN1促进了MYC及其靶基因CDK4、CCND1、p21、CAV1和SFRP1的表达。结论HN1通过上调MYC的表达促进乳腺癌的进展，有可能成为乳腺癌的治疗靶点。
BackgroundHematological and neurological expressed 1 (HN1) is upregulated in many tumors, but the role of HN1 in breast cancer progression and its regulatory mechanism have not been well understood.MethodsTo study the role of HN1 in the initiation and progression of breast cancer, we examined HN1 levels in breast cancer cells and tissues and analyzed the relationship between HN1 levels and patient survival. We used mammosphere formation assay, side population analysis, wound healing assay, transwell assay, soft agar formation assay, and xenografted tumor model to determine the effect of HN1 on the expansion of breast cancer stem cells, and the migration, invasion and tumorigenesis of breast cancer. To determine whether HN1 regulates MYC, we used quantitative real-time PCR and Western blot analysis to assess the expression of MYC and their targeted genes to determine the phenotype caused by knockdown of MYC in breast cancer cell with HN1 overexpression.ResultsIn this study, we found that HN1 was upregulated in breast cancer tissues. Patients with high levels of HN1 expression had significantly shorter survival than those with low HN1 expression. In breast cancer cell line, ectopic overexpression of HN1 not only promoted the expansion of breast cancer stem cells, but also promoted cell migration, invasion, and tumorigenesis, while knockdown of HN1 reduced these effects. Furthermore, there was a positive correlation between MYC (also known as c-MYC) level and HN1 level, mechanism analysis suggested HN1 promoted the expression of MYC and its targeted genes like CDK4, CCND1, p21, CAV1, and SFRP1. Downregulation of MYC abrogated the effect of HN1 overexpression in breast cancer cell lines.ConclusionTaken together, these data reveal that HN1 promotes the progression of breast cancer by upregulating MYC expression, and might be a therapeutic target for breast cancer.