Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling
Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling
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DOI：
10.1073/pnas.1320769111
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发表时间：
2014-06-17
影响因子：
11.1
通讯作者：
Chang, Jenny C.
中科院分区：
文献类型：
--
作者：
Dave, Bhuvanesh;Granados-Principal, Sergio;Chang, Jenny C.
我们之前描述了从患者活检中提取的乳腺癌干细胞（BCSCs）的基因标记。选择性shRNA敲低鉴定出核糖体蛋白L39 （RPL39）和髓系白血病因子2 （MLF2）是影响BCSC自我更新的首选候选因子。通过特异性siRNA纳米颗粒在患者来源和人类癌症异种移植物中敲低RPL39和MLF2可减少肿瘤体积和肺转移，同时减少BCSCs。RNA深度测序确定了这两个基因的破坏性突变。这些突变在患者肺转移中得到证实（n = 53），并且与较短的肺转移中位时间有统计学关联。这两个基因都影响一氧化氮合酶途径，并因缺氧而改变。这些发现支持原发性癌症存在广泛的肿瘤异质性；与茎样特性相关的不同亚群具有增加的转移潜力。
We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knockdown of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging mutations in both genes. These mutations were confirmed in patient lung metastases (n = 53) and were statistically associated with shorter median time to pulmonary metastasis. Both genes affect the nitric oxide synthase pathway and are altered by hypoxia. These findings support that extensive tumor heterogeneity exists within primary cancers; distinct subpopulations associated with stem-like properties have increased metastatic potential.