Leptin receptor maintains cancer stem-like properties in triple negative breast cancer cells
Leptin receptor maintains cancer stem-like properties in triple negative breast cancer cells
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DOI：
10.1530/erc-13-0329
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发表时间：
2013-12-01
影响因子：
3.9
通讯作者：
Reizes, Ofer
中科院分区：
文献类型：
--
作者：
Zheng, Qiao;Banaszak, Lauren;Reizes, Ofer
尽管有新的治疗方法，乳腺癌仍然是妇女癌症死亡的第二大原因，这是复发和转移的结果。近年来，已经鉴定出一群具有自我更新能力的癌细胞，称为癌症干细胞（CSCs），被认为是肿瘤复发和转移的基础。我们先前表明，脂肪组织细胞因子LEPTIN在肥胖症中增加，促进CSC在体内的存活。在这里，我们测试的假设，瘦素受体（LEPR），在乳腺癌细胞中表达，是必要的维持CSC样和转移性。我们通过shRNA慢病毒转导沉默LEPR，并确定干细胞自我更新转录因子NANOG，SOX 2和OCT 4（POU 5 F1）的表达受到抑制。LEPR-NANOG信号通路在物种之间是保守的，因为我们可以用小鼠LepR拯救人LEPR沉默细胞中的NANOG表达。使用NANOG启动子GFP报告基因，我们表明LEPR在NANOG启动子活性（GFP+）细胞中富集。在谱系追踪研究中，我们发现GFP + C细胞以对称和不对称的方式分裂。与对照细胞相比，LEPR沉默的MDA-MB-231细胞在形态学上表现出间充质向上皮的转变，E-CADHERIN表达增加，波形蛋白表达降低。最后，LEPR沉默的细胞表现出减少的细胞增殖，在肿瘤球测定中的自我更新，以及在异种移植研究中的肿瘤生长。鉴于NANOG在多种癌症中作为促癌蛋白的出现，这些研究表明，抑制LEPR可能是抑制NANOG从而中和CSC功能的有希望的治疗方法。
Despite new therapies, breast cancer continues to be the second leading cause of cancer mortality in women, a consequence of recurrence and metastasis. In recent years, a population of cancer cells has been identified, called cancer stem cells (CSCs) with self-renewal capacity, proposed to underlie tumor recurrence and metastasis. We previously showed that the adipose tissue cytokine LEPTIN, increased in obesity, promotes the survival of CSCs in vivo. Here, we tested the hypothesis that the leptin receptor (LEPR), expressed in mammary cancer cells, is necessary for maintaining CSC-like and metastatic properties. We silenced LEPR via shRNA lentivirus transduction and determined that the expression of stem cell self-renewal transcription factors NANOG, SOX2, and OCT4 (POU5F1) is inhibited. LEPR-NANOG signaling pathway is conserved between species because we can rescue NANOG expression in human LEPR-silenced cells with the mouse LepR. Using a NANOG promoter GFP reporter, we showed that LEPR is enriched in NANOG promoter active (GFP+) cells. In lineage tracing studies, we showed that the GFP + Ccells divide in a symmetric and asymmetric manner. LEPR-silenced MDA-MB-231 cells exhibit a mesenchymal to epithelial transition morphologically, increased E-CADHERIN and decreased VIMENTIN expression compared with control cells. Finally, LEPR-silenced cells exhibit reduced cell proliferation, self-renewal in tumor sphere assays, and tumor outgrowth in xenotransplant studies. Given the emergence of NANOG as a pro-carcinogenic protein in multiple cancers, these studies suggest that inhibition of LEPR may be a promising therapeutic approach to inhibit NANOG and thereby neutralize CSC functions.