PTTG1 Oncogene Promotes Tumor Malignancy via Epithelial to Mesenchymal Transition and Expansion of Cancer Stem Cell Population
PTTG1 Oncogene Promotes Tumor Malignancy via Epithelial to Mesenchymal Transition and Expansion of Cancer Stem Cell Population
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DOI：
10.1074/jbc.m111.337428
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发表时间：
2012-06-01
影响因子：
4.8
通讯作者：
Lee, Su-Jae
中科院分区：
文献类型：
--
作者：
Yoon, Chang-Hwan;Kim, Min-Jung;Lee, Su-Jae
乳腺癌患者的预后与转移程度有关。然而，上皮性肿瘤细胞逃离原发肿瘤并在远处定植的机制尚不完全清楚。在这里，我们分析了垂体肿瘤转化基因-1(Pttg1)的表达水平，这是一种相对没有特征的癌蛋白，在患者来源的乳腺癌组织和相应的正常乳腺组织中的表达水平。我们发现，与正常组织相比，Pttg1在乳腺癌患者中的表达水平较高。此外，Pttg1的表达水平与乳腺癌细胞系的恶性程度相关；侵袭性和侵袭性较强的乳腺癌细胞株MDA-MB-231和BT549的Pttg1表达水平高于侵袭性和侵袭性较弱的MCP7和SK-BR3以及正常MCF10A细胞系。通过调节Pttg1的表达水平，我们发现Pttg1通过诱导上皮细胞向间充质细胞的转变而增强了乳腺癌细胞的迁移和侵袭特性，这一点在形态和上皮/间充质细胞标志物的表达模式和转录因子Snail的上调中得到了证明。值得注意的是，Pttg1的下调还通过降低自我更新能力和成瘤能力，同时减少CD44(高)CD24(低)细胞和Sox2的表达，抑制了BT549细胞中的癌症干细胞数量。上调Pttg1的作用则相反，可增加球体形成能力和Sox2的表达。重要的是，Pttg1介导的恶性肿瘤特性至少部分归因于AKT的激活，AKT被认为是癌细胞中EMT和干性的关键调节因素。总之，这些结果表明，Pttg1可能是恶性乳腺癌的一个新的治疗靶点。
The prognosis of breast cancer patients is related to the degree of metastasis. However, the mechanisms by which epithelial tumor cells escape from the primary tumor and colonize at a distant site are not entirely understood. Here, we analyzed expression levels of pituitary tumor-transforming gene-1 (PTTG1), a relatively uncharacterized oncoprotein, in patient-derived breast cancer tissues with corresponding normal breast tissues. We found that PTTG1 is highly expressed in breast cancer patients, compared with normal tissues. Also, PTTG1 expression levels were correlated with the degree of malignancy in breast cancer cell lines; the more migratory and invasive cancer cell lines MDA-MB-231 and BT549 displayed the higher expression levels of PTTG1 than the less migratory and invasive MCP7 and SK-BR3 and normal MCF10A cell lines. By modulating PTTG1 expression levels, we found that PTTG1 enhances the migratory and invasive properties of breast cancer cells by inducing epithelial to mesenchymal transition, as evidenced by altered morphology and epithelial/mesenchymal cell marker expression patterns and up-regulation of the transcription factor Snail. Notably, down-regulation of PTTG1 also suppressed cancer stem cell population in BT549 cells by decreasing self-renewing ability and tumorigenic capacity, accompanying decreasing CD44(high) CD24(low) cells and Sox2 expression. Up-regulation of PTTG1 had the opposite effects, increasing sphere-forming ability and Sox2 expression. Importantly, PTTG1-mediated malignant tumor properties were due, at least in part, to activation of AKT, known to be a key regulator of both EMT and stemness in cancer cells. Collectively, these results suggest that PTTG1 may represent a new therapeutic target for malignant breast cancer.