Stat3 Mediates Expression of Autotaxin in Breast Cancer
Stat3 Mediates Expression of Autotaxin in Breast Cancer
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DOI：
10.1371/journal.pone.0027851
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发表时间：
2011-11-28
期刊：
影响因子：
3.7
通讯作者：
Bromberg, Jacqueline
中科院分区：
文献类型：
--
作者：
Azare, Janeen;Doane, Ashley;Bromberg, Jacqueline
我们确定信号转导子和转录激活子 3 (Stat3) 在 37% 的原发性乳腺肿瘤和 63% 的配对转移性腋窝淋巴结中被酪氨酸磷酸化。对原发性肿瘤中酪氨酸磷酸化（pStat3）分布的检查揭示了肿瘤内的异质表达，在肿瘤边缘的细胞中发现表达水平最高，在肿瘤中心部分的细胞中表达水平相对较低。为了确定可能参与迁移和转移的 Stat3 靶基因，我们鉴定了那些在原发性乳腺癌样本中作为 pStat3 水平函数差异表达的基因。除了已知的 Stat3 转录靶点（Twist、Snail、Tenascin-C 和 IL-8）之外，我们还鉴定出 ENPP2 是一种新的 Stat3 调控基因，它编码自分泌运动因子 (ATX)，这是一种介导乳腺肿瘤发生和癌细胞迁移的分泌型溶血磷脂酶。通过对原发性乳腺癌样本和匹配的腋窝淋巴结以及几种乳腺癌衍生细胞系的免疫组织化学分析，确定了核 pStat3 和 ATX 之间的正相关性。抑制 pStat3 或减少 Stat3 表达会导致 ATX 水平和细胞迁移降低。通过染色质免疫沉淀测定了 Stat3 和 ATX 启动子之间的关联，其中包含许多推定的 Stat3 结合位点。这些观察结果表明，激活的Stat3可能通过ATX的调节来调节乳腺癌细胞的迁移。
We determined that signal transducer and activator of transcription 3 (Stat3) is tyrosine phosphorylated in 37% of primary breast tumors and 63% of paired metastatic axillary lymph nodes. Examination of the distribution of tyrosine phosphorylated (pStat3) in primary tumors revealed heterogenous expression within the tumor with the highest levels found in cells on the edge of tumors with relatively lower levels in the central portion of tumors. In order to determine Stat3 target genes that may be involved in migration and metastasis, we identified those genes that were differentially expressed in primary breast cancer samples as a function of pStat3 levels. In addition to known Stat3 transcriptional targets (Twist, Snail, Tenascin-C and IL-8), we identified ENPP2 as a novel Stat3 regulated gene, which encodes autotaxin (ATX), a secreted lysophospholipase which mediates mammary tumorigenesis and cancer cell migration. A positive correlation between nuclear pStat3 and ATX was determined by immunohistochemical analysis of primary breast cancer samples and matched axillary lymph nodes and in several breast cancer derived cell lines. Inhibition of pStat3 or reducing Stat3 expression led to a decrease in ATX levels and cell migration. An association between Stat3 and the ATX promoter, which contains a number of putative Stat3 binding sites, was determined by chromatin immunoprecipitation. These observations suggest that activated Stat3 may regulate the migration of breast cancer cells through the regulation of ATX.