Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer
Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer
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DOI：
10.4049/jimmunol.172.1.464
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发表时间：
2004-01-01
影响因子：
4.4
通讯作者：
Gabrilovich, D
中科院分区：
文献类型：
--
作者：
Nefedova, Y;Huang, M;Gabrilovich, D
髓系细胞分化异常是癌症的标志之一。然而，这一过程的分子机制仍然难以捉摸。在这项研究中，我们研究了肿瘤衍生因子在髓系细胞向树突状细胞分化过程中对Janus Kinase(JAK)/STAT信号的影响。肿瘤细胞条件培养液可诱导JAK2和STAT3的激活，这与幼稚髓系细胞的聚集有关。JAK2/STAT3活性主要定位于这些髓系细胞，阻止了未成熟髓系细胞向成熟树突状细胞的分化。在去除肿瘤衍生因子后，这种分化得以恢复。STAT3的抑制消除了这些因子对髓系细胞分化的负面影响，而STAT3的过表达重现了肿瘤衍生因子的作用。因此，这是首次证明肿瘤衍生因子可能通过JAK2/STAT3的结构性激活影响肿瘤髓系细胞的分化。
Abnormal differentiation of myeloid cells is one of the hallmarks of cancer. However, the molecular mechanisms of this process remain elusive. In this study, we investigated the effect of tumor-derived factors on Janus kinase (Jak)/STAT signaling in myeloid cells during their differentiation into dendritic cells. Tumor cell conditioned medium induced activation of Jak2 and STAT3, which was associated with an accumulation of immature myeloid cells. Jak2/STAT3 activity was localized primarily in these myeloid cells, which prevented the differentiation of immature myeloid cells into mature dendritic cells. This differentiation was restored after removal of tumor-derived factors. Inhibition of STAT3 abrogated the negative effects of these factors on myeloid cell differentiation, and overexpression of STAT3 reproduced the effects of tumor-derived factors. Thus, this is a first demonstration that tumor-derived factors may affect myeloid cell differentiation in cancer via constitutive activation of Jak2/STAT3.