Signal transducer and activator of transcription 3 is required for hypoxia-inducible factor-1alpha RNA expression in both tumor cells and tumor-associated myeloid cells.
Signal transducer and activator of transcription 3 is required for hypoxia-inducible factor-1alpha RNA expression in both tumor cells and tumor-associated myeloid cells.
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DOI：
10.1158/1541-7786.mcr-07-2177
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发表时间：
2008-07
期刊：
影响因子：
--
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Niu G;Briggs J;Deng J;Ma Y;Lee H;Kortylewski M;Kujawski M;Kay H;Cress WD;Jove R;Yu H
缺氧诱导因子1（Hypoxia-inducible factor 1，HIF-1）是一种强有力的致瘤因子。其α亚基（HIF-1α）在正常组织中受到严格调控，在肿瘤中由于缺氧和过度活跃的生长信号通路而升高。尽管对癌细胞中HIF-1α的调节了解很多，但影响由缺氧和致癌信号通路调节的HIF-1α水平的关键分子靶点仍有待确定。此外，肿瘤微环境是否以及如何促进HIF-1α积累尚不清楚。这项研究证明了一种新的机制，通过这种机制，HIF-1α的可用性在肿瘤微环境中的癌细胞和骨髓细胞中受到调节。我们发现在缺氧和生长信号条件下，HIF-1α RNA的表达都需要Stat 3。此外，肿瘤源性骨髓细胞表达的HIF-1α mRNA水平相对于正常组织中的对应物以Stat 3依赖性方式升高。此外，肿瘤环境中非转化细胞中的Stat 3活性影响整个生长肿瘤的HIF-1α RNA表达。与Stat 3在调节HIF-1α RNA转录中的作用一致，Stat 3活性升高会增加HIF-1α启动子活性，并且Stat 3蛋白在转化细胞和生长肿瘤中均与HIF-1α启动子结合。总之，这些发现证明了一种新的模式，通过该模式，HIF-1α不仅在癌细胞中而且在肿瘤相关的炎性细胞中受到调节，这表明Stat 3是抑制由缺氧和过度活跃的生长信号传导途径诱导的HIF-1致癌潜力的重要分子靶点。
Hypoxia-inducible factor 1 (HIF-1) is a potent tumorigenic factor. Its alpha subunit (HIF-1α), which is tightly regulated in normal tissues, is elevated in tumors due to hypoxia and overactive growth signaling pathways. Although much is known about HIF-1α regulation in cancer cells, crucial molecular targets that affect HIF-1α levels modulated by both hypoxia and oncogenic signaling pathways remain to be identified. Additionally, whether and how the tumor microenvironment contributes to HIF-1α accumulation is unclear. This study demonstrates a novel mechanism by which HIF-1α availability is regulated in both cancer cells and in myeloid cells in the tumor microenvironment. We show a requirement of Stat3 for HIF-1α RNA expression under both hypoxia and growth signaling conditions. Furthermore, tumor-derived myeloid cells express elevated levels of HIF-1α mRNA relative to their counterparts from normal tissues in a Stat3-dependent manner. Additionally, Stat3 activity in the non-transformed cells in the tumor milieu impacts HIF-1α RNA expression of the entire growing tumor. Consistent with a role of Stat3 in regulating HIF-1α RNA transcription, elevated Stat3 activity increases HIF-1α promoter activity, and Stat3 protein binds to the HIF-1α promoter in both transformed cells and in growing tumors. Taken together, these findings demonstrate a novel mode by which HIF-1α is regulated not only in cancer cells but also in the tumor associated inflammatory cells, suggesting Stat3 as an important molecular target for inhibiting the oncogenic potential of HIF-1 induced by both hypoxia and overactive growth signaling pathways prevalent in cancer.