A feed-forward loop between nuclear translocation of CXCR4 and HIF-1α promotes renal cell carcinoma metastasis.
A feed-forward loop between nuclear translocation of CXCR4 and HIF-1α promotes renal cell carcinoma metastasis.
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CXCR4 和 HIF-1α 核易位之间的前馈回路促进肾细胞癌转移。
DOI：
10.1038/s41388-018-0452-4
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Wu Z
中科院分区：
文献类型：
--
作者：
Bao Y;Wang Z;Liu B;Lu X;Xiong Y;Shi J;Li P;Chen J;Zhang Z;Chen M;Wang L;Wu Z
CXC趋化因子受体4（CXCR 4）在肿瘤转移中起重要作用。有研究报道CXCR 4在肾细胞癌（RCC）转移灶中的核定位，认为其与癌转移有关。然而，CXCR 4核定位的潜在机制和临床意义仍然未知。在这里，我们表明，CXCR 4核定位更可能发生在肾细胞癌组织，特别是在转移，并与预后不良。CXCR 4核定位需要其核定位序列（NLS，残基146-RXR-149）。CXCR 4中的NLS突变后，CXCR 4在RCC细胞中的核定位丢失。CXCR 4的核定位在体外和体内均促进RCC的致瘤性。在机制上，我们发现CXCR 4和缺氧诱导因子-1 α（HIF-1α）共定位于RCC细胞中并相互作用。此外，CXCR 4的核定位促进了HIF-1α在核内的聚集，从而促进了HIF-1α下游基因的表达。相反，核HIF-1α促进CXCR 4转录，从而形成前馈环。亚细胞CXCR 4和HIF-1α表达水平是影响肾癌患者预后的独立因素，结合TNM分期可建立肾癌患者预后的预测诺模图。因此，我们的研究结果表明，CXCR 4核转位在RCC转移中起着关键作用，并可能作为预后生物标志物和潜在的治疗靶点。
CXC chemokine receptor 4 (CXCR4) has been suggested to play a critical role in cancer metastasis. Some studies have described CXCR4 nuclear localization in metastatic lesions of renal cell carcinoma (RCC), which has been suggested to be correlated with cancer metastasis. However, the underlying mechanism and clinical significance of CXCR4 nuclear localization remains unknown. Here, we show that CXCR4 nuclear localization is more likely to occur in RCC tissues, especially in metastases, and is associated with poor prognosis. CXCR4 nuclear localization requires its nuclear localization sequence (NLS, residues 146-RPRK-149). After the mutation of NLS in CXCR4, CXCR4 nuclear localization in RCC cells is lost. Nuclear localization of CXCR4 promoted RCC tumorigenicity both in vitro and in vivo. Mechanistically, we found that CXCR4 and hypoxia-inducible factor-1α (HIF-1α) colocalized in RCC cells and interacted with each other. Moreover, CXCR4 nuclear localization promoted nuclear accumulation of HIF-1α, thereby promoting the expression of genes downstream of HIF-1α. Reciprocally, nuclear HIF-1α promoted CXCR4 transcription, thus forming a feed-forward loop. Subcellular CXCR4 and HIF-1α expression levels were independent adverse prognostic factors and could be combined with TNM stage to generate a predictive nomogram of the clinical outcome of patients with RCC. Therefore, our findings indicate that CXCR4 nuclear translocation plays a critical role in RCC metastasis and may serve as a prognostic biomarker and potential therapeutic target.
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通过缺氧对趋化因子受体CXCR4的调节。
DOI：
10.1084/jem.20030267
发表时间：
2003-11-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.8
作者：
Wang, Shang-Chiung;Lin, Jen-Kou;Chang, Shih-Ching
通讯作者：
Chang, Shih-Ching
CXCR4表达的核模式与胃癌患者的总体生存更好。
影响因子：
--
作者：
Nikkhoo B;Jalili A;Fakhari S;Sheikhesmaili F;Fathi F;Rooshani D;Hoseinpour Feizi MA;Nikzaban M
通讯作者：
Nikzaban M
影响因子：
4
作者：
Wang, Linhui;Wang, Liang;Sun, Yinghao
通讯作者：
Sun, Yinghao
CXCR4 依赖于 NMMHC-IIA 的核定位促进肾细胞癌的迁移和侵袭
影响因子：
4.2
作者：
Xu, Zhipeng;Li, Peng;Wang, Linhui
通讯作者：
Wang, Linhui