G protein-coupled receptor kinase 6 deficiency promotes angiogenesis, tumor progression, and metastasis.
G protein-coupled receptor kinase 6 deficiency promotes angiogenesis, tumor progression, and metastasis.
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G 蛋白偶联受体激酶 6 缺乏会促进血管生成、肿瘤进展和转移。
DOI：
10.4049/jimmunol.1202058
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发表时间：
2013-05-15
期刊：
影响因子：
--
通讯作者：
Richardson RM
中科院分区：
文献类型：
--
作者：
Raghuwanshi SK;Smith N;Rivers EJ;Thomas AJ;Sutton N;Hu Y;Mukhopadhyay S;Chen XL;Leung T;Richardson RM
G蛋白偶联受体激酶(GRKs)使G蛋白偶联受体(GPCRs)的活化形式磷酸化，导致受体脱敏和下调。我们最近发现，趋化因子受体CXCR2与GRK6偶联，调节细胞反应，包括趋化作用、血管生成和伤口愈合。在这项研究中，我们使用人类肺癌的小鼠模型来研究GRK6在肿瘤发生中的作用。与对照(GRK6+/+)相比，GRK6缺陷小鼠(GRK6GRK6−/−)对Lewis肺癌的生长和转移有显著促进作用。GRK6缺失对原血管生成趋化因子和血管内皮生长因子的表达无影响，但上调基质金属蛋白酶2和9的释放、肿瘤浸润性中性粒细胞和微血管密度。由于βArr2−/−小鼠表现出与GRK6−/−相似的LLC生长和转移增加，我们建立了双重GRK6−/−/βArr2−/−小鼠模型。令人惊讶的是，与GRK6−/−/β−/−或GRK6−/−或βArr2−/−小鼠相比，GRK6 Arr2−/−小鼠的肿瘤生长速度更快。用抗CXCR2抗体处理的小鼠在GRK6−/−和GRK6−/−/βArr2−/−动物体内的肿瘤生长均受到抑制。综上所述，这些结果表明CXCR2与GRK6偶联，调节血管生成、肿瘤进展和转移。GRK6的缺失增加了宿主CXCR2的活性，导致更多的PMN在肿瘤微环境中的渗透和基质金属蛋白酶的释放，从而促进血管生成和转移。由于GRK6−/−/βArr2−/−比GRK6−/−或βArr2−/−小鼠表现出更大的肿瘤生长，数据进一步表明CXCR2偶联不同的机制来介导肿瘤的进展和转移。
G protein coupled receptor kinases (GRKs) phosphorylate the activated form of G protein coupled receptors (GPCRs) leading to receptor desensitization and down-regulation. We have recently shown that the chemokine receptor, CXCR2, couples to GRK6 to regulate cellular responses including chemotaxis, angiogenesis and wound healing. In this study, we investigate the role of GRK6 in tumorigenesis using murine models of human lung cancer. Mice deficient in GRK6 (GRK6−/−) exhibited a significant increase in Lewis lung cancer (LLC) growth and metastasis relative to control littermates (GRK6+/+). GRK6 deletion had no effect on the expression of proangiogenic chemokine or vascular endothelial growth factor (VEGF), but up-regulated matrix metalloproteinase (MMP)-2 and MMP-9 release, tumor-infiltrating PMNs and microvessel density. Since βarr2−/− mice exhibited increase LLC growth and metastasis similar to that of GRK6−/−we developed a double GRK6−/−/βarr2−/− mouse model. Surprisingly, GRK6−/−/βarr2−/− mice exhibited faster tumor growth relative to GRK6−/− or βarr2−/− mice. Treatment of the mice with anti-CXCR2 antibody inhibited tumor growth in both GRK6−/− and GRK6−/−/βarr2−/− animals. Altogether, the results indicate that CXCR2 couples to GRK6 to regulate angiogenesis, tumor progression and metastasis. Deletion of GRK6 increases the activity of the host CXCR2, resulting in greater PMN infiltration and MMP release in the tumor microenvironment thereby promoting angiogenesis and metastasis. Since GRK6−/−/βarr2−/− showed greater tumor growth relative to GRK6−/− or βarr2−/− mice, the data further suggest that CXCR2 couples to different mechanisms to mediate tumor progression and metastasis.
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影响因子：
4.6
作者：
Eck, M;Schmausser, B;Müller-Hermelink, HK
通讯作者：
Müller-Hermelink, HK
影响因子：
4.8
作者：
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4.4
作者：
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Strieter, RM
影响因子：
4.4
作者：
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通讯作者：
Richardson, RM
影响因子：
4.8
作者：
Eichmann, T;Lorenz, K;Quitterer, U
通讯作者：
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