Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment.
Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment.
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DOI：
10.1016/j.semcancer.2010.12.007
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发表时间：
2011-04
影响因子：
14.5
通讯作者：
Bar-Eli M
中科院分区：
文献类型：
--
作者：
Braeuer RR;Zigler M;Villares GJ;Dobroff AS;Bar-Eli M
与黑色素瘤细胞从放射状生长期（RGP）向垂直生长期（VGP）转变和转移表型相关的分子变化尚未得到很好的定义。然而，一些参与这一过程的基因及其转录调控正在开始被阐明。例如，从RGP到VGP的转换和转移表型与AP-2α转录因子的缺失有关。AP-2α调节c-KIT、MMP-2、VEGF和粘附分子MCAM/MUC18的表达。最近，我们报道了AP-2α还调节两种g蛋白偶联受体（GPCR） PAR-1和PAFR。反过来，凝血酶受体PAR-1调节间隙连接蛋白Connexin-43和肿瘤抑制基因Maspin的表达。PAR-1的激活还会导致IL-8、uPA、VEGF、PDGF等促血管生成因子以及某些整合素的过度表达和分泌。PAR-1还通过磷酸化CREB与PAFR协同调节MCAM/MUC18的表达。这些gpcr的配体凝血酶和PAF是由基质细胞分泌的，这强调了肿瘤微环境在黑色素瘤转移中的重要性。黑色素瘤的转移表型也与CREB/ATF-1的过表达和功能有关。AP-2α缺失和CREB/ATF-1过表达导致MCAM/MUC18过表达，MCAM/MUC18本身通过调节DNA结合-1抑制剂（Id-1）促进黑色素瘤转移。CREB/ATF-1也调节血管生成因子CYR-61。我们最近的数据表明，CREB/ATF-1调节AP-2α的表达，因此，支持CREB是黑色素瘤进展中重要的“主开关”的观点。
The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP) and the metastatic phenotype are not very well defined. However, some of the genes involved in this process and their transcriptional regulation are beginning to be elucidated. For example, the switch from RGP to VGP and the metastatic phenotype is associated with loss of the AP-2α transcription factor. AP-2α regulates the expression of c-KIT, MMP-2, VEGF, and the adhesion molecule MCAM/MUC18. Recently, we reported that AP-2α also regulates two G-protein coupled receptors (GPCR) PAR-1 and PAFR. In turn, the thrombin receptor, PAR-1, regulates the expression of the gap junction protein Connexin-43 and the tumor suppressor gene Maspin. Activation of PAR-1 also leads to overexpression and secretion of proangiogenic factors such as IL-8, uPA, VEGF, PDGF, as well certain integrins. PAR-1 also cooperates with PAFR to regulate the expression of the MCAM/MUC18 via phosphorylation of CREB. The ligands for these GPCRs, thrombin and PAF, are secreted by stromal cells, emphasizing the importance of the tumor microenvironment in melanoma metastasis. The metastatic phenotype of melanoma is also associated with overexpression and function of CREB/ATF-1. Loss of AP-2α and overexpression of CREB/ATF-1 results in the overexpression of MCAM/MUC18 which by itself contributes to melanoma metastasis by regulating the inhibitor of DNA binding-1 (Id-1). CREB/ATF-1 also regulates the angiogenic factor CYR-61. Our recent data indicate that CREB/ATF-1 regulates the expression of AP-2α, thus, supporting the notion that CREB is an important “master switch” in melanoma progression.
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影响因子：
11.4
作者：
Huang, S;Jean, D;Bar-Eli, M
通讯作者：
Bar-Eli, M
影响因子：
9.3
作者：
Elzarrad MK;Haroon A;Willecke K;Dobrowolski R;Gillespie MN;Al-Mehdi AB
通讯作者：
Al-Mehdi AB
DOI：
10.1093/jnci/djm279
发表时间：
2008-01-16
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Gray, Michael J.;Van Buren, George;Ellis, Lee M.
通讯作者：
Ellis, Lee M.
影响因子：
4.8
作者：
Axelrad, TW;Deo, DD;Hunt, JD
通讯作者：
Hunt, JD
DOI：
10.1073/pnas.92.18.8205
发表时间：
1995-08-29
影响因子：
11.1
作者：
BROMBERG, ME;KONIGSBERG, WH;GAREN, A
通讯作者：
GAREN, A