Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation.
Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation.
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缺氧通过增强的Notch和MAPK激活促进紫veal黑色素瘤的侵袭。
DOI：
10.1371/journal.pone.0105372
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Eberhart CG
中科院分区：
文献类型：
--
作者：
Asnaghi L;Lin MH;Lim KS;Lim KJ;Tripathy A;Wendeborn M;Merbs SL;Handa JT;Sodhi A;Bar EE;Eberhart CG
低氧诱导因子促进的转录反应与葡萄膜黑色素瘤的转移性扩散有关。我们发现缺氧诱导因子1α (HIF-1α)蛋白在血管化良好的肿瘤区域以及四种在常氧环境下生长的细胞系中表达，因此这一途径可能在氧合良好的葡萄膜黑色素瘤细胞中也很重要。正常缺氧条件下，雷帕霉素可抑制HIF-1α蛋白的积累。正如预期的那样，缺氧（1% pO2）进一步诱导HIF-1α蛋白水平及其靶基因VEGF和LOX。缺氧条件下的生长显著增加了所有5种葡萄膜黑色素瘤细胞系的细胞侵袭，将氧不敏感的HIF-1α突变体引入HIF-1α基线水平较低的Mel285细胞也是如此。相比之下，使用shRNA敲低HIF-1α可显著降低缺氧条件下的生长，并在4个HIF-1α基线水平高的细胞系中降低50%以上的肿瘤侵袭。地高辛阻断HIF-1α蛋白表达可显著抑制正常氧合和缺氧条件下的细胞侵袭。我们发现，缺氧时Notch通路组分，包括Jag1-2配体、Hes1-Hey1靶点和Notch1的胞内结构域，以及Erk1-2和Akt的磷酸化水平均增加。Notch的药理学和遗传学抑制在很大程度上阻断了缺氧诱导的侵袭，Erk1-2活性的药理学抑制也是如此。此外，缺氧导致的Erk1-2和Akt磷酸化的增加通过抑制Notch信号传导而部分降低。我们的研究结果支持了HIF-1α信号在缺氧和常氧条件下促进葡萄膜黑色素瘤细胞侵袭能力的功能重要性，并表明直接或通过阻断Notch或Erk1-2通路的药物靶向HIF-1α通路可以减缓肿瘤的扩散。
The transcriptional response promoted by hypoxia-inducible factors has been associated with metastatic spread of uveal melanoma. We found expression of hypoxia-inducible factor 1α (HIF-1α) protein in well-vascularized tumor regions as well as in four cell lines grown in normoxia, thus this pathway may be important even in well-oxygenated uveal melanoma cells. HIF-1α protein accumulation in normoxia was inhibited by rapamycin. As expected, hypoxia (1% pO2) further induced HIF-1α protein levels along with its target genes VEGF and LOX. Growth in hypoxia significantly increased cellular invasion of all 5 uveal melanoma lines tested, as did the introduction of an oxygen-insensitive HIF-1α mutant into Mel285 cells with low HIF-1α baseline levels. In contrast, HIF-1α knockdown using shRNA significantly decreased growth in hypoxia, and reduced by more than 50% tumor invasion in four lines with high HIF-1α baseline levels. Pharmacologic blockade of HIF-1α protein expression using digoxin dramatically suppressed cellular invasion both in normoxia and in hypoxia. We found that Notch pathway components, including Jag1-2 ligands, Hes1-Hey1 targets and the intracellular domain of Notch1, were increased in hypoxia, as well as the phosphorylation levels of Erk1-2 and Akt. Pharmacologic and genetic inhibition of Notch largely blocked the hypoxic induction of invasion as did the pharmacologic suppression of Erk1-2 activity. In addition, the increase in Erk1-2 and Akt phosphorylation by hypoxia was partially reduced by inhibiting Notch signaling. Our findings support the functional importance of HIF-1α signaling in promoting the invasive capacity of uveal melanoma cells in both hypoxia and normoxia, and suggest that pharmacologically targeting HIF-1α pathway directly or through blockade of Notch or Erk1-2 pathways can slow tumor spread.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
缺氧会增强乳腺癌中的 Notch 信号传导，导致 E-钙粘蛋白表达减少，细胞迁移和侵袭增加。
影响因子：
8.8
作者：
Chen, J.;Imanaka, N.;Chen, J.;Griffin, J. D.
通讯作者：
Griffin, J. D.
影响因子：
16.2
作者：
CORY, AH;OWEN, TC;CORY, JG
通讯作者：
CORY, JG
影响因子：
11.2
作者：
Liu, ZJ;Xiao, M;Herlyn, M
通讯作者：
Herlyn, M