The contributions of HIF-target genes to tumor growth in RCC.
The contributions of HIF-target genes to tumor growth in RCC.
复制标题
DOI：
10.1371/journal.pone.0080544
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Zhang T;Niu X;Liao L;Cho EA;Yang H
绝大多数肾透明细胞癌中存在VHL基因的体细胞突变或表达缺失，是导致肾癌发生的重要原因。在没有VHL的情况下，组成型活性转录因子HIF是强致癌的，并且对于肿瘤生长是必需的。然而，单个HIF-反应基因对肿瘤生长的贡献还不清楚。在这项研究中，我们研究了重要的HIF反应基因，如VEGF，CCND 1，ANGPTL 4，EGLN 3，ENO 2，GLUT 1和IGFBP 3在异种移植模型中使用免疫受损的裸鼠肿瘤生长的贡献。我们发现，抑制VEGF或CCND 1会损害肿瘤生长，这表明它们是肿瘤促进基因。我们进一步发现，缺乏ANGPTL 4、EGLN 3或ENO 2表达不会改变肿瘤生长。令人惊讶的是，GLUT 1或IGFBP 3的耗竭显著增加了肿瘤生长，表明它们具有肿瘤抑制功能。IGFBP 3的缺失没有导致IGFIR的明显激活。出乎意料的是，IGF 1 R蛋白的消耗导致IGFBP 3在蛋白和mRNA水平上的显著增加。同时，肿瘤生长大大受损，表明IGFBP 3可能以IGFIR非依赖性方式抑制肿瘤生长。总之，尽管HIF的总体转录活性是强烈的肿瘤促进作用，但每个单独的HIF应答基因的表达可以增强、减少肾癌肿瘤生长或对其没有作用。
Somatic mutations or loss of expression of tumor suppressor VHL happen in the vast majority of clear cell Renal Cell Carcinoma, and it’s causal for kidney cancer development. Without VHL, constitutively active transcription factor HIF is strongly oncogenic and is essential for tumor growth. However, the contribution of individual HIF-responsive genes to tumor growth is not well understood. In this study we examined the contribution of important HIF-responsive genes such as VEGF, CCND1, ANGPTL4, EGLN3, ENO2, GLUT1 and IGFBP3 to tumor growth in a xenograft model using immune-compromised nude mice. We found that the suppression of VEGF or CCND1 impaired tumor growth, suggesting that they are tumor-promoting genes. We further discovered that the lack of ANGPTL4, EGLN3 or ENO2 expression did not change tumor growth. Surprisingly, depletion of GLUT1 or IGFBP3 significantly increased tumor growth, suggesting that they have tumor-inhibitory functions. Depletion of IGFBP3 did not lead to obvious activation of IGFIR. Unexpectedly, the depletion of IGFIR protein led to significant increase of IGFBP3 at both the protein and mRNA levels. Concomitantly, the tumor growth was greatly impaired, suggesting that IGFBP3 might suppress tumor growth in an IGFIR-independent manner. In summary, although the overall transcriptional activity of HIF is strongly tumor-promoting, the expression of each individual HIF-responsive gene could either enhance, reduce or do nothing to the kidney cancer tumor growth.
登录
查看更多内容
癌代谢中的葡萄糖转运蛋白。
影响因子：
3.4
作者：
Adekola K;Rosen ST;Shanmugam M
通讯作者：
Shanmugam M
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
50.3
作者：
Kondo, K;Klco, J;Kaelin, WG
通讯作者：
Kaelin, WG
影响因子：
50.3
作者：
Maranchie, JK;Vasselli, JR;Klausner, RD
通讯作者：
Klausner, RD
影响因子：
11.2
作者：
Huang D;Ding Y;Zhou M;Rini BI;Petillo D;Qian CN;Kahnoski R;Futreal PA;Furge KA;Teh BT
通讯作者：
Teh BT