The Wilms' Tumor Gene WT1 - 17AA/- KTS Splice Variant Increases Tumorigenic Activity Through Up-Regulation of Vascular Endothelial Growth Factor in an In Vivo Ovarian Cancer Model.
The Wilms' Tumor Gene WT1 - 17AA/- KTS Splice Variant Increases Tumorigenic Activity Through Up-Regulation of Vascular Endothelial Growth Factor in an In Vivo Ovarian Cancer Model.
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DOI：
10.1016/j.tranon.2014.07.008
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发表时间：
2014-10
影响因子：
5
通讯作者：
Kurachi, Hirohisa
中科院分区：
文献类型：
--
作者：
Yamanouchi, Keiko;Ohta, Tsuyoshi;Liu, Zhiyang;Oji, Yusuke;Sugiyama, Haruo;Shridhar, Viji;Matsumura, Sohei;Takahashi, Toshifumi;Takahashi, Kazuhiro;Kurachi, Hirohisa
Wilms的肿瘤1基因WT1编码一种锌转录因子，参与多种癌症相关过程。在这项研究中，我们试图在体内卵巢癌模型中研究WT1剪接变异体对肿瘤形成活性和生存率的影响。为此，我们建立了稳定的卵巢癌细胞系，该细胞系由慢病毒载体转导，其中包含四个WT1剪接变体(−17AA/−KTS、+17AA/−KTS、−17AA/+KTS和+17AA/+KTS)中的每一个。在小鼠体内接种表达WT1−、17AA/−和KTS的SKOV3ip1细胞，与接种表达对照载体的细胞相比，小鼠的播散性肿瘤重量和腹水产量显著增加。用WT1−、17AA/−和KTS表达细胞接种的小鼠的总体存活时间明显短于接种对照细胞的小鼠(P=0.0115)。免疫印迹分析显示，WT1−、17AA/−和KTS组与对照组相比，血管内皮生长因子的表达明显增加。注射表达WT1−、17AA/−和KTS细胞的小鼠肿瘤中CD31免疫阳性血管数量明显多于对照组小鼠肿瘤。最后，WT1−、17AA/−和KTS组与对照组相比，肿瘤微血管密度显著增加(P<0.05)。用抗血管内皮生长因子抗体(贝伐单抗)治疗可以抑制肿瘤的生长、扩散和腹水的产生，小鼠体内注射了表达WT1−和17AA/−的KTS细胞。在体内卵巢癌模型中，WT1−、17AA/−和KTS的过表达通过上调血管内皮生长因子诱导卵巢癌细胞具有更强的侵袭性。我们的研究结果表明，WT1−和17AA/−可增强卵巢癌的致瘤活性，并可能通过上调卵巢癌中血管内皮生长因子的表达而降低患者的生存期。
The Wilms' tumor 1 gene WT1 encodes a zinc transcription factor involved in a variety of cancer-related processes. In this study, we sought to investigate the effects of WT1 splice variants on tumorigenic activity and survival in an in vivo ovarian cancer model. To this end, we established stable ovarian cancer cell lines transduced with lentiviral constructs containing each of the four WT1 splice variants (− 17AA/− KTS, + 17AA/− KTS, − 17AA/+ KTS, and + 17AA/+ KTS). In mice inoculated intraperitoneally with SKOV3ip1 cells expressing WT1 − 17AA/− KTS, disseminated tumor weights and production of ascites were significantly increased compared with those in mice inoculated with cells expressing the control vector. The overall survival in mice inoulated with WT1 − 17AA/− KTS-expressing cells was significantly shorter than that in mice inoculated with control cells (P = .0115). Immunoblot analysis revealed that WT1 − 17AA/− KTS significantly increased the expression of vascular endothelial growth factor (VEGF) compared with the control. Greater numbers of CD31-immunopositive vessels were observed in tumors from mice injected with cells expressing WT1 − 17AA/− KTS than in tumors from control mice. Finally, WT1 − 17AA/− KTS significantly increased tumor microvessel density compared with that in the control (P < .05). Treatment with anti-VEGF antibody (bevacizumab) inhibited tumor growth, dissemination, and ascites production in mice injected with cells expressing WT1 − 17AA/− KTS. The overexpression of WT1 − 17AA/− KTS induced a more aggressive phenotype in ovarian cancer cells through VEGF up-regulation in an in vivo ovarian cancer model. Our findings indicated that WT1 − 17AA/− KTS enhanced tumorigenic activity and could decreased patient survival through up-regulation of VEGF expression in ovarian cancers.
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影响因子：
8
作者：
Baudry, D;Faussillon, M;Jeanpierre, C
通讯作者：
Jeanpierre, C
影响因子：
64.5
作者：
CALL, KM;GLASER, T;HOUSMAN, DE
通讯作者：
HOUSMAN, DE
影响因子：
4.7
作者：
Hogdall, Estrid V. S.;Christensen, Lise;Hogdall, Claus K.
通讯作者：
Hogdall, Claus K.
影响因子：
158.5
作者：
Burger, Robert A.;Brady, Mark F.;Liang, Sharon X.
通讯作者：
Liang, Sharon X.
影响因子：
4.7
作者：
Hogdall, Estrid V. S.;Christensen, Lise;Hogdall, Claus K.
通讯作者：
Hogdall, Claus K.