Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells.
Novel anti-metastatic action of cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in HPV tumor cells.
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DOI：
10.1371/journal.pone.0005018
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Vozenin-Brotons MC
中科院分区：
文献类型：
--
作者：
Amine A;Rivera S;Opolon P;Dekkal M;Biard DS;Bouamar H;Louache F;McKay MJ;Bourhis J;Deutsch E;Vozenin-Brotons MC
宫颈癌的发生与HPV感染有关。E6和E7 HPV癌蛋白的表达是其致癌性的关键因素，也可能影响其毒力，包括转移转化。参与转移扩散的细胞机制仍然难以捉摸，但促粘附受体及其配体，如SDF-1α和CXCR 4都有牵连。在本研究中，我们评估了SDF-1α/CXCR 4信号传导、E6/E7状态和转移过程之间的可能关系。我们发现SDF-1α通过CXCR 4和随后的Rho/ROCK激活刺激了E6/E7阳性癌细胞系（HeLa和TC-1）在Matrigel中的侵袭。在TC-1细胞IV注射产生的肺转移灶中，高比例的细胞表达膜相关CXCR 4。在这两种情况下，模型（体外和体内）细胞粘附和侵袭被CXCR 4免疫阻断消除，支持SDF-1α/CXCR 4对转移过程的贡献。使用稳定敲除和批准的抗病毒剂，西多福韦使E6和E7沉默，降低CXCR 4基因表达以及组成型和SDF-1α诱导的细胞侵袭。此外，西多福韦抑制肺转移（粘附和侵袭），支持E6和E7癌蛋白对转移过程的贡献。最后，研究了激活下游SDF-1α/CXCR 4并参与表达E6/E7的肿瘤细胞肺归巢的潜在信号。Rho/ROCK途径的贡献由西多福韦引发的抑制作用提出，并使用Y-27632（小分子ROCK抑制剂）进一步证实。这些数据表明，一种新的和高度可转化的治疗方法，宫颈癌，通过抑制粘附和侵袭循环HPV阳性肿瘤细胞，使用西多福韦和/或ROCK抑制。
Cervical cancer is frequently associated with HPV infection. The expression of E6 and E7 HPV oncoproteins is a key factor in its carcinogenicity and might also influence its virulence, including metastatic conversion. The cellular mechanisms involved in metastatic spread remain elusive, but pro-adhesive receptors and their ligands, such as SDF-1α and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1α/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1α stimulated the invasion of E6/E7-positive cancer cell lines (HeLa and TC-1) in Matrigel though CXCR4 and subsequent Rho/ROCK activation. In pulmonary metastatic foci generated by TC-1 cells IV injection a high proportion of cells expressed membrane-associated CXCR4. In both cases models (in vitro and in vivo) cell adhesion and invasion was abrogated by CXCR4 immunological blockade supporting a contribution of SDF-1α/CXCR4 to the metastatic process. E6 and E7 silencing using stable knock-down and the approved anti-viral agent, Cidofovir decreased CXCR4 gene expression as well as both, constitutive and SDF-1α-induced cell invasion. In addition, Cidofovir inhibited lung metastasis (both adhesion and invasion) supporting contribution of E6 and E7 oncoproteins to the metastatic process. Finally, potential signals activated downstream SDF-1α/CXCR4 and involved in lung homing of E6/E7-expressing tumor cells were investigated. The contribution of the Rho/ROCK pathway was suggested by the inhibitory effect triggered by Cidofovir and further confirmed using Y-27632 (a small molecule ROCK inhibitor). These data suggest a novel and highly translatable therapeutic approach to cervix cancer, by inhibition of adhesion and invasion of circulating HPV-positive tumor cells, using Cidofovir and/or ROCK inhibition.
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影响因子：
3.1
作者：
Andrei, G;Snoeck, R;De Clercq, E
通讯作者：
De Clercq, E
影响因子：
45.3
作者：
Lai, Chyong-Huey;Chang, Chee-Jen;Chang, Ting-Chieh
通讯作者：
Chang, Ting-Chieh
影响因子：
14.9
作者：
Biard, D. S. F.
通讯作者：
Biard, D. S. F.
影响因子：
4.8
作者：
Amano, M;Ito, M;Kaibuchi, K
通讯作者：
Kaibuchi, K
影响因子：
8
作者：
Charette, S. T.;McCance, D. J.
通讯作者：
McCance, D. J.