Cyclosporine a mediates pathogenesis of aggressive cutaneous squamous cell carcinoma by augmenting epithelial-mesenchymal transition: role of TGFβ signaling pathway.
Cyclosporine a mediates pathogenesis of aggressive cutaneous squamous cell carcinoma by augmenting epithelial-mesenchymal transition: role of TGFβ signaling pathway.
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DOI：
10.1002/mc.20744
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发表时间：
2011-07
影响因子：
4.6
通讯作者：
Athar, Mohammad
中科院分区：
文献类型：
--
作者：
Walsh, Stephanie B.;Xu, Jianmin;Xu, Hui;Kurundkar, Ashish R.;Maheshwari, Akhil;Grizzle, William E.;Timares, Laura;Huang, Conway C.;Kopelovich, Levy;Elmets, Craig A.;Athar, Mohammad
关键词：
器官移植受者 (OTR) 会出现多种侵袭性和转移性非黑色素瘤皮肤癌 (NMSC)。然而，根本机制仍然难以捉摸。采用多种免疫受损的小鼠模型、免疫印迹、免疫组织化学和免疫荧光技术，我们发现，在用免疫抑制药物环孢素 A (CsA) 治疗后，裸鼠体内的人鳞状异种移植肿瘤生长更快，体积明显增大。从 CsA 处理的异种移植物中分离出的肿瘤细胞重新注射后，在裸鼠中继续形成比载体对照更大的肿瘤，并保留了钙调磷酸酶信号抑制的 CsA 特征。当这些肿瘤在 SCID 米色小鼠或接种同源肿瘤细胞的免疫活性小鼠中生长时，获得了类似的结果。一致地，CsA 组中的肿瘤表现出细胞增殖增强和细胞凋亡减少。 CsA治疗动物的肿瘤还表现出增强的上皮间质转化（EMT），其特征是纤连蛋白、α-SMA、波形蛋白、N-钙粘蛋白、MMP-9/-2、snail和twist表达增加，同时E-钙粘蛋白减少。 CsA 处理的异种移植肿瘤表现出 TGFβ1 表达增加和 TGFβ 依赖性信号传导，其特征是核 p-Smad2/3 增加。我们的数据表明，CsA 通过 TGFβ1 信号通路增强调节 EMT 的蛋白表达，从而将皮肤 SCC 的表型改变为侵袭性和侵袭性肿瘤类型，为 OTR 中多个侵袭性和转移性 NMSC 的发育提供至少一种独特的机制。
Organ transplant recipients (OTRs) develop multiple aggressive and metastatic non-melanoma skin cancers (NMSCs). Yet, the underlying mechanism remains elusive. Employing a variety of immune-compromised murine models, immunoblotting, immunohistochemical and immunofluorescence techniques, we show that human squamous xenograft tumors in nude mice grow faster and become significantly larger in size following treatment with the immunosuppressive drug, cyclosporine A (CsA). Re-injected tumor cells isolated from CsA-treated xenografts continued to form larger tumors in nude mice than those from vehicle-controls and retained the CsA-signatures of calcineurin signaling inhibition. Similar results were obtained when these tumors were grown in SCID-beige mice or in immuno-competent mice inoculated with syngeinic tumor cells. Consistently, tumors in the CsA group manifested enhanced cellular proliferation and decreased apoptosis. Tumors in CsA-treated animals also showed an augmented epithelial-mesenchymal transition (EMT) characterized by an increased expression of fibronectin, α-SMA, vimentin, N-cadherin, MMP-9/-2, snail and twist with a concomitant decrease in E-cadherin. CsA-treated xenograft tumors manifested increased TGFβ1 expression and TGFβ-dependent signaling characterized by increased nuclear p-Smad2/3. Our data demonstrate that CsA alters the phenotype of skin SCCs to an invasive and aggressive tumor-type by enhancing expression of proteins regulating EMT acting through the TGFβ1 signaling pathway providing at least one unique mechanism by which multiple aggressive and metastatic NMSCs develop in OTRs.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
5.5
作者：
Gafter-Gvili, A;Sredni, B;Kalechman, Y
通讯作者：
Kalechman, Y
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DOI：
10.1126/science.1114233
发表时间：
2005-09-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
O'Donovan P;Perrett CM;Zhang X;Montaner B;Xu YZ;Harwood CA;McGregor JM;Walker SL;Hanaoka F;Karran P
通讯作者：
Karran P
DOI：
10.1124/jpet.104.072421
发表时间：
2004-12-01
影响因子：
3.5
作者：
Iwamura, H;Sato, M;Wakitani, K
通讯作者：
Wakitani, K
影响因子：
64.5
作者：
Horsley, Valerie;Aliprantis, Antonios O.;Fuchs, Elaine
通讯作者：
Fuchs, Elaine