Inhibition of mTOR reduces anal carcinogenesis in transgenic mouse model.
Inhibition of mTOR reduces anal carcinogenesis in transgenic mouse model.
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抑制 mTOR 可减少转基因小鼠模型中的肛门癌发生
DOI：
10.1371/journal.pone.0074888
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kulkarni AB
中科院分区：
文献类型：
--
作者：
Sun ZJ;Zhang L;Zhang W;Hall B;Bian Y;Kulkarni AB
人类肛门鳞状细胞癌（ASCC）的分子机制尚不清楚，越来越多的证据表明ASCC与Akt/mTOR通路的激活有关。在这里，我们描述了一个自发性肛门鳞状细胞癌的小鼠模型，其中的Tgfbr 1和Pten在复层鳞状上皮细胞的联合缺失诱导使用诱导型K14-Cre。组织学分析证实，33.3%的小鼠表现出对ASCC和癌前病变的易感性增加。生物标志物分析表明，Akt通路在Tgfbr 1和Pten双敲除（2cKO）小鼠ASCC中的激活与在人类肛门癌中观察到的相似。使用mTOR受体-雷帕霉素治疗的化学预防实验显著延迟了ASCC肿瘤的发作，并通过降低Akt和S6的磷酸化降低了2cKO小鼠的肿瘤负荷。这是第一个条件性基因敲除小鼠模型，用于研究病毒和细胞因子在肛门癌发生中的作用，而无需致癌物介导的诱导，它将为评估治疗和/或预防此类癌症的新治疗方式提供平台。
The molecular mechanism of human anal squamous cell carcinoma (ASCC) is unclear, and the accumulating evidence indicate association of ASCC with the activation of the Akt/mTOR pathway. Here we describe a mouse model with spontaneous anal squamous cell cancer, wherein a combined deletion of Tgfbr1 and Pten in stratified squamous epithelia was induced using inducible K14-Cre. Histopathologic analyses confirmed that 33.3% of the mice showed increased susceptibility to ASCC and precancerous lesions. Biomarker analyses demonstrated that the activation of the Akt pathway in ASCC of the Tgfbr1 and Pten double knockout (2cKO) mouse was similar to that observed in human anal cancer. Chemopreventive experiments using mTOR inhibitor-rapamycin treatment significantly delayed the onset of the ASCC tumors and reduced the tumor burden in 2cKO mice by decreasing the phosphorylation of Akt and S6. This is the first conditional knockout mouse model used for investigating the contributions of viral and cellular factors in anal carcinogenesis without carcinogen-mediated induction, and it would provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer.
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影响因子：
5.4
作者：
Lee, Jee H.;Lydon, John P.;Kim, Chang H.
通讯作者：
Kim, Chang H.
影响因子：
1.6
作者：
Szmulowicz, Ursula M.;Wu, James S.
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影响因子：
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作者：
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通讯作者：
Kulkarni AB
影响因子：
37.3
作者：
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通讯作者：
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影响因子：
3.7
作者：
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通讯作者：
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