miR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death.
miR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death.
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DOI：
10.1186/1476-4598-12-105
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发表时间：
2013-09-11
期刊：
影响因子：
37.3
通讯作者：
Saluja AK
中科院分区：
文献类型：
--
作者：
Chen Z;Sangwan V;Banerjee S;Mackenzie T;Dudeja V;Li X;Wang H;Vickers SM;Saluja AK
胰腺癌是最致命的人类恶性肿瘤之一，主要由于缺乏有效的可用疗法，所有阶段的5年生存率<5%。癌细胞存活依赖于由抗凋亡蛋白如Mcl-1介导的促存活应答的上调。在这里，我们表明，胰腺肿瘤患者样本中Mcl-1的过度表达与疾病的进展有关。我们先前已经证明雷公藤内酯醇，一种二萜三环氧化物，在体外和体内都有效地杀死胰腺癌细胞。通过siRNA或雷公藤内酯醇处理降低Mcl-1水平导致细胞死亡。使用胰腺癌细胞系，我们已经表明，miR-204，一个假定的调节Mcl-1，被抑制在癌细胞系相比，正常细胞。通过miR-204模拟物或通过雷公藤内酯醇处理的miR-204的过表达导致Mcl-1水平的降低，以及随后的细胞活力的降低。使用荧光素酶报告基因测定，我们证实了miR-204通过直接结合Mcl-1 3' UTR下调Mcl-1的能力。使用用Minnelide（雷公藤甲素的水溶性变体）处理的人异种移植物样品，我们已经表明，与对照肿瘤相比，在处理的肿瘤中miR-204上调，Mcl-1下调。雷公藤内酯醇介导的miR-204增加通过Mcl-1的丢失导致胰腺癌细胞死亡。
Pancreatic cancer is one of the most lethal human malignancies, with an all-stage 5-year survival of <5%, mainly due to lack of effective available therapies. Cancer cell survival is dependent upon up-regulation of the pro-survival response, mediated by anti-apoptotic proteins such as Mcl-1. Here we show that over-expression of Mcl-1 in pancreatic patient tumor samples is linked to advancement of the disease. We have previously shown that triptolide, a diterpene triepoxide, is effective both in vitro and in vivo, in killing pancreatic cancer cells. Decrease of Mcl-1 levels, either by siRNA or by treatment with triptolide results in cell death. Using pancreatic cancer cell lines, we have shown that miR-204, a putative regulator of Mcl-1, is repressed in cancer cell lines compared to normal cells. Over-expression of miR-204, either by a miR-204 mimic, or by triptolide treatment results in a decrease in Mcl-1 levels, and a subsequent decrease in cell viability. Using luciferase reporter assays, we confirmed the ability of miR-204 to down-regulate Mcl-1 by directly binding to the Mcl-1 3’ UTR. Using human xenograft samples treated with Minnelide, a water soluble variant of triptolide, we have shown that miR-204 is up-regulated and Mcl-1 is down-regulated in treated vs. control tumors. Triptolide mediated miR-204 increase causes pancreatic cancer cell death via loss of Mcl-1.
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影响因子：
29.4
作者：
Mujumdar N;Mackenzie TN;Dudeja V;Chugh R;Antonoff MB;Borja-Cacho D;Sangwan V;Dawra R;Vickers SM;Saluja AK
通讯作者：
Saluja AK
DOI：
10.1016/j.jss.2010.03.067
发表时间：
2010-10
期刊：
The Journal of surgical research
影响因子：
--
作者：
Clawson KA;Borja-Cacho D;Antonoff MB;Saluja AK;Vickers SM
通讯作者：
Vickers SM
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.2
作者：
Antonoff, Mara B.;Chugh, Rohit;Saluja, Ashok K.
通讯作者：
Saluja, Ashok K.
影响因子：
4.3
作者：
Ma, Li;Weinberg, Robert A.
通讯作者：
Weinberg, Robert A.