miR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death

Molecular Cancer

Research

Huaizhi Wang¹  Xiaowu Li¹  Selwyn M Vickers²  Ashok K Saluja²  Veena Sangwan²  Sulagna Banerjee²  Vikas Dudeja²  Tiffany Mackenzie²  Zhiyu Chen³ 

[1] Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China;Department of Surgery, University of Minnesota, 55455, Minneapolis, MN, USA;Department of Surgery, University of Minnesota, 55455, Minneapolis, MN, USA;Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China;

关键词: Pancreatic cancer;    miR 204;    Mcl-1;    Triptolide;    Cell death;   

DOI  :  10.1186/1476-4598-12-105

 received in 2013-06-24, accepted in 2013-08-20,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundPancreatic 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.ResultsHere 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.ConclusionTriptolide mediated miR-204 increase causes pancreatic cancer cell death via loss of Mcl-1.

【 授权许可】

Unknown   
© Chen et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.