DCLK1 facilitates intestinal tumor growth via enhancing pluripotency and epithelial mesenchymal transition.
DCLK1 facilitates intestinal tumor growth via enhancing pluripotency and epithelial mesenchymal transition.
复制标题
DOI：
10.18632/oncotarget.2393
复制
发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Houchen CW
中科院分区：
文献类型：
--
作者：
Chandrakesan P;Weygant N;May R;Qu D;Chinthalapally HR;Sureban SM;Ali N;Lightfoot SA;Umar S;Houchen CW
双皮质素样激酶1 （Dclk1）在包括结直肠癌（CRC）在内的许多癌症中过表达，并特异性标记肠道肿瘤干细胞。然而，Dclk1在Apc突变条件下肠道肿瘤发生中的作用仍然知之甚少。我们发现，与年轻ApcMin/+小鼠和野生型小鼠相比，老年ApcMin/+小鼠肠上皮中Dclk1表达和Dclk1+细胞显著增加。ApcMin/+小鼠肠上皮细胞表现出增强的多能性、自我更新能力和EMT。此外，mirna失调，onco- mirna的表达显著增加，肿瘤抑制mirna减少。为了支持这些发现，在老年ApcMin/+小鼠中，敲低Dclk1通过降低多能性、EMT和onco- mirna来减轻肠腺瘤和腺癌，这表明Dclk1过表达促进了肠道肿瘤的发生。敲除Dclk1可削弱Dclk1依赖性肠道肿瘤发生过程。本研究表明，Dclk1通过增强Apc突变肠道肿瘤的多能性和EMT因子，在促进肠道肿瘤发生中起关键作用，也为治疗结直肠癌提供了潜在的治疗靶点。
Doublecortin-like kinase 1 (Dclk1) is overexpressed in many cancers including colorectal cancer (CRC) and it specifically marks intestinal tumor stem cells. However, the role of Dclk1 in intestinal tumorigenesis in Apc mutant conditions is still poorly understood. We demonstrate that Dclk1 expression and Dclk1+ cells are significantly increased in the intestinal epithelium of elderly ApcMin/+ mice compared to young ApcMin/+ mice and wild type mice. Intestinal epithelial cells of ApcMin/+ mice demonstrate increased pluripotency, self-renewing ability, and EMT. Furthermore, miRNAs are dysregulated, expression of onco-miRNAs are significantly increased with decreased tumor suppressor miRNAs. In support of these findings, knockdown of Dclk1 in elderly ApcMin/+ mice attenuates intestinal adenomas and adenocarcinoma by decreasing pluripotency, EMT and onco-miRNAs indicating that Dclk1 overexpression facilitates intestinal tumorigenesis. Knocking down Dclk1 weakens Dclk1-dependent intestinal processes for tumorigenesis. This study demonstrates that Dclk1 is critically involved in facilitating intestinal tumorigenesis by enhancing pluripotency and EMT factors in Apc mutant intestinal tumors and it also provides a potential therapeutic target for the treatment of colorectal cancer.
登录
查看更多内容
影响因子：
24.5
作者：
Lewis A;Segditsas S;Deheragoda M;Pollard P;Jeffery R;Nye E;Lockstone H;Davis H;Clark S;Stamp G;Poulsom R;Wright N;Tomlinson I
通讯作者：
Tomlinson I
影响因子：
3.7
作者：
Ali N;Allam H;Bader T;May R;Basalingappa KM;Berry WL;Chandrakesan P;Qu D;Weygant N;Bronze MS;Umar S;Janknecht R;Sureban SM;Huycke M;Houchen CW
通讯作者：
Houchen CW
影响因子：
4.7
作者：
Ritland, SR;Gendler, SJ
通讯作者：
Gendler, SJ
影响因子：
37.3
作者：
Weygant N;Qu D;Berry WL;May R;Chandrakesan P;Owen DB;Sureban SM;Ali N;Janknecht R;Houchen CW
通讯作者：
Houchen CW
影响因子：
10.2
作者：
Sureban SM;May R;Mondalek FG;Qu D;Ponnurangam S;Pantazis P;Anant S;Ramanujam RP;Houchen CW
通讯作者：
Houchen CW