Oncotarget

Research Papers:

DCLK1 facilitates intestinal tumor growth via enhancing pluripotency and epithelial mesenchymal transition

Parthasarathy Chandrakesan _, Nathaniel Weygant, Randal May, Dongfeng Qu, Harisha R. Chinthalapally, Sripathi M. Sureban, Naushad Ali, Stan A. Lightfoot, Shahid Umar and Courtney W. Houchen

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Oncotarget. 2014; 5:9269-9280. https://doi.org/10.18632/oncotarget.2393

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Abstract

Parthasarathy Chandrakesan1,2, Nathaniel Weygant1, Randal May1,4, Dongfeng Qu1,2, Harisha R. Chinthalapally1, Sripathi M. Sureban1,4, Naushad Ali1, Stan A. Lightfoot3, Shahid Umar5, Courtney W. Houchen1,2,4

1 Department of Medicine, University of Oklahoma Health Sciences center, Oklahoma City, OK 73104, USA

2 OU Cancer Institute, University of Oklahoma Health Sciences center, Oklahoma City, OK 73104, USA

3 Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

4 Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA

5 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA

Correspondence to

Courtney W. Houchen, M.D. e-mail: [email protected]

Key words: Dclk1; self-renewal; pluripotency; EMT; miRNAs; tumorigenesis

Received: August 18, 2014     Accepted: August 21, 2014     Published: September 02, 2014

ABSTRACT

Doublecortin-like kinase 1 (Dclk1) is overexpressed in many cancers including colorectal cancer (CRC) andit 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.


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