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

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

doi:10.18632/oncotarget.2393

Parthasarathy Chandrakesan, Naushad Ali + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.2393

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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.

Highlights

More than 80% of colorectal cancer (CRC) is associated with the APC mutation
H&E staining shows that the intestinal epithelium having hyperplastic crypts, polyps, and no sign of dysplasia and/or adenocarcinoma in 12 week old ApcMin/+ mice compared to 30 week old ApcMin/+ mice, which had intramucosal adenocarcinoma with low and high-grade dysplasia
The crypt architecture is distorted with no identifiable crypt structures in the places where we identified adenocarcinoma and high-grade dysplasia (Figure 1B and Supplementary Figure 1A, B, C, D)

Summary

Introduction

More than 80% of colorectal cancer (CRC) is associated with the APC mutation. APC is a tumor suppressor gene that is mutated in patients with familial adenomatous polyposis (FAP) and the majority of sporadic colorectal cancers [1, 2]. Apc mutations in intestinal stem cells may transform these cells and initiate expansion leading to cancer development. Like humans with germline mutations in APC, ApcMin/+ mice have a heterozygous mutation in the Apc gene, predisposing the mice to intestinal and colon tumor development. These mice start developing intestinal polyps by ~4 weeks of age, with progression to dysplasia at 18–21 weeks of age, adenocarcinoma is evident at ~26–34 weeks of age [6,7,8,9].

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