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Dclk1, a tumor stem cell marker, regulates pro-survival signaling and self-renewal of intestinal tumor cells

Overview of attention for article published in Molecular Cancer, February 2017
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Title
Dclk1, a tumor stem cell marker, regulates pro-survival signaling and self-renewal of intestinal tumor cells
Published in
Molecular Cancer, February 2017
DOI 10.1186/s12943-017-0594-y
Pubmed ID
Authors

Parthasarathy Chandrakesan, Jiannan Yao, Dongfeng Qu, Randal May, Nathaniel Weygant, Yang Ge, Naushad Ali, Sripathi M. Sureban, Modhi Gude, Kenneth Vega, Eddie Bannerman-Menson, Lijun Xia, Michael Bronze, Guangyu An, Courtney W. Houchen

Abstract

More than 80% of intestinal neoplasia is associated with the adenomatous polyposis coli (APC) mutation. Doublecortin-like kinase 1 (Dclk1), a kinase protein, is overexpressed in colorectal cancer and specifically marks tumor stem cells (TSCs) that self-renew and increased the tumor progeny in Apc (Min/+) mice. However, the role of Dclk1 expression and its contribution to regulating pro-survival signaling for tumor progression in Apc mutant cancer is poorly understood. We analyzed DCLK1 and pro-survival signaling gene expression datasets of 329 specimens from TCGA Colon Adenocarcinoma Cancer Data. The network of DCLK1 and pro-survival signaling was analyzed utilizing the GeneMANIA database. We examined the expression levels of Dclk1 and other stem cell-associated markers, pro-survival signaling pathways, cell self-renewal in the isolated intestinal epithelial cells of Apc (Min/+) mice with high-grade dysplasia and adenocarcinoma. To determine the functional role of Dclk1 for tumor progression, we knocked down Dclk1 and determined the pro-survival signaling pathways and stemness. We used siRNA technology to gene silence pro-survival signaling in colon cancer cells in vitro. We utilized FACS, IHC, western blot, RT-PCR, and clonogenic (self-renewal) assays. We found a correlation between DCLK1 and pro-survival signaling expression. The expression of Dclk1 and stem cell-associated markers Lgr5, Bmi1, and Musashi1 were significantly higher in the intestinal epithelial cells of Apc (Min/+) mice than in wild-type controls. Intestinal epithelial cells of Apc (Min/+) mice showed increased expression of pro-survival signaling, pluripotency and self-renewal ability. Furthermore, the enteroids formed from the intestinal Dclk1(+) cells of Apc (Min/+) mice display higher pluripotency and pro-survival signaling. Dclk1 knockdown in Apc (Min/+) mice attenuates intestinal adenomas and adenocarcinoma, and decreases pro-survival signaling and self-renewal. Knocking down RELA and NOTCH1 pro-survival signaling and DCLK1 in HT29 and DLD1 colon cancer cells in vitro reduced the tumor cells' ability to self-renew and survive. Our results indicate that Dclk1 is essential in advancing intestinal tumorigenesis. Knocking down Dclk1 decreases tumor stemness and progression and is thus predicted to regulate pro-survival signaling and tumor cell pluripotency. This study provides a strong rationale to target Dclk1 as a treatment strategy for colorectal cancer.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 72 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 1%
United States 1 1%
Unknown 70 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 17 24%
Researcher 11 15%
Student > Bachelor 9 13%
Student > Master 8 11%
Student > Doctoral Student 3 4%
Other 12 17%
Unknown 12 17%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 16 22%
Medicine and Dentistry 15 21%
Agricultural and Biological Sciences 13 18%
Immunology and Microbiology 4 6%
Pharmacology, Toxicology and Pharmaceutical Science 2 3%
Other 9 13%
Unknown 13 18%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 11 February 2017.
All research outputs
#20,403,545
of 22,953,506 outputs
Outputs from Molecular Cancer
#1,482
of 1,726 outputs
Outputs of similar age
#356,060
of 420,385 outputs
Outputs of similar age from Molecular Cancer
#37
of 43 outputs
Altmetric has tracked 22,953,506 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,726 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.7. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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We're also able to compare this research output to 43 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.