The recently suggested intestinal cancer stem cell marker DCLK1 is an epigenetic biomarker for colorectal cancer - PubMed (original) (raw)

The recently suggested intestinal cancer stem cell marker DCLK1 is an epigenetic biomarker for colorectal cancer

Hege Marie Vedeld et al. Epigenetics. 2014 Mar.

Erratum in

Abstract

Recently, Dclk1 expression was identified to be an intestinal cancer stem cell specific biomarker in mouse models, implicating a potential role for targeting the DCLK1-postive cancer cells as a treatment for colorectal cancer. Using quantitative methylation specific PCR (qMSP) we here demonstrated that the DCLK1 promoter is hypermethylated in the vast majority of colorectal cancers (134/164; 82%), with no methylation in the normal mucosa samples (0/106). We further showed by Affymetrix exon arrays that DCLK1 is significantly downregulated in human colorectal cancer (n = 125) compared with normal colonic mucosa (n = 15), which was further confirmed by real-time RT-PCR of a subgroup of the samples. Additionally, a significant negative correlation was observed between methylation and DCLK1 expression in 74 cancer cell lines derived from 15 different tissues, and gene expression increased significantly after epigenetic drug treatment of initially methylated cancer cell lines. These findings underscore the potential of DCLK1 as a colorectal cancer biomarker for early detection, but may also have clinical implications regarding the previously proposed therapy toward DCLK1-positive cancer cells. This therapy would at best affect the cancer stem cell population, but will, based on the present results, not be efficient to treat the bulk of the tumor.

Keywords: DCLK1; DNA methylation; biomarker; colorectal cancer.

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Figures

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Figure 1. Promoter DNA methylation of DCLK1 in colorectal cancer and normal colonic mucosa. (A) PMR values for colorectal cancer and normal mucosa samples. The scoring threshold is marked by a dotted line (PMR = 9), and outliers are excluded for better visualization (n = 6). (B) ROC curve for DCLK1 in colorectal cancer vs. normal mucosa samples.

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Figure 2. Expression and promoter methylation status of DCLK1. (A) Relative expression of DCLK1 in colorectal cancer (C; n = 50) and normal mucosa (NM; n = 20) samples assessed by three real-time RT-PCR assays. The assay Hs00178027_m1 covers three transcript variants; one with and two without a CpG island in the core promoter, whereas the two assays Hs00973863_m1 and Hs00973865_m1 cover the transcript variant with a CpG island in the core promoter (NM_004734.4). (B) PMR values (red) for DCLK1 (NM_004734.4; assay ID: Hs00973863_m1) and expression values (green) for 74 cell lines derived from 15 different cancer types. The expression levels are displayed as ratios between the median quantity of DCLK1 and the average quantity of the two controls VDAC2 and PES1.

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Figure 3. Relative expression of DCLK1 in cancer cell lines treated with epigenetic drugs. The expression levels are displayed as median fold difference across cell lines treated with TSA (0.5 mM for 12 h; n = 12), AZA (1 mM for 72 h; n = 12) or a combination of both drugs (n = 20) relative to the untreated ones.

References

    1. Giannakis M, Stappenbeck TS, Mills JC, Leip DG, Lovett M, Clifton SW, Ippolito JE, Glasscock JI, Arumugam M, Brent MR, et al. Molecular properties of adult mouse gastric and intestinal epithelial progenitors in their niches. J Biol Chem. 2006;281:11292–300. doi: 10.1074/jbc.M512118200. - DOI - PubMed
    1. May R, Riehl TE, Hunt C, Sureban SM, Anant S, Houchen CW. Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells. 2008;26:630–7. doi: 10.1634/stemcells.2007-0621. - DOI - PubMed
    1. Gerbe F, Brulin B, Makrini L, Legraverend C, Jay P. DCAMKL-1 expression identifies Tuft cells rather than stem cells in the adult mouse intestinal epithelium. Gastroenterology. 2009;137:2179–80, author reply 2180-1. doi: 10.1053/j.gastro.2009.06.072. - DOI - PubMed
    1. Nakanishi Y, Seno H, Fukuoka A, Ueo T, Yamaga Y, Maruno T, Nakanishi N, Kanda K, Komekado H, Kawada M, et al. Dclk1 distinguishes between tumor and normal stem cells in the intestine. Nat Genet. 2013;45:98–103. doi: 10.1038/ng.2481. - DOI - PubMed
    1. Metcalfe C, de Sauvage FJ. A tumor-specific stem cell. Nat Genet. 2013;45:7–9. doi: 10.1038/ng.2502. - DOI - PubMed

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