The role of pluripotency factors to drive stemness in gastrointestinal cancer

Müller, Martin C.; Hermann, Patrick C.; Liebau, Stefan; Weidgang, Clair E.; Seufferlein, Thomas; Kleger, Alexander; Perkhofer, Lukas

doi:10.1016/j.scr.2016.02.005

Cited by 81 publications

(62 citation statements)

References 124 publications

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“…This is supported by the result that knockdown of STRAP reduced the expression of some stem cell markers that are more frequently found in poorly differentiated tumors with poor clinical outcome (Fig. 3A–C) (37,38). Notably, mRNA of CD133 was rescued in HCT116 KD cells, and mRNA of CD44 was rescued in DLD-1 KD cells by NOTCH signaling.…”

Section: Discussionsupporting

confidence: 55%

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

Lin

Yuan

et al. 2017

Cancer Research

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NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer (CRC). Silencing STRAP sensitized CRC cells to chemotherapeutic drugs in vitro and in vivo. STRAP depletion also contributed to a reduced stem-like phenotype of CRC cells, as indicated by reduced expression of the CSC signature and NOTCH signaling regulators in vitro and by diminished tumorigenesis in vivo. Genes encoding some upstream activators of NOTCH were highly enriched for H3K27me3, which form repressive chromatin domains upon STRAP silencing. Mechanistically, STRAP competitively disrupted association of the PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly. Restoring the NOTCH pathway by lentiviral expression of NICD1 or HES1 in STRAP-depleted tumor cells reversed the CSC phenotype. In 90 CRC clinical specimens, a significant positive correlation was documented between the expression of STRAP and HES1. Overall, our findings illuminated a novel STRAP-NOTCH1-HES1 molecular axis as a CSC regulator in CRC, with potential implications to improve treatment of this disease.

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Section: Discussionsupporting

confidence: 55%

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

Lin

Yuan

et al. 2017

Cancer Research

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“…Like normal stem cells, CSCs exhibit self-renewal in a de-differentiated state, pluripotency, but form tumors with a very small number of cells [31]. Four key transcription factors, OCT4 (POU class 5 homeo box 1), KLF4 (Kruppel like factor 4), SOX2 (SRY-box 2), and c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) (OKSM), have been identified as pluripotency genes in CSCs.…”

Section: Resultsmentioning

confidence: 99%

“…Four key transcription factors, OCT4 (POU class 5 homeo box 1), KLF4 (Kruppel like factor 4), SOX2 (SRY-box 2), and c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) (OKSM), have been identified as pluripotency genes in CSCs. OKSM have been shown to induce dysplasia and tumorigenesis in vivo [31–36]. In view of this, we examined the expression of KLF4, Nanog, OCT4, and SOX2 in HCoEpiC in response to DCA/LCA.…”

Section: Resultsmentioning

confidence: 99%

Bile acid: a potential inducer of colon cancer stem cells

Farhana

Nangia‐Makker

Arbit³

et al. 2016

Stem Cell Res Ther

136

100

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BackgroundAlthough the unconjugated secondary bile acids, specifically deoxycholic acid (DCA) and lithocholic acid (LCA), are considered to be risk factors for colorectal cancer, the precise mechanism(s) by which they regulate carcinogenesis is poorly understood. We hypothesize that the cytotoxic bile acids may promote stemness in colonic epithelial cells leading to generation of cancer stem cells (CSCs) that play a role in the development and progression of colon cancer.MethodsNormal human colonic epithelial cells (HCoEpiC) were used to study bile acid DCA/LCA-mediated induction of CSCs. The expression of CSC markers was measured by real-time qPCR. Flow cytometry was used to isolate CSCs. T-cell factor/lymphoid-enhancing factor (TCF/LEF) luciferase assay was employed to examine the transcriptional activity of β-catenin. Downregulation of muscarinic 3 receptor (M3R) was achieved through transfection of corresponding siRNA.ResultsWe found DCA/LCA to induce CSCs in normal human colonic epithelial cells, as evidenced by the increased proportion of CSCs, elevated levels of several CSC markers, as well as a number of epithelial–mesenchymal transition markers together with increased colonosphere formation, drug exclusion, ABCB1 and ABCG2 expression, and induction of M3R, p-EGFR, matrix metallopeptidases, and c-Myc. Inhibition of M3R signaling greatly suppressed DCA/LCA induction of the CSC marker ALDHA1 and also c-Myc mRNA expression as well as transcriptional activation of TCF/LEF.ConclusionsOur results suggest that bile acids, specifically DCA and LCA, induce cancer stemness in colonic epithelial cells by modulating M3R and Wnt/β-catenin signaling and thus could be considered promoters of colon cancer.

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“…Stem cells are believed to play an important role in the etiology of many cancers and contribute to therapeutic resistance (40, 41). In the GI tract, stem cells were shown to be a critical cell-of-origin for intestinal polyp development through loss of Apc (42).…”

Section: Discussionmentioning

confidence: 99%

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

Montrose

Zhou

McNally

et al. 2016

Cancer Prevention Research

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Treatment with celecoxib, a selective COX-2 inhibitor, reduces formation of premalignant adenomatous polyps in the gastrointestinal tracts of humans and mice. In addition to its chemopreventive activity, celecoxib can exhibit anti-microbial activity. Differing bacterial profiles have been found in feces from colon cancer patients compared with that of normal subjects. Moreover, preclinical studies suggest that bacteria can modulate intestinal tumorigenesis by secreting specific metabolites. In the current study, we determined whether celecoxib treatment altered the luminal microbiota and metabolome in association with reducing intestinal polyp burden in mice. Administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APCMin/+ mice. Treatment with celecoxib also altered select luminal bacterial populations in both APCMin/+ and wild-type mice including decreased Lactobacillaceae and Bifidobacteriaceae as well as increased Coriobacteriaceae. Metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites linked to carcinogenesis including glucose, amino acids, nucleotides and lipids. Ingenuity Pathway Analysis suggested that these changes in metabolites may contribute to reduced cell proliferation. To this end, we showed that celecoxib reduced cell proliferation in the base of normal appearing ileal and colonic crypts of APCMin/+ mice. Consistent with this finding, lineage tracing indicated that celecoxib treatment reduced the rate at which Lgr5-positive stem cells gave rise to differentiated cell types in the crypts. Taken together, these results demonstrate that celecoxib alters the luminal microbiota and metabolome along with reducing epithelial cell proliferation in mice. We hypothesize that these actions contribute to its chemopreventive activity.

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The role of pluripotency factors to drive stemness in gastrointestinal cancer

Cited by 81 publications

References 124 publications

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

Bile acid: a potential inducer of colon cancer stem cells

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

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