Intestinal regulation of suppression of tumorigenicity 14 (ST14) and serine peptidase inhibitor, Kunitz type -1 (SPINT1) by transcription factor CDX2

Danielsen, E. Thomas; Olsen, Anders; Coskun, Mehmet; Nonboe, Annika W.; Larsen, Sylvester; Dahlgaard, Katja; Bennett, Eric; Mitchelmore, Cathy; Vogel, Lotte K.; Troelsen, Jesper T.

doi:10.1038/s41598-018-30216-z

Cited by 9 publications

(9 citation statements)

References 74 publications

(78 reference statements)

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“…This result does not correlate with the decrease in activity that was seen when the CDX2 binding sites were mutated (Figure 4). The lack of effect when overexpressing CDX2 and analyzing enhancer activity in Caco-2 cells has previously been observed with other CDX2 regulated genes [43].…”

Section: Resultsmentioning

confidence: 94%

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HNF4α and CDX2 Regulate Intestinal YAP1 Promoter Activity

Larsen

Davidsen

Dahlgaard

et al. 2019

IJMS

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The Hippo pathway is important for tissue homeostasis, regulation of organ size andgrowth in most tissues. The co‐transcription factor yes‐associated protein 1 (YAP1) serves as a maindownstream effector of the Hippo pathway and its dysregulation increases cancer development andblocks colonic tissue repair. Nevertheless, little is known about the transcriptional regulation ofYAP1 in intestinal cells. The aim of this study to identify gene control regions in the YAP1 gene andtranscription factors important for intestinal expression. Bioinformatic analysis of caudal typehomeobox 2 (CDX2) and hepatocyte nuclear factor 4 alpha (HNF4α) chromatin immunoprecipitatedDNA from differentiated Caco‐2 cells revealed potential intragenic enhancers in the YAP1 gene.Transfection of luciferase‐expressing YAP1 promoter‐reporter constructs containing the potentialenhancer regions validated one potent enhancer of the YAP1 promoter activity in Caco‐2 and T84cells. Two potential CDX2 and one HNF4α binding sites were identified in the enhancer by in silicotranscription factor binding site analysis and protein‐DNA binding was confirmed in vitro usingelectrophoretic mobility shift assay. It was found by chromatin immunoprecipitation experimentsthat CDX2 and HNF4α bind to the YAP1 enhancer in Caco‐2 cells. These results reveal a previouslyunknown enhancer of the YAP1 promoter activity in the YAP1 gene, with importance for highexpression levels in intestinal epithelial cells. Additionally, CDX2 and HNF4α binding areimportant for the YAP1 enhancer activity in intestinal epithelial cells.

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Section: Resultsmentioning

confidence: 94%

“…It was, however, somewhat surprising that CDX2 overexpression did not increase the reporter gene expression. However, we have previously seen that CDX2 overexpression in Caco-2 cells, which have a high endogenous level of CDX2 [39], does not necessarily result in increased reporter gene expression when CDX2 binds to enhancer regions [43].…”

Section: Discussionmentioning

confidence: 99%

HNF4α and CDX2 Regulate Intestinal YAP1 Promoter Activity

Larsen

Davidsen

Dahlgaard

et al. 2019

IJMS

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“…To investigate the role of CDX2 in cell adhesion, the colon cancer cell line LS174T with inducible CDX2 was used. This cell line has previously been used to study the effect of CDX2 on intestinal transcriptional regulation [36][37][38]. Western blotting analysis of the LS174T wild type and LS174T with inducible CDX2 cells was performed to detect CDX2 levels.…”

Section: Resultsmentioning

confidence: 99%

CDX2 expression and perioperative patient serum affects the adhesion properties of cultured colon cancer cells

et al. 2020

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Background: Colon cancer is one of the most commonly diagnosed types of cancer with surgical resection of the tumor being the primary choice of treatment. However, the surgical stress response induced during treatment may be related to a higher risk of recurrence. The aim of this study was to examine the effect of surgery on adhesion of cultured colon cancer cells with or without expression of the tumour suppressor CDX2. Method: We enrolled 30 patients undergoing elective, curatively intended laparoscopic surgery for colon cancer in this study. Blood samples were drawn 1 day prior to surgery and 24 h after surgery. The samples of pre-and postoperative serum was applied to wild type colon cancer LS174T cells and CDX2 inducible LS174T cells and adhesion was measured with Real-Time Cell-Analysis iCELLigence using electrical impedance as a readout to monitor changes in the cellular adhesion. Results: Adhesion abilities of wild type LS174T cells seeded in postoperative serum was significantly increased compared to cells seeded in preoperative serum. When seeding the CDX2 inducible LS174T cells without CDX2 expression in pre-and postoperative serum, no significant difference in adhesion was found. However, when inducing CDX2 expression in these cells, the adhesion abilities in pre-and postoperative serum resembled those of the LS174T wild type cell line. Conclusions: We found that the adhesion of colon cancer cells was significantly increased in postoperative versus preoperative serum, and that CDX2 expression affected the adhesive ability of cancer cells. The results of this study may help to elucidate the pro-metastatic mechanisms in the perioperative phase and the role of CDX2 in colon cancer metastasis.

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“…The CRC-specific EV marker DMBT1 may act as a tumor suppressor [34,35], whose loss could be a poor prognostic factor [47]. Specific for the CRC cell line HT29, the suppressor of tumorigenicity 14 (ST14) protein maintains epithelial barrier integrity and suppresses intestinal carcinogenesis [48]. The ability to suppress cancer metastasis was shown for HTC116 line-specific EV protein stomatin (STOM) [49].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Approach for Searching for Universal, Tissue-Specific, and Line-Specific Markers of Extracellular Vesicles in Lung and Colorectal Adenocarcinoma Cell Lines

Novikova

Shushkova

Farafonova

et al. 2020

IJMS

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Tumor-derived extracellular vesicles (EVs), including exosomes, contain proteins that mirror the molecular landscape of producer cells. Being potentially detectible in biological fluids, EVs are of great interest for the screening of cancer biomarkers. To reveal universal, tissue-specific, and line-specific markers, we performed label-free mass spectrometric profiling of EVs originating from the human colon cancer cell lines Caco-2, HT29, and HCT-116, as well as from the lung cancer cell lines NCI-H23 and A549. A total of 651 proteins was identified in the EV samples using at least two peptides. These proteins were highly enriched in exosome markers. We found 11 universal, eight tissue-specific, and 29 line-specific markers, the levels of which were increased in EVs compared to the whole lysates. The EV proteins were involved in the EGFR, Rap1, integrin, and microRNA signaling associated with metastasis and cancer progression. An EV protein-based assay could be developed as a liquid biopsy tool.

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Intestinal regulation of suppression of tumorigenicity 14 (ST14) and serine peptidase inhibitor, Kunitz type -1 (SPINT1) by transcription factor CDX2

Cited by 9 publications

References 74 publications

HNF4α and CDX2 Regulate Intestinal YAP1 Promoter Activity

HNF4α and CDX2 Regulate Intestinal YAP1 Promoter Activity

CDX2 expression and perioperative patient serum affects the adhesion properties of cultured colon cancer cells

Proteomic Approach for Searching for Universal, Tissue-Specific, and Line-Specific Markers of Extracellular Vesicles in Lung and Colorectal Adenocarcinoma Cell Lines

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