scholarly journals The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

2015 ◽  
Vol 112 (13) ◽  
pp. E1550-E1558 ◽  
Author(s):  
Matthew F. Jones ◽  
Toshifumi Hara ◽  
Princy Francis ◽  
Xiao Ling Li ◽  
Sven Bilke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Cell Lines ◽  
Stem Cell Differentiation ◽  
Small Rna Sequencing ◽  
Rna Seq ◽  
Genome Wide ◽  
Cell Line Panel ◽  
Poorly Differentiated ◽  
Transcriptional Target

The transcription factor caudal-type homeobox 1 (CDX1) is a key regulator of differentiation in the normal colon and in colorectal cancer (CRC). CDX1 activates the expression of enterocyte genes, but it is not clear how the concomitant silencing of stem cell genes is achieved. MicroRNAs (miRNAs) are important mediators of gene repression and have been implicated in tumor suppression and carcinogenesis, but the roles of miRNAs in differentiation, particularly in CRC, remain poorly understood. Here, we identified microRNA-215 (miR-215) as a direct transcriptional target of CDX1 by using high-throughput small RNA sequencing to profile miRNA expression in two pairs of CRC cell lines: CDX1-low HCT116 and HCT116 with stable CDX1 overexpression, and CDX1-high LS174T and LS174T with stable CDX1 knockdown. Validation of candidate miRNAs identified by RNA-seq in a larger cell-line panel revealed miR-215 to be most significantly correlated with CDX1 expression. Quantitative ChIP–PCR and promoter luciferase assays confirmed that CDX1 directly activates miR-215 transcription. miR-215 expression is depleted in FACS-enriched cancer stem cells compared with unsorted samples. Overexpression of miR-215 in poorly differentiated cell lines causes a decrease in clonogenicity, whereas miR-215 knockdown increases clonogenicity and impairs differentiation in CDX1-high cell lines. We identified the genome-wide targets of miR-215 and found that miR-215 mediates the repression of cell cycle and stemness genes downstream of CDX1. In particular, the miR-215 target gene BMI1 has been shown to promote stemness and self-renewal and to vary inversely with CDX1. Our work situates miR-215 as a link between CDX1 expression and BMI1 repression that governs differentiation in CRC.

scholarly journals Genome-wide analysis of promoter and enhancer usage in hematopoietic stem cell differentiation

2013 ◽  
Vol 6 (S1) ◽  
Author(s):  
Annarita Miccio ◽  
Clelia Peano ◽  
Oriana Romano ◽  
Guidantonio Tagliazucchi ◽  
Luca Petiti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Differentiation ◽  
Hematopoietic Stem ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Hematopoietic Stem Cell Differentiation

scholarly journals Genome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing-Lan Li ◽  
Xiang Lin ◽  
Ya-Li Yu ◽  
Lin Chen ◽  
Qi-Xin Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colorectal Cancer Patient ◽  
Nucleotide Polymorphisms ◽  
Rna Seq ◽  
Motif Analysis ◽  
Single Nucleotide ◽  
Super Enhancer ◽  
Genome Wide ◽  
Functional Factors ◽  
Cancer Tissues

AbstractColorectal cancer is one of the most common cancers in the world. Although genomic mutations and single nucleotide polymorphisms have been extensively studied, the epigenomic status in colorectal cancer patient tissues remains elusive. Here, together with genomic and transcriptomic analysis, we use ChIP-Seq to profile active enhancers at the genome wide level in colorectal cancer paired patient tissues (tumor and adjacent tissues from the same patients). In total, we sequence 73 pairs of colorectal cancer tissues and generate 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq samples. Our analysis identifies 5590 gain and 1100 lost variant enhancer loci in colorectal cancer, and 334 gain and 121 lost variant super enhancer loci. Multiple key transcription factors in colorectal cancer are predicted with motif analysis and core regulatory circuitry analysis. Further experiments verify the function of the super enhancers governing PHF19 and TBC1D16 in regulating colorectal cancer tumorigenesis, and KLF3 is identified as an oncogenic transcription factor in colorectal cancer. Taken together, our work provides an important epigenomic resource and functional factors for epigenetic studies in colorectal cancer.

scholarly journals Genome-wide ChIP-seq and RNA-seq analyses of Pou3f1 during mouse pluripotent stem cell neural fate commitment

Genomics Data ◽  
2015 ◽  
Vol 5 ◽  
pp. 375-377 ◽  
Author(s):  
Lu Song ◽  
Na Sun ◽  
Guangdun Peng ◽  
Jun Chen ◽  
Jing-Dong Jackie Han ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Rna Seq ◽  
Neural Fate ◽  
Genome Wide

Colorectal cancer stem cells: Characterization and functional analysis

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4124-4124
Author(s):  
T. Yeung ◽  
J. Wilding ◽  
W. Bodmer
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Tumour Growth ◽  
Colorectal Cancer Cell Lines ◽  
Colorectal Cancer Stem Cells

4124 Background: Cancer stem cells are defined as cells within a tumour that are able to self-renew and differentiate into all cell lineages within that tumour. With our extensive panel of colorectal cell lines, our aims are: 1) To characterise and isolate cancer stem cells based on stem cell markers, morphological appearances and the ability to form multiple lineages; 2) To understand how cancer stem cells drive tumour growth and progression. Methods: 1) Fluorescent Activated Cell Sorting (FACS); 2) In vitro soft agar clonogenic and Matrigel differentiation assays; 3) In vivo tumourigenic NOD/SCID mice assay; 4) Confocal immunofluorescence imaging. Results: 1) A subpopulation of cells can differentiate into crypt-like megacolonies, retaining the ability to self-renew and differentiate. SW1222 cell line forms heterogeneous colonies when single cells are plated in Matrigel. Megacolonies can both self-renew and form terminally differentiated small colonies, whereas small colonies cannot form megacolonies. Megacolonies develop crypt-like structures and increase their expression of differentiation markers (CDX-1, CK-20) over time. Experiments are currently under way to confirm that cells from megacolonies are able to initiate tumours in NOD/SCID mice. Some cell lines retain the ability to differentiate into both neuroendocrine and epithelial lineages. 2) CD44+CD24+ enriches for the cancer stem cell population. Colorectal cancer cell lines HCT116, HT29, LS180, LS174T and SW1222 express both CD44 and CD24. The CD44+CD24+ subpopulation is the most clonogenic. In SW1222, CD44+CD24+ cells enrich for megacolonies and can reform all four CD44/CD24 subpopulations. 3) Hypoxia reduces differentiation, increases stem-like phenotype and enhances clonogenicity. Hypoxia increases the proportion of undifferentiated colorectal cancer cells when plated on Matrigel and increases clonogenicity. Conclusions: 1) Colorectal cancer cell lines contain subpopulations of cells that have the ability to self-renew, differentiate and drive tumour growth, and may be characterised by their cell surface markers and colony morphology. 2) CD44+CD24+ can be used as markers for colorectal cancer stem cells. 3) Hypoxia increases the stem-like phenotype of cancer cells, reduces differentiation and increases clonogenicity. No significant financial relationships to disclose.

scholarly journals Stage prediction of embryonic stem cell differentiation from genome-wide expression data

2011 ◽  
Vol 27 (18) ◽  
pp. 2546-2553 ◽  
Author(s):  
Lan Zagar ◽  
Francesca Mulas ◽  
Silvia Garagna ◽  
Maurizio Zuccotti ◽  
Riccardo Bellazzi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Expression Data ◽  
Genome Wide ◽  
Genome Wide Expression

scholarly journals Molecular Characterization of the Oncogene BTF3 and Its Targets in Colorectal Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Hantao Wang ◽  
Junjie Xing ◽  
Wei Wang ◽  
Guifen Lv ◽  
Haiyan He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Transcription Factor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Rna Seq ◽  
A Subunit ◽  
Cancer Types ◽  
Functional Mechanisms ◽  
Transcriptional Target

Colorectal cancer (CRC) is one of the most commonly diagnosed and leading causes of cancer mortality worldwide, and the prognosis of patients with CRC remains unsatisfactory. Basic transcription factor 3 (BTF3) is an oncogene and hazardous prognosticator in CRC. Although two distinct functional mechanisms of BTF3 in different cancer types have been reported, its role in CRC is still unclear. In this study, we aimed to molecularly characterize the oncogene BTF3 and its targets in CRC. Here, we first identified the transcriptional targets of BTF3 by applying combined RNA-Seq and ChIP-Seq analysis, identifying CHD1L as a transcriptional target of BTF3. Thereafter, we conducted immunoprecipitation (IP)-MS and E3 ubiquitin ligase analysis to identify potential interacting targets of BTF3 as a subunit of the nascent-polypeptide-associated complex (NAC). The analysis revealed that BTF3 might also inhibit E3 ubiquitin ligase HERC2-mediated p53 degradation. Finally, miRNAs targeting BTF3 were predicted and validated. Decreased miR-497-5p expression is responsible for higher levels of BTF3 post-transcriptionally. Collectively, we concluded that BTF3 is an oncogene, and there may exist a transcription factor and NAC-related proteolysis mechanism in CRC. This study provides a comprehensive basis for understanding the oncogenic mechanisms of BTF3 in CRC.

scholarly journals Targeting chemoresistant colorectal cancer via systemic administration of a BMP7 variant

Oncogene ◽  
2019 ◽  
Vol 39 (5) ◽  
pp. 987-1003 ◽  
Author(s):  
Veronica Veschi ◽  
Laura R. Mangiapane ◽  
Annalisa Nicotra ◽  
Simone Di Franco ◽  
Emanuela Scavo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Bone Morphogenetic Proteins ◽  
Stem Cell Differentiation ◽  
Metastatic Lesion ◽  
Lesion Size ◽  
Antiangiogenic Effect ◽  
Pi3k Inhibitors

Abstract Despite intense research and clinical efforts, patients affected by advanced colorectal cancer (CRC) have still a poor prognosis. The discovery of colorectal (CR) cancer stem cell (CSC) as the cell compartment responsible for tumor initiation and propagation may provide new opportunities for the development of new therapeutic strategies. Given the reduced sensitivity of CR-CSCs to chemotherapy and the ability of bone morphogenetic proteins (BMP) to promote colonic stem cell differentiation, we aimed to investigate whether an enhanced variant of BMP7 (BMP7v) could sensitize to chemotherapy-resistant CRC cells and tumors. Thirty-five primary human cultures enriched in CR-CSCs, including four from chemoresistant metastatic lesions, were used for in vitro studies and to generate CR-CSC-based mouse avatars to evaluate tumor growth and progression upon treatment with BMP7v alone or in combination with standard therapy or PI3K inhibitors. BMP7v treatment promotes CR-CSC differentiation and recapitulates the cell differentiation-related gene expression profile by suppressing Wnt pathway activity and reducing mesenchymal traits and survival of CR-CSCs. Moreover, in CR-CSC-based mouse avatars, BMP7v exerts an antiangiogenic effect and sensitizes tumor cells to standard chemotherapy regardless of the mutational, MSI, and CMS profiles. Of note, tumor harboring PIK3CA mutations were affected to a lower extent by the combination of BMP7v and chemotherapy. However, the addition of a PI3K inhibitor to the BMP7v-based combination potentiates PIK3CA-mutant tumor drug response and reduces the metastatic lesion size. These data suggest that BMP7v treatment may represent a useful antiangiogenic and prodifferentiation agent, which renders CSCs sensitive to both standard and targeted therapies.

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