STRAP is involved in mutated Apc-induced stemness and tumorigenesis in colon cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE160428 | GEO | 2021/09/20
REPOSITORIES: GEO
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Project description:STRAP is involved in mutated Apc-induced stemness and tumorigenesis in colon cancer
| PRJNA673189 | ENA
Project description:Aberrant DNA methylation is frequently observed in colorectal cancer (CRC), but the underlying mechanisms and pathological consequences are poorly understood. Ten-Eleven Translocation (TET) dioxygenases and Thymine DNA Glycosylase (TDG) are involved in active DNA demethylation by generating and removing novel oxidized cytosine species. TET1 and TDG mutations, and alterations of the levels of oxidized cytosines have been identified in human CRC. To clarify the biological significance of the TET-TDG demethylation axis in intestinal tumorigenesis, we generated ApcMin mice that are devoid of Tet1 and/or Tdg, and characterized the methylome and transcriptome of intestinal adenomas by DREAM and RNA sequencing, respectively. Tet1-deficient and Tet1/Tdg-double heterozygous ApcMin adenomas manifested increased adenoma size and features of erosion or invasion, whereas an increased number (>30) of adenomas was found in Tdg-mutant ApcMin mice. Methylome analysis revealed progressive loss of global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-deficient ApcMin mice, and hypermethylation of CpG islands in Tet1-deficient ApcMin mice. In addition, RNA sequencing showed upregulation of genes in inflammatory, immune and interferon response in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. The corresponding 135-gene inflammatory signature separated human colonic adenocarcinomas into four groups, closely aligned with their microsatellite or chromosomal instability profile, and characterized by different levels of DNA methylation and DNMT1 expression levels that anti-correlated with TET1 expression levels. These findings demonstrate a novel mechanism of epigenetic regulation during intestinal tumorigenesis by which TET1-TDG-mediated active DNA demethylation decreases not only methylation levels, but also inflammatory/interferon/immune response, which impinges on the intrinsic features of genomic instability of the tumors. This study establishes a novel link, via inflammatory response, between epigenomic and genomic instability.
2023-10-01 | GSE179526 | GEO
Project description: Not available
| S-EPMC3775784 | biostudies-literature
Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer. mRNAs from normal (WT, Notch-activated and Notch-inactivated) and tumor (WT, Notch-activated and Notch-inactivated) tissues were profiled.
2011-04-19 | E-GEOD-21392 | biostudies-arrayexpress
Project description:Purpose: Serine-threonine kinase receptor-associated protein (STRAP) plays an important role in neural development but also in tumor growth. Neuroblastoma, a tumor of neural crest origin, is the most common extracranial malignancy of childhood, and it continues to carry a poor prognosis. The recent discovery of the role of STRAP in another pediatric solid tumor, osteosarcoma, and its known function in neural development, led us to investigate the role of STRAP in neuroblastoma tumorigenesis. Methods: STRAP protein expression was abrogated in two human neuroblastoma cell lines, SK-N-AS (AS) and SK-N-BE(2). Methods included transient knockdown with siRNA, stable knockdown with shRNA lentiviral transfection, and CRISPR-Cas9 genetic knockout of STRAP. STRAP knockdown and knockout cells were examined for phenotypic alterations in vitro and tumor growth in vivo. Results: Cell proliferation, viability, motility, and growth were significantly decreased in STRAP knockout compared to wild-type cells. Indicators of stemness, including mRNA abundance of common stem cell markers Oct4, Nanog, and Nestin, the percentage of cells expressing CD133 on their surface, and the ability to form tumorspheres, were significantly decreased in the STRAP KO cells. In vivo, AS STRAP knockout cells formed tumors less readily than wild-type tumor cells. Conclusion: These novel findings demonstrated that STRAP plays a role in tumorigenesis and maintenance of neuroblastoma stemness.
2021-07-14 | GSE169322 | GEO
Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer.
2011-04-19 | GSE21392 | GEO
Project description:We report the application of next generation sequencing for evaluating alternative splicing (AS) events on lineage-committed WT and Strap-KO embryoid body (EB) cells. We also analyzed AS during mouse embryo development using RNA-seq data. Of all STRAP-regulated AS, exon-skipping events were the most frequent ones with significant changes in 49% (240 out of 489) cases. Retained introns were also overrepresented (20%, 97 out of 489) as compared to other types of AS STRAP appears to function in promoting both exon inclusion and skipping at different exons. GO function revealed STRAP-regulated AS events involve in protein catabolism, molecular binding and cell motility. More specifically, they included neuronal migration and development. Together, these analyses uncovered the previous unknown role of STRAP involved in the substantial transcriptional diversity at the exon level in certain development stage. Our study also represents the first detailed analysis of AS events in the mouse early organogenesis with biologic replicates, generated by RNA-seq technology.
2020-09-16 | GSE131471 | GEO
Project description:We report the application of enhanced cross-linking immunoprecipitation (eCLIP) sequencing technology for high-throughput profiling of STRAP-RNA interactions in mouse embryos (E9.5) or embryoid body (EB) cells. Based on the eCLIP-seq data, we computationally identified a transcriptome-wide set of high-confidence peaks (over ten thousands) and most of STRAP-peaks distributed in the murine genome by defining certain exons and introns as well as their intersection. STRAP eCLIP signals in embryos were dramatically enriched at exon/intron and intron/exon borders. Numerous STRAP peaks are significantly enriched on the genes with critical roles in early organ development. Finally, we show two examples of STRAP-RNA binding that link to its regulated genes at the alternative splicing level. Together, we uncover the position- and context- dependent effects of STRAP on splicing regulation during mouse embryonic stem cells lineage commitment. Our studies provide a very useful platform to decipher STRAP’s role in the many steps in RNA biogenesis for future studies.
2020-09-16 | GSE131472 | GEO
Project description:We assessed differential gene expression using RNAseq in intestinal adenomas between Apc loss-of-function (Apcmin) mice, or by Apc1322T mice encoding a partially-functional Apc truncation commonly found in colorectal carcinomas.
2018-12-31 | GSE121142 | GEO
Project description:To address the in vivo relevance of CSF1R regulation by miR-34a during intestinal tumor formation, we generated ApcMin/+ mice with intestinal-epithelial cell (IEC)-specific deletions of the Mir34a and/or Csf1r genes. The mRNA expression profiles of intestinal adenomas with and without functional miR-34a and/or Csf1r were compared.
2022-10-04 | GSE167448 | GEO