Identification of Mouse Genes With Highly Specific Expression Patterns in Differentiated Intestinal Epithelium

Schröder, Natalia; Sekhar, Aravind; Geffers, Insa; Müller, Julia; Dittrich–Breiholz, Oliver; Wedemeyer, Jochen; Gossler, Achim

doi:10.1053/j.gastro.2005.12.025

Cited by 13 publications

(12 citation statements)

References 44 publications

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“…At present, REG4 can be considered as a protein overexpressed by tumor and epithelial cells of the transitional mucosa [present study and (11)] which may play an important role in colorectal carcinogenesis from the first steps of tumor development. Indeed, REG4 expression was shown to be deregulated early on in aberrant crypt foci (33,34) and in adenomatous polyps regardless of the grade of dysplasia (present study). REG4 overexpression is maintained in most colorectal carcinomas [present study and (6,7,11)].…”

Section: Discussionsupporting

confidence: 57%

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

Rafa

Dessein²,

Devisme³

et al. 2010

Int J Oncol

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Abstract. REG4, the latest member of the regenerating gene family, is overexpressed in inflammatory bowel diseases and gastrointestinal carcinomas. To date, its pathophysiologic role has not been well established. Using HT-29 models, we previously identified REG4 as being overexpressed in colorectal tumor cells displaying a drug-resistance phenotype; some also displayed invasive properties. Thus, we investigated the potential functions of REG4 in biological processes involved in colorectal tumor progression such as cell proliferation, migration and invasion. Colon cancer cells secreting REG4 (HT29-5M21, HT29-5F7 and HT29/REG4-8) or not (HT-29, HT29/CT1 and Caco-2/TC7) were used to analyze the autocrine and paracrine effects of REG4. REG4 was continuously secreted into the culture medium of colon cancer cells. REG4 stimulated cell growth in a paracrine manner after 24 h of treatment. Notably, REG4 promoted migration and invasion of tumor cells in both an autocrine and paracrine manner, and these effects were significantly decreased by concomitant treatment with an anti-REG4 antibody. Using pharmacological inhibitors, we showed that PI3K/Akt, PKAs, PKCs and Rho-like GTPases, but not MAPK, are involved in REG4 invasion signals. In addition, REG4 expression was found to be increased in tissues harboring proliferation and migration properties such as the developing intestine and tissues from inflammatory bowel disease, hyperplastic polyps, adenoma and colorectal cancers. In various situations, REG4 expression was not confined to proliferating cells, regenerating cells or cells of the invasive front of metastatic tumors, suggesting that extracellular REG4 may act on epithelial cells in a paracrine manner. Altogether, our results indicate that REG4 is a multifunctional secreted protein which acts on colorectal cancer cells in an autocrine and paracrine manner. According to its biological functions and tissue expression, REG4 may play an important role in the development and progression of colorectal cancer, as well as in intestinal morphogenesis and epithelium restitution.

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Section: Discussionsupporting

confidence: 57%

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

Rafa

Dessein²,

Devisme³

et al. 2010

Int J Oncol

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“…Next, we compared our microarray results with several previous intestine gene profiling studies (Bates et al, 2002; Li et al, 2007; Schroder et al, 2006). Among genes that show significant enrichment in E18.5 intestinal epithelium over mesenchyme (Li et al, 2007), 35.3% were significantly altered in Cdx2 -deficient intestine.…”

Section: Resultsmentioning

confidence: 99%

“…Likewise, 39.8% of genes that show enrichment in intestine over stomach (Bates et al, 2002) were significantly affected in our model. Furthermore, genes with highly specific expression patterns in the differentiated intestinal epithelium (Schroder et al, 2006) were all significantly downregulated in Cdx2 -deficient mice.…”

Section: Resultsmentioning

confidence: 99%

Establishment of Intestinal Identity and Epithelial-Mesenchymal Signaling by Cdx2

2009

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SUMMARY We demonstrate that conditional ablation of the homeobox transcription factor Cdx2 from early endoderm results in the replacement of the posterior intestinal epithelium with keratinocytes, a dramatic cell fate conversion caused by ectopic activation of the foregut/esophageal differentiation program. This anterior homeotic transformation is first evident in the early embryonic Cdx2-deficient gut as expression of several key foregut endoderm regulators was shifted caudally. While the intestinal transcriptome was severely affected, Cdx2-deficiency only transiently modified selected posterior Hox genes and the primary enteric Hox code was maintained. Further, we demonstrate that Cdx2-directed intestinal cell fate adoption plays an important role in the establishment of normal epithelial-mesenchymal interactions, as multiple signaling pathways involved in this process were severely affected. We conclude that Cdx2 controls important aspects of intestinal identity and development, and that this function is largely independent of the enteric Hox code.

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“…Although the mouse has already been in the scope of RNA-Seq studies, only a few individual tissues or cell types were analyzed, including embryonic stem cells [15,16], oocytes [17], myoblasts [18], brain [19,20], muscle, liver [11] and heart [21]. Deep annotation of the intestinal mRNA sequence space is still missing, although microarray studies suggested a high complexity of region-specific expression patterns [22,23] and disturbances of intestinal homeostasis are linked to a broad variety of diseases (e.g. infections, idiopathic inflammatory bowel disease and intestinal malignancies) [24,25].…”

Section: Introductionmentioning

confidence: 99%

A tissue-specific landscape of sense/antisense transcription in the mouse intestine

Klostermeier¹,

Barann²,

Wittig³

et al. 2011

BMC Genomics

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BackgroundThe intestinal mucosa is characterized by complex metabolic and immunological processes driven highly dynamic gene expression programs. With the advent of next generation sequencing and its utilization for the analysis of the RNA sequence space, the level of detail on the global architecture of the transcriptome reached a new order of magnitude compared to microarrays.ResultsWe report the ultra-deep characterization of the polyadenylated transcriptome in two closely related, yet distinct regions of the mouse intestinal tract (small intestine and colon). We assessed tissue-specific transcriptomal architecture and the presence of novel transcriptionally active regions (nTARs). In the first step, signatures of 20,541 NCBI RefSeq transcripts could be identified in the intestine (74.1% of annotated genes), thereof 16,742 are common in both tissues. Although the majority of reads could be linked to annotated genes, 27,543 nTARs not consistent with current gene annotations in RefSeq or ENSEMBL were identified. By use of a second independent strand-specific RNA-Seq protocol, 20,966 of these nTARs were confirmed, most of them in vicinity of known genes. We further categorized our findings by their relative adjacency to described exonic elements and investigated regional differences of novel transcribed elements in small intestine and colon.ConclusionsThe current study demonstrates the complexity of an archetypal mammalian intestinal mRNA transcriptome in high resolution and identifies novel transcriptionally active regions at strand-specific, single base resolution. Our analysis for the first time shows a strand-specific comparative picture of nTARs in two tissues and represents a resource for further investigating the transcriptional processes that contribute to tissue identity.

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Identification of Mouse Genes With Highly Specific Expression Patterns in Differentiated Intestinal Epithelium

Cited by 13 publications

References 44 publications

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

Establishment of Intestinal Identity and Epithelial-Mesenchymal Signaling by Cdx2

A tissue-specific landscape of sense/antisense transcription in the mouse intestine

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