Unknown,Transcriptomics,Genomics,Proteomics

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Differential gene expression in Lrig1null duodenal tumors compared to normal duodenum

ABSTRACT: Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1) is a pan-ErbB negative regulator and intestinal stem cell marker downregulated in many malignancies. Over 91% Lrig1-CreERT2/CreERT2 (Lrig1-/-) mice developed duodenal adenomas, providing the first in vivo evidence Lrig1 acts as a tumor suppressor. We thus characterize the differential expressing transcripts in these duodenal adenomas to explore the pathegenesis. Elevated expression of the Egfr ligands was detected in adenomas compared to adjacent normal tissue. These adenomas also expressed the gastric-specific genes Gastrokine1 and Mucin5ac, indicating gastric metaplasia. In this dataset, we include the expression data obtained from proximal adenomas as well as adjacent normal tissue and wildtype proximal duodenum. These data are used to obtain 679 upregulated and 874 downregulated transcripts in tumors. Total RNA from matched duodenal tumors or adjacent normal or wildtype duodenum was isolated with Rneasy (with Dnase digestion) and used to probe the Affymetrix Mouse Gene 1.0 ST chip; the probe was prepared with Ambion Expression Target preparation Kit P/N 4411974.

ORGANISM(S): Mus musculus

SUBMITTER: Robert Coffey

PROVIDER: E-GEOD-64640 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Spontaneous metastasis of gastric carcinoma to secondary organs is seldom reproduced in the mice. In this study, we established highly reproducible, experimental mice model in which gastric carcinoma progressively grows in the site of gastric walls and metastasize to secondary sites. A highly tumorigenic GC cells were engineered to express type 2 luciferase and injected via orthotopic route into BALB/c nude mice. The mice developed highly progressive GC tumors in the gastric wall where implanted and slow metastases to liver, spleen, lung, kidney and ovary, with rate of metastases to ovary being 63.6% of implanted mice. The tumors colonized in the ovary expressed a GI marker MUC5A, suggestive of typical human Krukenberg tumor. Immuno-histochemical stainings revealed that many mesenchymal markers were strongly positive in motile tumor cells in the vein of ovary and became gradually weak during extravasations to colonize in the ovary. When routes of metastasis were further investigated, the mesenchymal marker SMA stained low in the tumor cells of the primary site of stomach wall, became high in intravasating vein in the stomach wall, remained high in extravasating veins in the liver and ovary and finally returned low in the colonized tumor in the liver and ovary. However, expression of an epithelial marker Claudin did not show in the opposite profile to SMA, indicating that acquisition of mesenchymal phenotypes rather than loss of epithelial characteristics may more give rise to metastatic potential. Dissociated cells derived from tumors in the implanted mouse stomach or metastasized to ovaries retain their tumorigenicity and metastatic potentials. The mRNA microarray and Western blot analyses showed that metastatic tumor-derived cells showed significantly higher expression of GAGE12 gene family than orthotopic tumors-derived cells. The shRNA-mediated knock-down of the GAGE12 family in the metastatic tumors-derived cells abolished the tumor formation in gastric wall and metastasis as well. In conclusion, we established an in vivo orthotopic gastric cancer mouse model spontaneously metastasizing to secondary organs including ovary, which exhibits typical characteristics of a Krukenberg tumor. Expression of mesenchymal markers should be functionally associated with the gain of metastatic ability in this study. A hightly tumorigenic gastric carcinoma SNU-16 cells were orthotpically injected into stomach wall. Tumors formed in the stomach wall (16S) and mestasized to ovary (16O) were dissociated and cultured for 7 day. These cells were re-injected orthotopically and tumors formed in the stomach from 16S (16SS) and ovary from 16O injection (16OO) were dissociated. Total RNAs were isolated from 16S, 16SS, 16O and 16OO2 and subjected to mRNA microarrays

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Differential gene expression in Lrig1null duodenal tumors compared to normal duodenum

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