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Reversal of gene expression changes in the colorectal normal-adenoma pathway by NS398 selective COX2 inhibitor.

Galamb O, Spisák S, Sipos F, Tóth K, Solymosi N, Wichmann B, Krenács T, Valcz G, Tulassay Z, Molnár B - Br. J. Cancer (2010)

Bottom Line: The results were validated using RT-PCR and immunohistochemistry.NS398 has a reversal effect on the expression of several genes that altered in colorectal adenoma-carcinoma sequence.NS398 more efficiently inverted the expression changes seen in the normal-adenoma than in the normal-carcinoma transition.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Semmelweis University, Budapest, Hungary. orsg1@yahoo.com

ABSTRACT

Background and aims: Treatment of colorectal adenomas with selective cyclooxygenase-2 inhibitors can contribute to the chemoprevention of colorectal cancer (CRC), but the molecular background of their effect is not fully understood. We analysed the gene expression modulatory effect of N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide (NS398) on HT29 cells to be correlated with expression data gained from biopsy samples.

Methods: HT29 colon adenocarcinoma cells were treated with NS398, and global mRNA expression was analysed on HGU133Plus2.0 microarrays. Discriminatory transcripts between normal and adenoma and between adenoma and CRC biopsy samples were identified using HGU133Plus2.0 microarrays. The results were validated using RT-PCR and immunohistochemistry.

Results: Between normal and adenoma samples, 20 classifiers were identified, including overexpressed cadherin 3, KIAA1199, and downregulated peptide YY, glucagon, claudin 8. Seventeen of them changed in a reverse manner in HT29 cells under NS398 treatment, 14 (including upregulated claudin 8, peptide YY, and downregulated cadherin 3, KIAA1199) at a significance of P<0.05. Normal and CRC could be distinguished using 38 genes, the expression of 12 of them was changed in a reverse manner under NS398 treatment.

Conclusion: NS398 has a reversal effect on the expression of several genes that altered in colorectal adenoma-carcinoma sequence. NS398 more efficiently inverted the expression changes seen in the normal-adenoma than in the normal-carcinoma transition.

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Related in: MedlinePlus

Functional classification of differentially expressed genes in HT29 cells under NS398 treatment. (A) Distribution of differentially expressed transcripts in the main cell functional groups. (B) Distribution of downregulated transcripts in the main cell functional groups. (C) Distribution of upregulated transcripts in the main cell functional groups.
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fig1: Functional classification of differentially expressed genes in HT29 cells under NS398 treatment. (A) Distribution of differentially expressed transcripts in the main cell functional groups. (B) Distribution of downregulated transcripts in the main cell functional groups. (C) Distribution of upregulated transcripts in the main cell functional groups.

Mentions: In all, 1925 differentially expressed genes were identified between the NS398-treated and untreated control group using SAM at a significance of P<0.05 (Supplementary Table 1). A further feature selection criterion was the logFC (log fold change) value. Within the differentially expressed genes, 1156 at least two-fold-overexpressed genes were found with a logFC value higher than 1, whereas 769 at least two-fold downregulated genes were determined with a logFC value lower than −1. The expression of genes involved in cell proliferation and cell cycle regulation (such as overexpressed CDKN3, BTG2, TGFB1, CNOT8, KAT2B, RARRES3, CDKN2C, RARRES1, MAGED1, PPAP2A, MXD4, TENC1, SESN1, and downregulated CDCA4, VEGFA), intracellular signal transduction, transcription regulation, metabolic and transport processes and apoptosis (overexpressed CDKN2C, BIK, CASP6, TIA, DAPK3, and dowregulated ANXA1, CEBPB, CBX4) are mainly changed under NS398 treatment. However, the function of several differentially expressed transcripts is not known yet. The functional classification of genes is represented in Figure 1.


Reversal of gene expression changes in the colorectal normal-adenoma pathway by NS398 selective COX2 inhibitor.

Galamb O, Spisák S, Sipos F, Tóth K, Solymosi N, Wichmann B, Krenács T, Valcz G, Tulassay Z, Molnár B - Br. J. Cancer (2010)

Functional classification of differentially expressed genes in HT29 cells under NS398 treatment. (A) Distribution of differentially expressed transcripts in the main cell functional groups. (B) Distribution of downregulated transcripts in the main cell functional groups. (C) Distribution of upregulated transcripts in the main cell functional groups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2837560&req=5

fig1: Functional classification of differentially expressed genes in HT29 cells under NS398 treatment. (A) Distribution of differentially expressed transcripts in the main cell functional groups. (B) Distribution of downregulated transcripts in the main cell functional groups. (C) Distribution of upregulated transcripts in the main cell functional groups.
Mentions: In all, 1925 differentially expressed genes were identified between the NS398-treated and untreated control group using SAM at a significance of P<0.05 (Supplementary Table 1). A further feature selection criterion was the logFC (log fold change) value. Within the differentially expressed genes, 1156 at least two-fold-overexpressed genes were found with a logFC value higher than 1, whereas 769 at least two-fold downregulated genes were determined with a logFC value lower than −1. The expression of genes involved in cell proliferation and cell cycle regulation (such as overexpressed CDKN3, BTG2, TGFB1, CNOT8, KAT2B, RARRES3, CDKN2C, RARRES1, MAGED1, PPAP2A, MXD4, TENC1, SESN1, and downregulated CDCA4, VEGFA), intracellular signal transduction, transcription regulation, metabolic and transport processes and apoptosis (overexpressed CDKN2C, BIK, CASP6, TIA, DAPK3, and dowregulated ANXA1, CEBPB, CBX4) are mainly changed under NS398 treatment. However, the function of several differentially expressed transcripts is not known yet. The functional classification of genes is represented in Figure 1.

Bottom Line: The results were validated using RT-PCR and immunohistochemistry.NS398 has a reversal effect on the expression of several genes that altered in colorectal adenoma-carcinoma sequence.NS398 more efficiently inverted the expression changes seen in the normal-adenoma than in the normal-carcinoma transition.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Semmelweis University, Budapest, Hungary. orsg1@yahoo.com

ABSTRACT

Background and aims: Treatment of colorectal adenomas with selective cyclooxygenase-2 inhibitors can contribute to the chemoprevention of colorectal cancer (CRC), but the molecular background of their effect is not fully understood. We analysed the gene expression modulatory effect of N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide (NS398) on HT29 cells to be correlated with expression data gained from biopsy samples.

Methods: HT29 colon adenocarcinoma cells were treated with NS398, and global mRNA expression was analysed on HGU133Plus2.0 microarrays. Discriminatory transcripts between normal and adenoma and between adenoma and CRC biopsy samples were identified using HGU133Plus2.0 microarrays. The results were validated using RT-PCR and immunohistochemistry.

Results: Between normal and adenoma samples, 20 classifiers were identified, including overexpressed cadherin 3, KIAA1199, and downregulated peptide YY, glucagon, claudin 8. Seventeen of them changed in a reverse manner in HT29 cells under NS398 treatment, 14 (including upregulated claudin 8, peptide YY, and downregulated cadherin 3, KIAA1199) at a significance of P<0.05. Normal and CRC could be distinguished using 38 genes, the expression of 12 of them was changed in a reverse manner under NS398 treatment.

Conclusion: NS398 has a reversal effect on the expression of several genes that altered in colorectal adenoma-carcinoma sequence. NS398 more efficiently inverted the expression changes seen in the normal-adenoma than in the normal-carcinoma transition.

Show MeSH
Related in: MedlinePlus