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The expression profile of 5-fluorouracil pathway genes in colorectal carcinoma

ABSTRACT: This study addressed involvement of fourteen 5-fluorouracil pathway genes in the prognosis of colorectal carcinoma patients. The major goal of our study was to investigate associations of gene expression of enzymes metabolizing 5-fluorouracil with therapy response and survival of colorectal carcinoma patients Downregulation of DPYD and upregulation of PPAT, UMPS, RRM2, and SLC29A1 transcripts were found in tumors compared to adjacent mucosas in testing and validation sets of patients. Low RRM2 transcript level significantly associated with poor response to the first-line palliative 5-FU-based chemotherapy in the testing set and with poor disease-free interval of patients in the validation set.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67111 | GEO | 2015/08/31

SECONDARY ACCESSION(S): PRJNA278973

REPOSITORIES: GEO

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Project description:Colorectal cancer (CRC) is still one of the most common causes of cancer-related death worldwide (World Health Organization, Fact sheet NM-BM-0297, October 2011). Though, therapeutic options improved over the past years, the prognosis of metastatic colorectal cancer (mCRC) remains poor with a median survival of 18-21 months. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) are used for the palliative treatment of metastatic colorectal cancer (mCRC) carrying a KRAS-wildtype. Among the tumors with a KRAS-wildtype, only 35% respond, and alterations of other signaling molecules and pathways modulate therapeutic response. In this study we analyzed the effect of KRAS-mutations on intracellular signaling cascades to find new therapeutic approaches for patients with mCRC. Reverse-phase protein array and gene array technology was applied to sixteen adenocarcinomas of the sigmoid colon carrying either wildtype (n=8) or mutant (n=8) KRAS. Differential expression was validated on 49 sigmoid cancers by RT-PCR, Western blot and immunohistochemistry. In a screening for members of signaling pathways known to have a high impact on tumor development in colon cancer, we found 14 proteins downregulated in tumors with mutated KRAS. Subsequently, we compared the data of the protein arrays with the results of gene expression arrays performed with the same samples. We confirmed the differential expression of eight genes as a function of the KRAS genotype of the tumor. To further validate the differential expression of these candidates, we performed quantitative expression analysis and immunohistochemical staining of an independent validation series comprising 49 CRC patient samples. It was clearly demonstrated that the expression of EGFR is decreased in colorectal carcinomas with a mutant KRAS genotype. mRNA was obtained from 16 patients with colorectal cancer (8 with and 8 without KRAS-mutation). mRNA was extracted from neoplastic and non-neoplastic colon mucosa and analyzed separately by Affymetrix Human Gene 1.1 ST GeneChips finally generating 32 separate data sets.

Project description:Hepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear. In this study, palliative hepatectomy was performed in an orthotopic nude mice model of HCC (MHCC97H) with high metastatic potential. Using Human Tumor Metastasis Microarray, we screened the metastasis-related genes in tumor tissues following palliative resection, and found that Metastasis suppressor 1 (MTSS1) located in the central position of gene function net of residual HCC; MTSS1 was up-regulated in residual tumor after palliative resection. Further studies found that MTSS1 enhanced the metastasis of residual HCC. In hepatitis B-related HCC patients undergone palliative hepatectomy, those with higher MTSS1 mRNA expression accompanied by the activation of matrix metalloproteinase 2 (MMP2) in residual HCC, had earlier residual HCC detection after hepatectomy and poorer survival when compared to those with lower MTSS1 level. In different cell lines, the levels of MTSS1 mRNA increased in parallel with metastatic potential. MTSS1 down regulation via siRNA decreased MMP2 activity, reduced invasive potentials of HCC by 28.9% in vitro, and averted the deteriorated lung metastatic extent in vivo. In conclusion, the poor prognosis of hepatitis B-related HCC patients following palliative hepatectomy associates with elevated MTSS1 mRNA expression; therefore, MTSS1 may provide a new research field for HCC diagnosis and treatment. Eighteen nude mice bearing HCC xenografts were randomized into three groups 14 days after orthotopic implantation: palliative resection group (mice received partial HCC resection with preservation of 2 mm tumor pedicles), sham operation group (mice only undergone an exposure of liver but without resection), and blank control group (mice without further surgical intervention). All mice were sacrificed by cervical dislocation 14 days following palliative resection based on pre-experimental results. The first time surgically removed HCC tissues were named tumor tissues T1; the second time surgically removed HCC tissues from sham operation group were named tumor tissues T2; Tissues from blank control group were named tumor tissues T3; Tissues from palliative resection group were named tumor tissues T4 that was residual HCC. Randomly selected 5 tumor specimens from each group were used for the screen of genes related to metastasis by microarray techniques.

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The expression profile of 5-fluorouracil pathway genes in colorectal carcinoma

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