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Function of UDP-glucuronosyltransferase 2B17 (UGT2B17) is involved in endometrial cancer.

ABSTRACT: Endometrial cancer (EC) is a steroid hormone-dependent cancer. Uridine 5'-diphospho-glucuronosyltransferase enzymes conjugate and detoxify endogenous and exogenous steroid hormones and environmental carcinogens. Among these enzymes, the function of UGT2B17 is unknown except for glucuronidation. The messenger RNA expression of UGT2B17 and myeloid cell leukemia-1 (Mcl-1) was significantly increased in EC tissues compared with matched normal endometrial tissues. Therefore, we focused on the function of UGT2B17 in EC. A total of nine patients with confirmed EC were enrolled in this study to investigate the expression of UGT2B17 and target genes. EC cell lines were used for functional tests including cell growth, invasion, apoptosis and cell cycle analyses. To find the target genes of UGT2B17, we performed microarray analysis to see which genes were upregulated or downregulated by UGT2B17-transfected cells. Functional analysis showed decreased numbers of viable cells and increased numbers of apoptotic cells in si-UGT2B17-transfected Ishikawa cells. Among microarray target genes, Mcl-1 was significantly downregulated in si-UGT2B17-transfected cells. We also found upregulation of Puma protein, a target of Mcl-1, in si-UGT2B17-transfected cells. This is the first report to show that UGT2B17 and Mcl-1 expression are upregulated in EC tissues and that UGT2B17 depletion induces inhibition of cell growth and apoptosis in EC cells through Mcl-1 downregulation.

SUBMITTER: Hirata H

PROVIDER: S-EPMC2930802 | biostudies-other | 2010 Sep

REPOSITORIES: biostudies-other

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Function of UDP-glucuronosyltransferase 2B17 (UGT2B17) is involved in endometrial cancer.

Hirata Hiroshi H Hinoda Yuji Y Zaman Mohd S MS Chen Yi Y Ueno Koji K Majid Shahana S Tripsas Christina C Rubin Mary M Chen Lee-May LM Dahiya Rajvir R

Carcinogenesis 20100616 9

Endometrial cancer (EC) is a steroid hormone-dependent cancer. Uridine 5'-diphospho-glucuronosyltransferase enzymes conjugate and detoxify endogenous and exogenous steroid hormones and environmental carcinogens. Among these enzymes, the function of UGT2B17 is unknown except for glucuronidation. The messenger RNA expression of UGT2B17 and myeloid cell leukemia-1 (Mcl-1) was significantly increased in EC tissues compared with matched normal endometrial tissues. Therefore, we focused on the functio ...[more]

PMID: 20554747

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Project description:BackgroundPolymorphism of genes encoding drug-metabolizing enzymes is known to play an important role in increased susceptibility of colorectal cancer. UGT1A gene locus has been suggested to define tissue-specific glucuronidation activity. Reduced capacity of glucuronidation is correlated with the development of colorectal cancer. Therefore, we sought to explore polymorphism of UGTlA gene in human colorectal cancer.MethodsCancerous and healthy tissues were obtained from selectedpatients. Blood samples were collected and UGTlA mRNA transcriptions were analyzed. Genomic DNA was prepared and UGTlA8 exon-1 sequences were amplified, visualized and purified. The extracted DNA was subcloned and sequenced. Two-tailed Fisher's exact test, Odds ratios (ORs), confidence interval (CIs) and Logistics Regression Analysis were used for statistical analysis.ResultsUGTlA mRNA expression was reduced in cancerous tissues compared with healthy tissues from the same patient . The UGTlA mRNA expression of healthy tissue in study patients was lower than control . The mRNA expression of cancerous tissue was down-regulated in UGTlAl, 1A3, 1A4, lA6, 1A9 and up-regulated in UGTlA8 and UGTlAl0 UGT1A5 and UGT1A7 were not expressed in colonic tissue of either group. The allele frequency of WT UGTlA8*1 was higher (p?=?0.000), frequency of UGTlA8*3 was lowered in control group (p?=?0.000). The expression of homozygous UGTlA8*1 was higher in control group (p?=?0.000). Higher frequency of both heterozygous UGTlA8*1/*3 and UGTlA8*2/*3 were found in study group (p?=?0.000; p?=?0.000). The occurrence of colorectal cancer was mainly related to the presence of polymorphic UGTlA8*3 alleles (p?=?0.000).ConclusionRegulation of human UGT1A genes is tissue-specific. Individual variation in polymorphic expressions of UGTlA gene locus was noted in all types of colonic tissue tested, whereas hepatic tissue expression was uniform. The high incidence of UGTlA8 polymorphism exists in colorectal cancer patients. UGTlA8*1 allele is a protective factor and UGTlA8*3 allele is a risk factor.

Dataset Information

Function of UDP-glucuronosyltransferase 2B17 (UGT2B17) is involved in endometrial cancer.

Publications

Function of UDP-glucuronosyltransferase 2B17 (UGT2B17) is involved in endometrial cancer.

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