• BMB Reports
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• v.46 no.6
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• pp.322-327
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• 2013

The ATP-binding cassette transporters ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. To identify cis-regulatory elements of the two genes, we have cloned and analyzed twenty-three evolutionary conserved region (ECR) fragments using the CMV-luciferase reporter system in HepG2 cells. Two ECRs were found to be responsive to the Liver-X-Receptor (LXR). Through elaborate deletion studies, regions containing putative LXREs were identified and the binding of $LXR{\alpha}$ was demonstrated by EMSA and ChIP assay. When the LXREs were inserted upstream of the intergenic promoter, synergistic activation by $LXR{\alpha}/RXR{\alpha}$ in combination with GATA4, $HNF4{\alpha}$, and LRH-1, which had been shown to bind to the intergenic region, was observed. In conclusion, we have identified two LXREs in ABCG5/ABCG8 genes for the first time and propose that these LXREs, especially in the ECR20, play major roles in regulating these genes.

• Korean Journal of Clinical Pharmacy
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• v.26 no.1
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• pp.53-58
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• 2016

Objective: To estimate the association between ABCG2 C421A polymorphism and response to imatinib in chronic myeloid leukemia. Methods: A systematic review was conducted to evaluate the effect of ABCG2 C421A polymorphism on imatinib response. The databases of PubMed, Embase, Web of science, CINAHL with FullText, and Cochrane Library were searched for all published studies from inception to December 2015. The following terms were used with functions of 'AND' and 'OR': 'chronic myeloid leukemia', 'CML', 'drug transporter', 'ABCG2', 'BCRP', 'polymorphisms', 'SNPs', and 'imatinib'. The studies reporting the association between ABCG2 polymorphism and imatinib response were evaluated. Results: A total of 7 studies were included in the present meta-analysis. The pooled analysis showed that ABCG2 c.421CC genotype was significantly associated with poor response to imatinib under the dominant model (CC vs CA+AA; OR: 0.56; 95% CI: 0.41, 0.77; p = 0.0004). The subgroup analysis of Asian studies demonstrated a significantly lower response in c.421CC genotype than in c.421CA or c.421AA genotype (OR: 0.52; 95% CI: 0.37, 0.73; p = 0.0002). In subgroup analyses of 5 studies, the patients with the c.421CC genotype exhibited higher risk for worse response than the patients with c.421CA or c.421AA genotype (heterozygote codominant model: CC vs. AC; OR: 0.49, 95% CI: 0.33, 0.73; p = 0.0006; homozygote codominant model: CC vs AA; OR: 0.43; 95% CI: 0.25, 0.75, p = 0.003). Conclusion: The ABCG2 c.421CC genotype was significantly associated with poor response to imatinib compared to the c.421CA and c.421AA genotypes in chronic myeloid leukemia, especially in Asian patients.

• Genomics & Informatics
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• v.12 no.4
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• pp.231-235
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• 2014

Elevated serum uric acid levels are associated with a variety of adverse health outcomes, including gout, hypertension, diabetes mellitus, metabolic syndrome, and cardiovascular diseases. Several genome-wide association studies on uric acid levels have implicated the ATP-binding cassette, subfamily G, member 2 (ABCG2) gene as being possibly causal. We investigated an association between the single-nucleotide polymorphism (SNP) rs2725220 in the ABCG2 gene and uric acid levels in the Korean population. A total of 991 subjects in Seoul City were used for a replication study with ABCG2 SNP rs2725220. The rs2725220 SNP in the ABCG2 gene was associated with mean uric acid levels (effect per allele 0.25 mg/dL, p < 0.0001). Subjects with the GC/CC genotype had a 1.78-fold (range, 1.22- to 2.62-fold) higher risk of having abnormal uric acid levels (${\geq}7.0mg/dL$) than subjects with the GG genotype. When analyzed by gender, the association with ABCG2 was stronger in men than in women. The association with ABCG2 was much stronger in male subjects with body mass index (BMI) ${\geq}26.4$ (odds ratio, 5.09; 95% confidence interval, 2.41 to 10.8) than in male subjects with BMI < 26.4. This study clearly demonstrates that genetic variations in ABCG2 influence uric acid levels in Korean adults.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.1
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• pp.11-16
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• 2012

Cancer stem cells (CSCs) are often characterized by the elevated expression of drug-resistance related stem-cell surface markers, such as CD133 and ABCG2. Recently, we reported that CSCs have a high level of expression of the IL-6 receptor (IL-6R). The purpose of this study was to investigate the effect of anticancer drugs on the expression of the drug resistance-related cancer stem cell markers, ABCG2, IL-6R, and CD133 in non-small cell lung cancer (NSCLC) cell lines. A549, H460, and H23 NSCLC cell lines were treated with the anticancer drugs 5-fluorouracil (5-FU; $25{\mu}g/ml$) and methotrexate (MTX; $50{\mu}g/ml$), and the expression of putative CSC markers was analyzed by fluorescent activated cell sorter (FACS) and the gene expression level of abcg2, il-6r and cd133 by reverse transcriptase-polymerase chain reaction (RT-PCR). We found that the fraction of ABCG2-positive(+) cells was significantly increased by treatment with both 5-FU and MTX in NSCLC cells, and the elevation of abcg2, il-6r and cd133 expressions in response to these drugs was also confirmed using RT-PCR. Also, the number of IL-6R(+) cells was increased by MTX in the 3 cell lines mentioned and increased by 5-FU in the H460 cell line. The number of CD133(+) cells was also significantly increased by both 5-FU and MTX treatment in all of the cell lines tested. These results indicate that 5-FU and MTX considerably enhance the expression of drug-resistance related CSC markers in NSCLC cell lines. Thus, we suggest that antimetabolite cancer drugs, such as 5-FU and MTX, can lead to the propagation of CSCs through altering the expression of CSC markers.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.2271-2275
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• 2016

Background: The value of 5-aminolevulinic acid (ALA) in fluorescence detection of peritoneal metastases and the underlying mechanisms were evaluated in patients with peritoneal surface malignancies. Materials and Methods: Oral 5-ALA was administered at a concentration of 20 mg/kg body weight with 50 ml of water 2 hours prior to surgery (n=115). The diagnostic value of 5-ALA based fluorescence production was evaluated following white light inspection during prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Then, peptide transporter PEPT1 (ALA influx transporter) and ATP-binding cassette transporter ABCG2 (porphyrin efflux transporter) gene expression was determined with quantitative real time (qRT)-PCR and pathological diagnoses confirmed for all tissue samples. Results: The 5-ALA based photodynamic detection rate was 17% for appendiceal mucinous neoplasms, 54% for colorectal cancers, 33% for gastric cancers, 67% for diffuse malign peritoneal mesotheliomas, and 89% for epithelial ovarian cancer of peritoneal metastases. 5-ALA was detected in all cases of peritoneal metastases originating from cholangiocarcinomas whereas it was not able to detect any in granulosa cell and gastrointestinal stromal tumor cases. Furthermore, PEPT1 was overexpressed whereas ABCG2 expression was downregulated in tumors detected with fluorescence. Conclusions: 5-ALA provided 100% specificity and high sensitivity to detect peritoneal metastases in subgroups of patients with peritoneal surface mailgnancies. ALA influx transporter PEPT1 and porphyrin efflux transporter ABCG2 genes are important in tumor specific 5-ALA induced fluorescence in vivo. Further studies should clarify diagnostic utility of 5-ALA in peritoneal surface malignancies.

• Nutrition Research and Practice
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• v.4 no.6
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• pp.462-469
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• 2010

Protamine has been widely used as a pharmaceutical product and natural food preservative. However, few studies have been conducted to assess the beneficial function of dietary protamine. This study examined the effects of dietary salmon protamine on serum and liver lipid levels and the expression levels of genes encoding proteins involved in lipid homeostasis in the liver of rats. Groups of male Wistar rats were fed AIN93G diet containing 2% or 5% protamine. After 4 weeks of feeding these diets, markedly decreased serum and liver cholesterol (CHOL) and triacylglycerol levels were noted. Increased activity of liver carnitine palmitoyltransferase-2 and acyl-CoA oxidase, which are key enzymes of fatty acid ${\beta}$-oxidation in the mitochondria and peroxisomes, was found in rats fed on protamine. Furthermore, rats fed protamine showed enhanced fecal excretion of CHOL and bile acid and increased liver mRNA expression levels of ATP-binding cassette (ABC) G5 and ABCG8, which form heterodimers and play a major role in the secretion of CHOL into bile. The decrease in triacylglycerol levels in protamine-fed rats was due to the enhancement of liver ${\beta}$-oxidation. Furthermore, rats fed protamine exhibited decreased CHOL levels through the suppression of CHOL and bile acid absorption and the enhancement of CHOL secretion into bile. These results suggest that dietary protamine has beneficial effects that may aid in the prevention of lifestyle-related diseases such as hyperlipidemia and atherosclerosis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.5
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• pp.1931-1936
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• 2014

Background: Gastric cancer (GC) ranks as one of the major causes of mortality due to cancer worldwide. In Chile, it is currently the leading cause of cancer death. Identification of novel molecular markers that may help to improve disease diagnosis at early stages is imperative. Materials and Methods: Using whole-genome DNA microarrays we determined differential mRNA levels in fresh human GC samples compared to adjacent healthy mucosa from the same patients. Genes significantly overexpressed in GC were validated by RT-PCR in a group of 14 GC cases. Results: The genes CD248, NSD1, RAB17, ABCG8, Ephb1 and P2RY2 were detected as the top overexpressed in GC biopsies. P2RY2, Ephb1 and CD248 showed the best sensitivity for GC detection with values of 92.9%, 85.7% and 64.3% (p<0.05), respectively. Specificity was 85.7%, 71.4% and 71.4% (p<0.05), for each respectively.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5433-5438
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• 2012

Background: Hepatocellular carcinoma (HCC) is a common and aggressive malignancy. Despite of the improvements in its treatment, HCC prognosis remains poor due to its recurrence after resection. This study provides complete genetic profile for Egyptian HCC. Genome-wide analyses were performed to identify the predictive signatures. Patients and Methods: Liver tissue was collected from 31 patients with diagnosis of HCC and gene expression levels in the tumours and their adjacent non-neoplastic tissues samples were studied by analyzing changes by microarray then correlate these with the clinico-pathological parameters. Genes were validated in an independent set by qPCR. The genomic profile was associated with genetic disorders and cancer focused on gene expression, cell cycle and cell death. Molecular profile analysis revealed cell cycle progression and arrest at G2/M, but progression to mitosis; unregulated DNA damage check-points, and apoptosis. Result: Nine hundred fifty eight transcripts out of the 25,000 studied cDNAs were differentially expressed; 503 were up-regulated and 455 were down-regulated. A total of 19 pathways were up-regulated through 27 genes and 13 pathways were down-regulated through 19 genes. Thirty-seven genes showed significant differences in their expression between HCC cases with high and low Alpha Feto Protein ($AFP{\geq}600$ IU/ml). The validation for the microarray was done by real time PCR assay in which PPP3CA, ATG-5, BACE genes showed down-regulation and ABCG2, RXRA, ELOVL2, CXR3 genes showed up-regulation. cDNA microarrays showed that among the major upregulated genes in HCC are sets. Conclusion: The identified genes could provide a panel of new diagnostic and prognostic aids for HCC.

• Biomolecules & Therapeutics
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• v.25 no.5
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• pp.490-496
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• 2017

Imatinib resistance has become a major clinical problem for chronic myeloid leukemia. The aim of the present study was to investigate the involvement of MEG3, a lncRNA, in imatinib resistance and demonstrate its underlying mechanisms. RNAs were extracted from CML patients' peripheral blood cells and human leukemic K562 cells, and the expression of MEG3 was measured by RT-qPCR. Cell proliferation and cell apoptosis were evaluated. Western blotting was used to measure the protein expression of several multidrug resistant transporters. Luciferase reporter assay was performed to determine the binding between MEG3 and miR-21. Our results showed that MEG3 was significantly decreased in imatinib-resistant CML patients and imatinib-resistant K562 cells. Overexpression of MEG3 in imatinib-resistant K562 cells markedly decreased cell proliferation, increased cell apoptosis, reversed imatinib resistance, and reduced the expression of MRP1, MDR1, and ABCG2. Interestingly, MEG3 binds to miR-21. MEG3 and miR-21 were negatively correlated in CML patients. In addition, miR-21 mimics reversed the phenotype of MEG3-overexpression in imatinib-resistant K562 cells. Taken together, MEG3 is involved in imatinib resistance in CML and possibly contributes to imatinib resistance through regulating miR-21, and subsequent cell proliferation, apoptosis and expression of multidrug resistant transporters.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.4
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• pp.1859-1862
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• 2014

Recently, the main therapy of medullary thyroid cancer (MTC) is surgical, but by which way there is a poor prognosis with a mean survival of only 5 years. In some cases, some researchers found that it is the medullary thyroid cancer stem cells (MTCSCs) that cause metastasis and recurrence. This study aimed to eradicate MTCSCs through administration of all-trans-retinoic acid (ATRA). Here we demonstrate that MTCSCs possess stemlike properties in serum-free medium. The ABCG2, OCT4 and sodium iodide symporter (NIS) were changed by ATRA. Additionally, we found that ATRA can increase the expression of NIS in vivo. All the data suggested that ATRA could increase the iodine uptake of MTCSCs through NIS.