A family study of congenital nephrogenic diabetes insipidus combined with hyperuricemia / 中华内分泌代谢杂志

Objective:To investigate the clinical and genetic characteristics, pathogenesis and treatment strategy of congenital nephrogenic diabetes insipidus(CNDI)combined with hyperuricemia.Methods:The clinical manifestations and laboratory data of an infant patient diagnosed as CNDI with hyperuricemia and his family members were collected and retrospectively analyzed. Whole exome sequencing(WES)was applied to detect the proband′s genome variation of each exon and suspected variants of AVPR2 and ABCG2 were verified by PCR-Sanger sequencing of members from his pedigree. Furthermore, we retrospectively collected the serum uric acid levels of patients(≤14-year-old) with CNDI in the First Affiliated Hospital of Zhengzhou University from January 2015 to January 2022.Results:The proband was clinically diagnosed with CNDI and the rest of the family members had no symptoms of polydipsia or polyuria. In addition to the proband, his father was also suffered from hyperuricemia. WES showed that the proband carried a hemizygous AVPR2 gene variation(p.S331R)and a heterozygous ABCG2 gene variation(p.N308K). The former was X-linked recessive inheritance from his mother, and the latter was autosomal dominant inheritance from the father. Fraction excretion of uric acid(FEUA)of the proband and his father with hyperuricemia were 3.1% and 2.7%, respectively. Twelve children(≤14-year-old)were diagnosed with CNDI from the respective study. Among all the cases, 11 patients were male and 1 was female, ranging from 3-month to 14-year-old. Five patients were accompanied with hyperuricemia.Conclusion:Children with CNDI may be complicated with hyperuricemia, and the regimen of hydrochlorothiazide combined with benzbromarone is effective. The pathogenicity of the AVPR2 gene variation(p.S331R)and ABCG2 gene variation(p.N308K)in this pedigree needs to be further studied.

MET inhibitor tepotinib antagonizes multidrug resistance mediated by ABCG2 transporter: In vitro and in vivo study

Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.

The establishment of a high-resolution melting curve genotyping method for ABCG2*376T allele of Jr(a-) and its distribution frequency study / 中国输血杂志

【Objective】 To establish a high-throughput detection method for ABCG2*376T allele of Jr(a-), and apply it to the study of the frequency of this allele in the Chinese population. 【Methods】 The specific primers were designed and synthesized, the sample carrying homozygous ABCG2*376T alleles, obtained in the previous study, was used as the homozygous positive control, and the sample carrying heterozygous allele as the heterozygous positive control. The wild-type sample was used as a negative control, and a high-resolution melting curve(HRM) method for detecting this allele was established. The established method was used to screen DNA samples from blood donors in Guangzhou, and the samples carrying ABCG2*376T alleles were sequenced to confirm the accuracy of the HRM method. 【Results】 A HRM method, which can detect ABCG2*376T allele and accurately type homozygotes and heterozygotes at the same time, had been established successfully. Fifteen individuals with heterozygous alleles were screened out of 1 560 blood donors in Guangzhou, while none homozygous allele was detected. 【Conclusion】 The HRM method can be used to accurately screen and type ABCG2*376T allele. The frequency of this allele in Chinese population is about 0.48%(15/3120).

Anti-Jra developed in Jra(-) pregnant woman, case report with molecular genetic analysis / 中国输血杂志

【Objective】 To identify the antibody specificity in a pregnant women who had no history of blood transfusion but presented the antibodies against high-frequency antigens. 【Methods】 ABO, RhD blood group antigens were identified by saline. Antibody screening and identification were performed by saline and indirect Coomb’s technique. Further antibody identification tests were conducted using papain, trypsin and chymotrypsin-treated cells. Antibody titer in serum was tested. PCR amplification and sequencing analysis of 16 exons of ABCG2 gene were conducted. 【Results】 The blood type of the patient were B, RhD positive. The serum reacted with antibody screening/identified cells by indirect antiglobin test(both 2+ ) but not by saline. The agglutination was enhanced after papain treatment (4+ ), but remained unchanged after trypsin and chymotrypsin treatment (2+ ). The IgG titer was 1∶2. The sequencing analysis of ABCG2 gene revealed a homozygous nonsense mutation(c.376C>T, p. Gln126X) in exon 4 of the women. 【Conclusion】 In this case, the development of anti-Jra in Jr(a-) mother was stimulated by mother-child serology incompatibility during pregnancy.

Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy

Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three polyoxypregnanes (POPs) as the most abundant constituents of

The ABCG2 mRNA Synthesized in vitro Promoted Uric Acid Excretion in Mice / 中国生物化学与分子生物学报

Hyperuricemia is a chronic metabolic disease caused by the accumulation of uric acid in the body caused by purine metabolism disorder. In recent years, the incidence of hyperuricemia has increased and the age of onset is showing a younger trend. Finding effective therapeutic targets and treatment methods is a hot spot of current research. The urate transporter ATP-binding cassette subfamily G member 2 (ABCG2) is mainly expressed in the kidney and promotes uric acid excretion. In this study, ABCG2 mRNA was synthesized in vitro and transfected into hyperuricemia model mice to observe its effect on mouse uric acid levels. Firstly, the DNA template of ABCG2 mRNA was chemically synthesized, and then transcribed into mRNA in vitro, followed by modification and transfection into mouse TCMK-1 renal tubular epithelial cells. Finally, the protein expression in the cells was detected by Western blot. The results showed that the amount of protein expression in TCMK-1 cells was positively correlated with the amount of transfected mRNA (P < 0. 01), indicating a successful transfection. In animal experiments, twenty-four SPF mice were randomly divided into four groups (n = 6): control group, hyperuricemia model group, benzbromarone group [20 mg/(kg•d)] and mRNA group [2 mg/(kg•3d)]. The mice have been modeled and treated for 28 days. During this period, the body weight and growth status of the mice were monitored daily. After the treatment, the levels of serum uric acid, urine uric acid, serum creatinine, blood urea nitrogen and liver xanthine oxidase were analyzed. The results showed that compared with the model group of mice, mRNA treatment can significantly reduce the levels of serum uric acid (100. 38 ± 10. 94), blood urea nitrogen (6. 30 ± 1. 10), and serum creatinine (30. 86 ± 5. 78, P<0. 05 or P<0. 01). It can also increase the level of urine uric acid (617. 48 ± 50. 34, P<0. 05) in mice and promote the excretion of uric acid. But it has no significant effect on the activity of xanthine oxidase (26. 19 ± 2. 58) in the liver. The pathological changes of mice kidney were observed by HE staining. The results showed that compared with mice in the model group, pathological damages such as renal tubular cell edema and inflammatory cell infiltration in the mRNA treatment group were significantly improved. The relative expression of mRNA in mice kidney was detected by qRT-PCR, and the protein expression of ABCG2 in mice kidney was detected by immunohistochemistry and Western blot. The results showed that the relative expression of ABCG2 mRNA and its protein were significantly up-regulated in the kidney tissues of mice in the mRNA group (P < 0. 01), indicating that the transfection was successful in vivo. In conclusion, ABCG2 mRNA synthetized and modified in vitro can be successfully expressed in hyperuricemia mice and promote excretion of uric acid and other organic ions, as well as improvement of renal injury in mice. These results provide experimental basis for the clinical application of ABCG2 as a target for the treatment of hyperuricemia related diseases.

Isolation and Biological Characterization of Lung Cancer Stem Cells / 中国医学科学院学报

To explore the methods of screening and biological characteristics of lung cancer stem cells. We selected the ABCG2 and ABCG2 cells from SPC-A-1/adriamycin(ADM)cell line induced by ADM and analyzed the tumorigenicity of ABCG2 and ABCG2 cells by flow cytometry and transplantation in nude mice. The average fluorescence intensity of SPC-A-1 cells was(1.001±0.014)×10 ,which was significantly lower than that of SPC-A-1/ADM cells [(10.257±0.023) ×10 ](=17.320,=0.001);the difference was also statistically significant between the ABCG2/BCRP-FITC treatment group and the SPC-A-1 control group(=5.269,=0.021) and the SPC-A-1 control group(=6.869, =0.012) and between the SPC-A-1/ADM cell control group and the SPC-A-1/ADM cell homotype control group(=8.112,=0.015).The positive rate of SPC-A-1/ADM cells treated with ABCG2/BCRP-FITC was 9.8%,39.84 times higher than that of SPC-A-1 cells;it showed significant difference between the ABCG2/BCRP-FITC group and the SPC-A-1/ADM group(=9.120,=0.005) and the SPC-A-1/ADM group(=8.257,= 0.006).The positive rate of group B cells was 684 times that of group A cells,and the difference was statistically significant(=11.235,=0.001),and the fluorescence intensity of group B cells was strong.The average tumorigenic volume of the mice inoculated with SPC-A-1 cells,group A cells,and group B cells was(6.96±1.82),(6.70±2.55),and(9.17±2.41) mm ,respectively.Among them,group B was the highest,but there was no significant difference among these three groups(=2.362,=0.086).The tumorigenic rate of group B cells was 75.00%,which was significantly higher than that of SPC-A-1 cells and group A cells(=19.780,=0.002). ABCG2 cells from human lung adenocarcinoma SPC-A-1/ADM cell line can be isolated by ABCG2 antibody combined with immunomagnetic beads sorting method,and the tumor formation rate in nude mice can be observed to explore the identification and biological characterization of lung cancer stem cells.

Bioengineered miR-328-3p modulates GLUT1-mediated glucose uptake and metabolism to exert synergistic antiproliferative effects with chemotherapeutics

MicroRNAs (miRNAs or miRs) are small noncoding RNAs derived from genome to control target gene expression. Recently we have developed a novel platform permitting high-yield production of bioengineered miRNA agents (BERA). This study is to produce and utilize novel fully-humanized BERA/miR-328-3p molecule (hBERA/miR-328) to delineate the role of miR-328-3p in controlling nutrient uptake essential for cell metabolism. We first demonstrated successful high-level expression of hBERA/miR-328 in bacteria and purification to high degree of homogeneity (>98%). Biologic miR-328-3p prodrug was selectively processed to miR-328-3p to suppress the growth of highly-proliferative human osteosarcoma (OS) cells. Besides glucose transporter protein type 1, gene symbol solute carrier family 2 member 1 (GLUT1/), we identified and verified large neutral amino acid transporter 1, gene symbol solute carrier family 7 member 5 (LAT1/) as a direct target for miR-328-3p. While reduction of LAT1 protein levels by miR-328-3p did not alter homeostasis of amino acids within OS cells, suppression of GLUT1 led to a significantly lower glucose uptake and decline in intracellular levels of glucose and glycolytic metabolite lactate. Moreover, combination treatment with hBERA/miR-328 and cisplatin or doxorubicin exerted a strong synergism in the inhibition of OS cell proliferation. These findings support the utility of novel bioengineered RNA molecules and establish an important role of miR-328-3p in the control of nutrient transport and homeostasis behind cancer metabolism.

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells and o

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.

ABCG2 aptamer selectively delivers doxorubicin to drug-resistant breast cancer cells

Chemotherapy is the most widely used treatment for cancer therapy, but its efficacy is limited by the side effects of non-specificcytotoxic drugs. Ligand-based targeting drug-delivery system is a solution to circumvent this issue. In this study, an ABCG2aptamer–doxorubicin complex was prepared, and its efficacy in targeted drug delivery to mitoxantrone-resistance breast cancer cellline (MCF7/MX) was evaluated. The formation of aptamer–doxorubicin physical complex was analyzed by fluorometric analysis.The cytotoxicities of doxorubicin and aptamer–doxorubicin complex on MCF7 and MCF7/MX cell lines were evaluated by theMTT assay, and IC50 values were obtained. Cellular uptake of aptamer–doxorubicin complex was assessed by flow cytometrycellular uptake assay. Results: Fluorometric analysis of aptamer–doxorubicin showed 1–1.5 molar ratio of the drug to the aptamercould efficiently quench Dox fluorescence. MTTassay results showed that MCF7/MX cells were more resistant to doxorubicin thanMCF7 cells (IC50 : 3.172 ± 0.536 and 1.456 ± 0.154 lM, respectively). Flow cytometry and MTT assay results showed that theaptamer–doxorubicin complex could increase the uptake and cytotoxicity of doxorubicin in MCF7/MX cell line in comparison withfree doxorubicin, while the same treatments had no effect on IC50 of Dox on MCF7 cells. The results proposed that the ABCG2aptamer–drug complex can be effectively used for specific drug delivery to ABCG2-overexpressing cells.

Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression

Secalonic acid D (SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant (MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1, H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mRNA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mRNA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2 (ABCG2)-mediated MDR cells.

Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition the regulation of target ADME gene expression

Drug-metabolizing enzymes, transporters, and nuclear receptors are essential for the absorption, distribution, metabolism, and excretion (ADME) of drugs and xenobiotics. MicroRNAs participate in the regulation of ADME gene expression imperfect complementary Watson-Crick base pairings with target transcripts. We have previously reported that Cytochrome P450 3A4 (CYP3A4) and ATP-binding cassette sub-family G member 2 (ABCG2) are regulated by miR-27b-3p and miR-328-3p, respectively. Here we employed our newly established RNA bioengineering technology to produce bioengineered RNA agents (BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, fermentation. When introduced into human cells, BERA/miR-27b-3p and BERA/miR-328-3p were selectively processed to target miRNAs and thus knock down and mRNA and their protein levels, respectively, as compared to cells treated with vehicle or control RNA. Consequently, BERA/miR-27b-3p led to a lower midazolam 1'-hydroxylase activity, indicating the reduction of CYP3A4 activity. Likewise, BERA/miR-328-3p treatment elevated the intracellular accumulation of anticancer drug mitoxantrone, a classic substrate of ABCG2, hence sensitized the cells to chemotherapy. The results indicate that biologic miRNA agents made by RNA biotechnology may be applied to research on miRNA functions in the regulation of drug metabolism and disposition that could provide insights into the development of more effective therapies.

Development of precision medicine approaches based on inter-individual variability of BCRP/

Precision medicine is a rapidly-developing modality of medicine in human healthcare. Based on each patient׳s unique characteristics, more accurate dosages and drug selection can be made to achieve better therapeutic efficacy and less adverse reactions in precision medicine. A patient׳s individual parameters that affect drug transporter action can be used to develop a precision medicine guidance, due to the fact that therapeutic efficacy and adverse reactions of drugs can both be affected by expression and function of drug transporters on the cell membrane surface. The purpose of this review is to summarize unique characteristics of human breast cancer resistant protein (BCRP) and the genetic variability in the BCRP encoded gene in the development of precision medicine. Inter-individual variability of BCRP/ can impact choices and outcomes of drug treatment for several diseases, including cancer chemotherapy. Several factors have been implicated in expression and function of BCRP, including genetic, epigenetic, physiologic, pathologic, and environmental factors. Understanding the roles of these factors in controlling expression and function of BCRP is critical for the development of precision medicine based on BCRP-mediated drug transport.

Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 and

Overexpressing of ATP-binding cassette (ABC) transporters is the essential cause of multidrug resistance (MDR), which is a significant hurdle to the success of chemotherapy in many cancers. Therefore, inhibiting the activity of ABC transporters may be a logical approach to circumvent MDR. Olmutinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has been approved in South Korea for advanced EGFR T790M-positive non-small cell lung cancer (NSCLC). Here, we found that olmutinib significantly increased the sensitivity of chemotherapy drug in ABCG2-overexpressing cells. Furthermore, olmutinib could also increase the retention of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABC transporter subfamily G member 2 (ABCG2)-overexpressing cells. In addition, olmutinib was found to stimulate ATPase activity and inhibit photolabeling of ABCG2 with [I]-iodoarylazidoprazosin (IAAP). However, olmutinib neither altered ABCG2 expression at protein and mRNA levels nor blocked EGFR, Her-2 downstream signaling of AKT and ERK. Importantly, olmutinib enhanced the efficacy of topotecan on the inhibition of S1-MI-80 cell xenograft growth. All the results suggest that olmutinib reverses ABCG2-mediated MDR by binding to ATP bind site of ABCG2 and increasing intracellular chemotherapeutic drug accumulation. Our findings encouraged to further clinical investigation on combination therapy of olmutinib with conventional chemotherapeutic drugs in ABCG2-overexpressing cancer patients.

Impact of chrysosplenetin, per se or in combination with artemisinin, on breast cancer resistance protein (Bcrp)/ABCG2 mRNA expression levels in mice small intestine

ABSTRACT Our previous work revealed that chrysosplenetin in combination with artemisinin inhibited in vivo P-glycoprotein (P-gp, one of classic multi-drug resistance proteins) mediated digoxin transportation activity by reversing the upregulated P-gp/Mdr1 mRNA expression levels by artemisinin. Therefore, chrysosplenetin might be a potential artemisinin-resistance reversal agent as a P-gp inhibitor. But it still remains unknown if chrysosplenetin has an impact on another pivotal multi-drug resistance protein, breast cancer resistance protein (Bcrp), which is co-expressed with P-gp in apical membrane of intestinal epithelial cell and overlaps some of the substrates and inhibitors. This study, therefore, further addressed the impact of chrysosplenetin, per se or in combination with artemisin, on Bcrp/ABCG2 mRNA expression levels in mice small intestine determined by western blot and real time-quantitative polymerase chain reaction (RT-qPCR) assay. The drugs were intragastrically administrated once per day for 7 days. Novobiocin, a known Bcrp inhibitor, was observed to have no impact on Bcrp/ABCG2 levels with or without artemisinin versus vehicle. Interestingly, artemisinin alone attenuated Bcrp level while chrysosplenetin alone increased it (p < 0.05). Relative mRNA level was significantly decreased when co-used with artemisinin and chrysosplenetin in ratio of 1:2 (p < 0.05). The discrepant results for chrysosplenetin on Bcrp/ABCG2 mRNA expressions might be closely related to the transcriptional or posttranscriptional regulation.

Evidence of progenitor cells in the adult human cochlea: sphere formation and identification of ABCG2

OBJECTIVES: The aim of this study was to search for evidence of stem or progenitor cells in the adult human cochlea by testing for sphere formation capacity and the presence of the stem cell marker ABCG2. METHODS: Cochleas removed from patients undergoing vestibular schwannoma resection (n=2) and from brain-dead organ donors (n=4) were dissociated for either flow cytometry analysis for the stem cell marker ABCG2 or a sphere formation assay that is widely used to test the sphere-forming capacity of cells from mouse inner ear tissue. RESULTS: Spheres were identified after 2-5 days in vitro, and the stem cell marker ABCG2 was detected using flow cytometric analysis after cochlear dissociation. CONCLUSIONS: Evidence suggests that there may be progenitor cells in the adult human cochlea, although further studies are required.

Expression and significance of ABCG2 and ALDH1 in malignant transformation of ovarian endometriosis / 重庆医学

Objective To investigate the expression and significance of ABCG2 and ALDH1 in malignant transformation of ovarian endometriosis.Methods The protein expressions of ABCG2 and ALDH1 were detected with immunohistochemistry in 38 cases of malignant transformation of ovarian endometriosis(EMs malignant transformation group),35 cases of endometriosis(EMs group)and 30 cases of normal endometrium(control group).Results The positive rates of ABCG2 and ALDH1 expressions in EMs malignant transformation group were significantly higher than those in EMs group and control group(P0.05).There was no correlation between the expression of ABCG2 and ALDH1 in malignant transformation of ovarian endometriosis(P>0.05).Conclusion The expressions of ABCG2 and ALDH1 might be involved in malignant transformation of ovarian endometriosis.

Relationship between ABCG2 expression and chemotherapeutic efficacy and drug resistance of anthracyclines after breast cancer surgery / 中国生化药物杂志

Objective To investigate the relationship between adenosine triphosphate-binding cassette superfamily G member 2 (ABCG2) mRNA and protein expressions and chemotherapeutic efficacy and drug resistance in breast cancer patients. Methods 24 patients with breast cancer were selected as study subjects, all patients were treated with anthracycline chemotherapy after chemotherapy, according to WHO criteria, the patients were divided into effective group, stable group and advanced group according to chemotherapy effect. The levels of ABCG2 mRNA and protein in the breast tissue were detected by qPCR and ELISA before and after chemotherapy. Results After chemotherapy, the total effective rate was 41.67%, 58.33% of patients still developed drug resistance. The expressions of ABCG2 mRNA and protein in patients after chemotherapy were significantly higher than those before chemotherapy (P<0.05). The expressions of ABCG2 mRNA and protein were significantly lower in the effective group than in the stable group and advanced group (P<0.05). The expressions of ABCG2 mRNA and protein in the stable group was significantly lower than that in the advanced group (P<0.05). Conclusion The expression level of ABCG2 was correlated with the chemotherapeutic efficacy and drug resistance of breast cancer patients. The higher the ABCG2 expression level, the stronger the ability of promoting the excretion of drugs, the more significant the drug resistance of tumor cells and the worsen the chemotherapy effect.

ABCG2 Polymorphism Is Associated with Hyperuricemia in a Study of a Community-Based Korean Cohort

The purpose of the present study was to find novel loci associated with hyperuricemia using data from a genome-wide association study (GWAS) conducted on healthy Koreans. We conducted a GWAS using data from a community-based cohort study where 3,647 subjects aged 40–89 were recruited by the Korea National Institute of Health (KNIH). The community-based cohort consisted of subjects who did not suffer from any of 6 major diseases (hypertension, hyperlipidemia, diabetes, heart diseases, brain diseases, and cancers). Epidemiologic information includes 249 traits such as epidemiological surveys, physical examinations, and laboratory tests. A total of 3,647 participants, including 234 hyperuricemia cases (serum uric acid [SUA] level was 7 mg/dL or higher) and 3,413 controls, were genotyped by Illumina HumanOmni1-Quad BeadChip GWAS array at KNIH. In the multivariate regression analysis of clinical variables, significant variables associated with hyperuricemia were male gender (odds ratio [OR], 5.526; P = 3.2 × 10⁻¹⁰), old age (OR, 1.017; P = 0.040), high body mass index (BMI) (OR, 1.147; P = 5.4 × 10⁻⁷), current alcohol intake (OR, 2.413; P = 4.7 × 10⁻⁷), and high creatinine (OR, 1.647; P = 1.6 × 10⁻¹³). We identified a hyperuricemia susceptible loci (rs2054576 in ABCG2, OR, 1.883; P = 4.7 × 10⁻⁸) that passed a genome-wide significance threshold, adjusted by clinical variables (male, age, BMI, current alcohol, and creatinine). It was first identified that rs2054576 in ABCG2 is associated with hyperuricemia. Our results should be validated through replication studies among other Korean subjects or various ethnic groups.

Effects of Sappan Lignum and Chuanxiong Rhizoma on Expression of ABCG2 Protein of PG-BE1 Stem Like Cells in Vivo / 中国中医药信息杂志

Objective To observe the effects of different doses of Sappan Lignum and Chuanxiong Rhizoma on tumor stem cells marker ABCG2 in vivo. Methods Sphere cells obtained from serum culture were inoculated in nude mouse armpit, which were randomly divided into 5 groups: control group, Sappan Lignum high- and low-dose groups, and Chuanxiong Rhizoma high- and low-dose groups. Each medication group was given relevant medicine for gavage. 21 days later, inhibition tumor rate and ABCG2 protein and mRNA expression were detected with confocal microscope, Western blot, and RT-PCR. Results The sphere cells obtained from serum free culture had the abilities of cancer stem cells, such as proliferation, anti-aptosis and high expression of cancer stem cells markers. Chuanxiong Rhizoma high- and low-dose groups could inhibit tumor growth (P0.05). Compared with the control group, Chuanxiong Rhizoma low-dose group could significantly inhibit the expression of resistant protein of ABCG2. Sappan Lignum high- and low-dose groups could not inhibit the protein expression of ABCG2. Each medication group up-regulated the mRNA expression of ABCG2 except for Chuanxiong Rhizoma low-dose group. Conclusion Low dose of Chuanxiong Rhizoma can inhibit the expression of ABCG2 protein levels, which can be the targeting killer for cancer stem cells.