Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients

Spitzwieser, Melanie; Pirker, Christine; Koblmüller, Bettina; Hacker, Stefan; Berger, Walter; Heffeter, Petra; Cichna‐Markl, Margit

doi:10.18632/oncotarget.12332

Cited by 32 publications

(32 citation statements)

References 53 publications

(80 reference statements)

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“…To analyze ABCG2 methylation, we examined 4 CpGs in a region of 360 bp in the ABCG2 promoter region. We did not observe any changes in methylation of these 4 CpGs during the development of IM-resistance, these findings are in line with those of different cancer entities, such as glioblastoma multiforme [ 50 ], breast-cancer [ 26 ] or multiple myeloma [ 51 ], where no or only partial impact of ABCG2 methylation could be observed. For ABCB1 , we did not observe changes in methylation during the development of IM-resistance.…”

Section: Discussionsupporting

confidence: 89%

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MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

et al. 2017

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BCR-ABL-independent resistance against tyrosine kinase inhibitor is an emerging problem in therapy of chronic myeloid leukemia. Such drug resistance can be linked to dysregulation of ATP-binding cassette (ABC)-transporters leading to increased tyrosine kinase inhibitor efflux, potentially caused by changes in microRNA expression or DNA-methylation. In an in vitro-imatinib-resistance model using K-562 cells, microRNA-212 was found to be dysregulated and inversely correlated to ABC-transporter ABCG2 expression, targeting its 3′-UTR. However, the functional impact on drug sensitivity remained unknown. Therefore, we performed transfection experiments using microRNA-mimics and –inhibitors and investigated their effect on imatinib-susceptibility in sensitive and resistant leukemic cell lines. Under imatinib-treatment, miR-212 inhibition led to enhanced cell viability (p = 0.01), reduced apoptosis (p = 0.01) and cytotoxicity (p = 0.03). These effects were limited to treatment-naïve cells and were not observed in cells, which were resistant to various imatinib-concentrations (0.1 μM to 2 μM). Further analysis in treatment-naïve cells revealed that miR-212 inhibition resulted in ABCG2 upregulation and increased ABCG2-dependent efflux. Furthermore, we observed miR-212 promoter hypermethylation in 0.5 and 2 μM IM-resistant sublines, whereas ABCG2 methylation status was not altered. Taken together, the miR-212/ABCG2-axis influences imatinib-susceptibility contributing to development of imatinib-resistance. Our data reveal new insights into mechanisms initiating imatinib-resistance in leukemic cells.

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Section: Discussionsupporting

confidence: 89%

“…In several cancer entities, aberrant ABCB1 or ABCG2 methylation was shown, i.e. in leukemia or solid tumors [ 23 – 25 ] and was also observed in drug-resistance [ 26 , 27 ]. In CML patients, aberrant DNA methylation of various genes could be associated to disease progression and potentially, IM-resistance [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

et al. 2017

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“…Our data suggested that HOXA5 inhibited the progression of GC. In order to further explore the underlying mechanisms, we used RT-qPCR to detect the expression of the following genes in 30 GC tissues, including tumorigenesis-related genes ( p21, p53 and β-catenin ), proliferation-related genes ( cyclin B1, cyclin D1, c-Myc and Ki67 ), angiogenesis-related genes [vascular endothelial growth factor ( VEGF ) A, VEGFR2 and epidermal growth factor ( EGFR )], metastasis-related genes [matrix metalloproteinase ( MMP2 ) and ( MMP7 )], apoptosis-related genes ( BCL2 and caspase-3 ), EMT markers (vimentin, N-cadherin and E-cadherin), stemness markers ( Lgr5, CD44 and EpCAM ) and multi-drug resistance genes ( ABCC1, ABCG2 and Beclin1) ( 10 – 15 ). A Spearman's correlation model was used to examine the correlation between each of these genes and HOXA5 mRNA expression.…”

Section: Resultsmentioning

confidence: 99%

HOXA5 is a tumor suppressor gene that is decreased in gastric cancer

et al. 2018

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The abnormal expression of homeobox A5 (HOXA5) has been observed in breast and colon cancer; however, the clinical significance of HOXA5 in gastric cancer (GC) is not yet clear. In this study, we found that HOXA5 expression was decreased in GC tissues at the mRNA and protein level compared with paracancerous tissues using reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis, respectively. Immunohistochemistry and Kaplan-Meier survival analysis confirmed that the underexpression of HOXA5 was associated with GC progression and indicated a poor prognosis of patients with GC. Given that proliferation-related genes may be potential target genes of HOXA5, we performed a series of experiments in vitro to examine the effects of HOXA5 on the proliferation of GC cells. A CCK-8 assay, colony formation assay and flow cytometry revealed that HOXA5 inhibited the abnormal proliferation of GC cells, and this finding was further supported by a 5-ethynyl-2′-deoxyuridine (EdU) assay. Further mechanistic investigation clarified that HOXA5 promoted the protein expression of p21 and inhibited the protein expression of c-Myc and Ki67. Additionally, the use of nude mouse models also verified that HOXA5 suppressed the proliferation of GC cells in vivo. Collectively, the findings of this study demonstrate that HOXA5 acts as a tumor suppressor gene during the development and progresion of GC, possibly functioning by inhibiting the abnormal proliferation of cancer cells.

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“…ATP-binding cassette transporter super-family has vital effect on MDR in cancer, which is reported to a main leading cause of chemotherapeutic failure in various cancers through regulating the efflux of chemotherapeutic drugs [ 15 – 18 ]. Previous reports have exhibited ABCC1 to be up-regulated in colorectal cancer [ 19 ], lung cancer [ 20 ], and breast cancer [ 21 ]. MDR-1 serving as a protein scavenger also can capture and transport various chemotherapeutic agents out of cells [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of miR-210-3p encourages chemotherapy resistance of renal cell carcinoma via modulating ABCC1

Yang

Wang

et al. 2018

Cell Biosci

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BackgroundATP-binding cassette transporter super-family including ABCC1 and MDR-1 were involved in multi-drug resistance (MDR) of renal cell carcinoma (RCC) patients. Several miRNAs were confirmed to promote the MDR and the survival of tumor cells.MethodsThe RCC cell lines Caki-2 with vinblastine-resistant (Caki-2/VBL) or doxorubicin-resistant (Caki-2/DOX) were constructed, respectively. The expressions of miR-210-3p, ABCC1 and MDR-1 protein were determined by qRT-PCR and Western blot assays. The viability of RCC cells was assessed by MTT assay. The regulatory relationship between miR-210-3p and ABCC1 was analyzed by Dual Luciferase assay. The effect of miR-210-3p in vivo was investigated with a tumor xenograft model in mice.ResultsMiR-210-3p expression was observed to significantly decrease in Caki-2/VBL and Caki-2/DOX cells. Meanwhile, ABCC1 and MDR-1 were significantly increased in Caki-2/VBL and Caki-2/DOX cells. ABCC1 was a novel target of miR-210-3p and negatively regulated by miR-210-3p. And miR-210-3p improved drug-sensitivity of RCC cells. Down-regulation of ABCC1 could reverse the effect of miR-210-3p knockdown on the drug-resistance and the level of MDR-1 in drug-sensitive RCC cells.ConclusionWe confirmed that down-regulation of miR-210-3p increased ABCC1 expression, thereby enhancing the MRP-1-mediated multidrug resistance of RCC cells.

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Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients

Cited by 32 publications

References 53 publications

MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

HOXA5 is a tumor suppressor gene that is decreased in gastric cancer

Down-regulation of miR-210-3p encourages chemotherapy resistance of renal cell carcinoma via modulating ABCC1

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