Gene Summary

Gene:ABCC2; ATP binding cassette subfamily C member 2
Aliases: DJS, MRP2, cMRP, ABC30, CMOAT
Summary:The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein is expressed in the canalicular (apical) part of the hepatocyte and functions in biliary transport. Substrates include anticancer drugs such as vinblastine; therefore, this protein appears to contribute to drug resistance in mammalian cells. Several different mutations in this gene have been observed in patients with Dubin-Johnson syndrome (DJS), an autosomal recessive disorder characterized by conjugated hyperbilirubinemia. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:canalicular multispecific organic anion transporter 1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ABCC2 (cancer-related)

Jagoda EM, Vasalatiy O, Basuli F, et al.
Immuno-PET Imaging of the Programmed Cell Death-1 Ligand (PD-L1) Using a Zirconium-89 Labeled Therapeutic Antibody, Avelumab.
Mol Imaging. 2019 Jan-Dec; 18:1536012119829986 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The goal is to evaluate avelumab, an anti-PD-L1 monoclonal immunoglobulin G antibody labeled with zirconium-89 in human PD-L1-expressing cancer cells and mouse xenografts for clinical translation.

Sone K, Oguri T, Uemura T, et al.
Genetic variation in the ATP binding cassette transporter ABCC10 is associated with neutropenia for docetaxel in Japanese lung cancer patients cohort.
BMC Cancer. 2019; 19(1):246 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Docetaxel is a widely used cytotoxic agent for treatments of various cancers. The ATP binding cassette (ABC) transporter / multidrug resistance protein (MRP) ABCC10/MRP7, involved in transporting taxanes, has been associated with resistance to these agents. Since genetic variation in drug transporters may affect clinical outcomes, we examined whether polymorphism of ABCC10 could affect clinical responses to docetaxel.
METHODS: Using 18 NSCLC cell lines and CRISPR-based genome-edited HeLa cells, we analyzed whether genetic variants of ABCC10 (rs2125739, rs9349256) affected cytotoxicity to docetaxel. Subsequently, we analyzed genetic variants [ABCC10 (rs2125739), ABCB1 (C1236T, C3435T, G2677 T/A), ABCC2 (rs12762549), and SLCO1B3 (rs11045585)] in 69 blood samples of NSCLC patients treated with docetaxel monotherapy. Clinical outcomes were evaluated between genotype groups.
RESULTS: In the cell lines, only one genetic variant (rs2125739) was significantly associated with docetaxel cytotoxicity, and this was confirmed in the genome-edited cell line. In the 69 NSCLC patients, there were no significant differences related to rs2125739 genotype in terms of RR, PFS, or OS. However, this SNP was associated with grade 3/4 neutropenia (T/C group 60% vs. T/T group 87%; P = 0.028). Furthermore, no patient with a T/C genotype experienced febrile neutropenia.
CONCLUSIONS: Our results indicate that genetic variation in the ABCC10 gene is associated with neutropenia for docetaxel treatment.

Tsui KH, Hou CP, Chang KS, et al.
Metallothionein 3 Is a Hypoxia-Upregulated Oncogene Enhancing Cell Invasion and Tumorigenesis in Human Bladder Carcinoma Cells.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
Metallothioneins have been viewed as modulators in a number of biological regulations regarding cancerous development; however, the function of metallothionein 3 (

Malinen MM, Ito K, Kang HE, et al.
Protein expression and function of organic anion transporters in short-term and long-term cultures of Huh7 human hepatoma cells.
Eur J Pharm Sci. 2019; 130:186-195 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Human-derived hepatic cell lines are a valuable alternative to primary hepatocytes for drug metabolism, transport and toxicity studies. However, their relevance for investigations of drug-drug and drug-organic anion (e.g., bile acid, steroid hormone) interactions at the transporter level remains to be established. The aim of the present study was to determine the suitability of the Huh7 cell line for transporter-dependent experiments. Huh7 cells were cultured for 1 to 4 weeks and subsequently were analyzed for protein expression, localization and activity of solute carrier (SLC) and ATP-binding cassette (ABC) transporters involved in organic anion transport using liquid chromatography-tandem mass spectroscopy, immunocytochemistry, and model substrates [

Zhang Y, Tao L, Fan LX, et al.
Cx32 mediates cisplatin resistance in human ovarian cancer cells by affecting drug efflux transporter expression and activating the EGFR‑Akt pathway.
Mol Med Rep. 2019; 19(3):2287-2296 [PubMed] Related Publications
Our previous study demonstrated that connexin 32 (Cx32) was upregulated and redistributed to the cytoplasm in A2780 human ovarian cancer cells with acquired resistance to cisplatin; this increased Cx32 feedback promoted cisplatin resistance. To further investigate the mechanism underlying Cx32‑mediated cisplatin resistance, alterations in drug transporters, the DNA repair system and the anti‑apoptotic signalling pathway were investigated by overexpressing or knocking down Cx32 in parental cells (A2780); cisplatin‑resistant human ovarian cancer cells (A2780/CDDP) were also acquired. Upregulation of efflux transporters [multi‑drug resistance protein 2 (MRP‑2), ATPase copper transporting α (ATP7A) and ATPase copper transporting β] and downregulation of the influx transporter copper uptake protein 1 mediated cisplatin resistance in A2780/CDDP cells. A2780/CDDP cells also exhibited increased expression of the DNA repair enzyme excision repair cross‑complementation group 1 (ERCC1) and activation of the epidermal growth factor receptor (EGFR) signalling pathway. Small interfering RNA‑mediated knockdown of Cx32 in A2780/CDDP cells decreased the expression of efflux transporters (MRP‑2 and ATP7A). Knockdown of Cx32 in A2780/CDDP cells also decreased the expression of ERCC1, inhibited the activation of the EGFR signalling pathway and enhanced the cytotoxicity of cisplatin. When Cx32 was overexpressed in A2780 cells, an opposite effect on the expression of efflux transporters (MRP‑2 and ATP7A) and the activation of the EGFR signalling pathway was observed, which resulted in insensitivity to cisplatin‑induced apoptosis. Thus, Cx32 expression may induce cisplatin resistance by modulating drug efflux transporter expression and activating the EGFR‑protein kinase B signalling pathway in ovarian cancer cells.

Treenert A, Areepium N, Tanasanvimon S
Effects of ABCC2 and SLCO1B1 Polymorphisms on Treatment Responses in Thai Metastatic Colorectal Cancer Patients Treated with Irinotecan-Based Chemotherapy
Asian Pac J Cancer Prev. 2018; 19(10):2757-2764 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Purpose: Irinotecan is an anticancer medicine which is used mostly in metastatic colorectal cancer (mCRC) treatment as second or third line chemotherapy. Several factors affect its efficacy and toxicity, including pharmacogenomics. This study aimed to investigate the impacts of ABCC2 and SLCO1B1 polymorphisms on treatment responses in irinotecan-based chemotherapy in 49 Thai mCRC patients. Materials and Methods: Forty-nine participants with mCRC enrolled in this study received irinotecan-based chemotherapy from January to June 2017. Genotypic analyses of ABCC2 (C>T, rs717620) and SLCO1B1 (A>G, rs2306283) were performed. Treatment responses were evaluated after at least three cycles of chemotherapy were given. Results: Allele frequencies of ABCC2 (C>T) and SLCO1B1 (A>G) were found at 18.37% and 78.57%, respectively. Neither was associated with treatment responses. However, combined genotypes of ABCC2 and SLCO1B1 tended to be associated with clinical benefits in terms of partial responses (PR) and stable disease (SD). All patients (100%) with at least one variant allele of SLCO1B1 and ABCC2 were in a PR or SD group, while patients with other genotypes had progressive disease (PD) at 45.5% to 70%, (p = 0.059). Conclusion: The combined effect of ABCC2 and SLCO1B1 polymorphisms tended to be associated with treatment responses in irinotecan-based treated mCRC patients. Therefore, such polymorphisms could be factors impacting inter-individual variation of irinotecan efficacy in Thai mCRC patients.

Ruiz-Pinto S, Martin M, Pita G, et al.
Pharmacogenetic variants and response to neoadjuvant single-agent doxorubicin or docetaxel: a study in locally advanced breast cancer patients participating in the NCT00123929 phase 2 randomized trial.
Pharmacogenet Genomics. 2018; 28(11):245-250 [PubMed] Related Publications
OBJECTIVES: Taxanes and anthracyclines are widely used in the treatment of breast cancer, although the benefit is limited to a proportion of patients and predictive biomarkers for clinical outcome remain elusive.
PATIENTS AND METHODS: We carried out a pharmacogenetic study in 181 patients with locally advanced breast cancer enrolled in a phase 2 randomized clinical trial (NCT00123929), where patients were randomly assigned to receive neoadjuvant single-agent docetaxel 100 mg/m(2) (n=84) or doxorubicin 75 mg/m(2) (n=97). We studied the association of 226 single nucleotide polymorphisms (SNPs) in 15 key drug biotransformation genes with neoadjuvant pathological tumor response residual cancer burden index to docetaxel and to doxorubicin.
RESULTS: We identified a significant association for rs162561, an intronic SNP located in the cytochrome P450 family 1 subfamily B member 1 (CYP1B1) gene, with tumor response in patients treated with single-agent docetaxel (dominant model: β=1.02, 95% confidence interval=0.49-1.55; P=1.77×10(-4)), and for rs717620, an SNP located in the promoter of the ATP-binding cassette subfamily C member 2 (ABCC2) gene, in patients treated with neoadjuvant doxorubicin (recessive model: β=1.67; 95% confidence interval=0.26-3.11; P=0.02).
CONCLUSION: We identified two polymorphisms in CYP1B1 and ABCC2 associated with tumor pathological response following docetaxel or doxorubicin neoadjuvant monotherapy, respectively. Although further validation is required, these variants could be potential predictive genetic markers for treatment outcome in breast cancer patients.

Chua PJ, Lim JP, Guo TT, et al.
Y-box binding protein-1 and STAT3 independently regulate ATP-binding cassette transporters in the chemoresistance of gastric cancer cells.
Int J Oncol. 2018; 53(6):2579-2589 [PubMed] Related Publications
Y-box binding protein-1 (YB-1) facilitates cancer chemoresistance through the upregulation of ATP-binding cassette (ABC) transporters associated with multidrug resistance, which is one of the primary obstacles in cancer treatment. Since aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is also implicated in chemoresistance in numerous human malignancies, the interaction between YB-1 and JAK/STAT signaling was explored underlying the chemoresistance of NUGC3 gastric cancer cells. It was demonstrated that YB-1 translocated into the nuclei of NUGC3 cells exposed to doxorubicin hydrochloride, suggesting its important role in chemoresistance. Consistently, knockdown of YB-1 significantly decreased the chemoresistance of cells to doxorubicin hydrochloride and epirubicin hydrochloride, as evidenced by a decrease in cell viability. Notably, JAK inhibitor AG490 treatment further decreased the cell viability caused by YB-1 inhibition and doxorubicin hydrochloride. It was also observed that YB-1 transcriptionally regulated the ABCC3 transporter, whereas STAT3 modulated ABCC2 transporter levels. These findings suggest that YB-1 and STAT3 act together to facilitate chemoresistance via modulating the expression of different ABC transporters in NUGC3 cells. Notably, siYB-1 did not exhibit any significant effect on STAT3 expression. Similarly, siSTAT3 failed to alter YB-1 expression, suggesting that the two may not regulate each other in a mutual manner. However, double knockdown of YB-1 and STAT3 led to a synergistic inhibition of cell invasion in NUGC3 cells. Nonetheless, the combined treatment of YB-1 antagonists with STAT3 inhibitors may serve as an effective therapy in gastric cancer.

Zhuang X, Li X, Zhang J, et al.
Conditioned medium mimicking the tumor microenvironment augments chemotherapeutic resistance via ataxia‑telangiectasia mutated and nuclear factor‑κB pathways in gastric cancer cells.
Oncol Rep. 2018; 40(4):2334-2342 [PubMed] Related Publications
The tumor microenvironment affects the processes involved in the development of gastric cancer and contributes to multidrug resistance (MDR). Although the metabolism of gastric cancer cells is known to be associated with the development of the tumor microenvironment, the exact role of metabolism in microenvironment‑induced MDR formation remains unclear. In the present study, conditioned medium (CM) formed through the metabolism of SGC‑7901 gastric carcinoma cells was used to mimic the tumor microenvironment. The effects of CM on drug resistance were evaluated in gastric carcinoma cells. The results revealed that CM was not only able to upregulate the expression levels of ATP‑binding cassette subfamily G member 2 (ABCG2) and MDR‑associated protein 2 (MRP2), but also upregulated the expression of certain anti‑apoptotic proteins in SGC‑7901 cells. In addition, CM activated the ataxia‑telangiectasia mutated (ATM) and NF‑κB pathways, while CM‑induced ABCG2, MRP2 and anti‑apoptotic protein upregulation was impaired by ATM and NF‑κB inhibitors. The results of the present study indicated that CM augmented chemotherapeutic resistance by activating the ATM and NF‑κB pathways in gastric cancer cells, and that these pathways may be potential therapeutic targets for cases of chemotherapeutic resistance in gastric cancer.

Macauda A, Castelli E, Buda G, et al.
Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients.
Br J Haematol. 2018; 183(3):375-384 [PubMed] Related Publications
Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.

Sági JC, Egyed B, Kelemen A, et al.
Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma.
BMC Cancer. 2018; 18(1):704 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes.
METHODS: Echocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs.
RESULTS: Our results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p = 5.60E-03; OR = 6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p = 6.50E-03; OR = 11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10 years after treatment (p = 7.38E-03, p = 7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10 years after the diagnosis (p = 4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p = 1.71E-03), 5-10 years after the diagnosis.
CONCLUSIONS: Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.

Jabir RS, Ho GF, Annuar MABA, Stanslas J
Association of Allelic Interaction of Single Nucleotide Polymorphisms of Influx and Efflux Transporters Genes With Nonhematologic Adverse Events of Docetaxel in Breast Cancer Patients.
Clin Breast Cancer. 2018; 18(5):e1173-e1179 [PubMed] Related Publications
PURPOSE: Nonhematologic adverse events (AEs) of docetaxel constitute an extra burden in the treatment of cancer patients and necessitate either a dose reduction or an outright switch of docetaxel for other regimens. These AEs are frequently associated with genetic polymorphisms of genes encoding for proteins involved docetaxel disposition. Therefore, we investigated that association in Malaysian breast cancer patients.
MATERIALS AND METHODS: A total of 110 Malaysian breast cancer patients were enrolled in the present study, and their blood samples were investigated for different single nucleotide polymorphisms using polymerase chain reaction restriction fragment length polymorphism. AEs were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0.
RESULTS: Fatigue, nausea, oral mucositis, and vomiting were the most common nonhematologic AEs. Rash was associated with heterozygous and mutant genotypes of ABCB1 3435C>T (P < .05). Moreover, patients carrying the GG genotype of ABCB1 2677G>A/T reported more fatigue than those carrying the heterozygous genotype GA (P < .05). The presence of ABCB1 3435-T, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-G alleles was significantly associated with nausea and oral mucositis. The coexistence of ABCB1 3435-C, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-A was significantly associated with vomiting (P < .05).
CONCLUSION: The prevalence of nonhematologic AEs in breast cancer patients treated with docetaxel has been relatively high. The variant allele of ABCB1 3435C>T polymorphism could be a potential predictive biomarker of docetaxel-induced rash, and homozygous wild-type ABCB1 2677G>A/T might predict for a greater risk of fatigue. In addition, the concurrent presence of specific alleles could be predictive of vomiting, nausea, and oral mucositis.

Chen Z, Huang C, Ma T, et al.
Reversal effect of quercetin on multidrug resistance via FZD7/β-catenin pathway in hepatocellular carcinoma cells.
Phytomedicine. 2018; 43:37-45 [PubMed] Related Publications
BACKGROUND: Chemotherapy has been widely used to treat cancer, but the appearance of multidrug resistance (MDR) is the biggest obstacle to successful chemotherapy. One of the conventional mechanisms of MDR is overexpression of ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp/ABCB1) and multidrug resistance-associated proteins (MRPs/ABCCs) that limits the prolonged and efficient use of chemotherapeutic drugs. To enhance the chemosensitivity of tumor cells, attentions have been focused on effective MDR modulators.
PURPOSE: This study aimed to investigate the reversal effect of quercetin on MDR, and explored its mechanism of action in vitro.
STUDY DESIGN/METHODS: The effect and mechanism of quercetin on MDR was examined by using MTT assay, flow cytometry, real-time PCR and western blot analysis in human hepatocellular carcinoma cells.
RESULTS: Our data found that the intracellular accumulation of rhodamine-123 (Rh123) and doxorubicin (ADR) were increased, the sensitivity of BEL/5-FU cells to chemotherapeutic drugs were increased, and the expressions of ABCB1, ABCC1 and ABCC2 were all down-regulated, which indicated that the functions and expressions of ABCB1, ABCC1 and ABCC2 efflux pump were inhibited by quercetin treatment. Moreover, the suppression of ABCB1, ABCC1 and ABCC2 by quercetin was dependent on the FZD7 through the Wnt/β-catenin pathway. Further research revealed that reduction of FZD7 by RNA interference (siFZD7) enhanced the sensitivity to chemotherapeutic drugs, increased the cellular accumulation of Rh123 and ADR, and induced inhibitory effects on the expression of FZD7, ABCB1, ABCC1, ABCC2 and β-catenin, similar to quercetin. In the meanwhile, overexpression of FZD7 showed the inversely effect on the expressions. Interesting, it was confirmed that quercetin could inhibit the expression levels of FZD7, ABCB1, ABCC1, ABCC2 and β-catenin in BEL-7402 cells; furthermore, treatment by quercetin combined with siFZD7 in BEL/5-FU cells, the expressions of these genes were effectively decreased in comparison to quercetin combined with siRNA negative control (sncRNA).
CONCLUSION: Overall, these data suggested the effectiveness of using quercetin, at least in part, via inhibiting FZD7 to combat chemoresistance and showed that quercetin could be developed into an efficient natural sensitizer for resistant human hepatocellular carcinoma.

Rigalli JP, Reichel M, Tocchetti GN, et al.
Human papilloma virus (HPV) 18 proteins E6 and E7 up-regulate ABC transporters in oropharyngeal carcinoma. Involvement of the nonsense-mediated decay (NMD) pathway.
Cancer Lett. 2018; 428:69-76 [PubMed] Related Publications
Oropharyngeal cancer incidence increased dramatically in the last decades, being infection with human papillomaviruses (HPV) a determinant of this trend. Concerning etiology, treatment response and prognosis, HPV

An Q, Zhou L, Xu N
Long noncoding RNA FOXD2-AS1 accelerates the gemcitabine-resistance of bladder cancer by sponging miR-143.
Biomed Pharmacother. 2018; 103:415-420 [PubMed] Related Publications
Increasing evidences have proved that long noncoding RNAs (lncRNAs) modulate the tumorigenesis of bladder cancer involved in multiple pathophysiological processes. In the study, we investigate the role of lncRNA FOXD2-AS1 in the gemcitabine (GEM) resistant bladder cancer and explore its potential mechanism. Results showed that lncRNA FOXD2-AS1 was high-expressed in gemcitabine-resistant bladder cancer cells. In vitro experiments, FOXD2-AS1 knockdown suppressed the 50% inhibitive concentration (IC50) of gemcitabine, drug-resistance related genes (MDR1, MRP2, LRP1) expression, invasion and ABCC3 protein expression in gemcitabine-resistant bladder cancer cells (T24/GEM, 5637/GEM). In vivo of xenograft assay, FOXD2-AS1 knockdown inhibited the tumor growth of bladder cancer cells. Bioinformatics program and validation experiments confirmed that FOXD2-AS1 positively regulated ABCC3 protein through targeting miR-143, acting as a competing endogenous RNA (ceRNA). In summary, our results revealed the vital roles of FOXD2-AS1/miR-143/ABCC3 axis in gemcitabine resistance of bladder cancer cells, providing a novel therapeutic strategy for bladder cancer.

Luo Q, Wu X, Zhang Y, et al.
ARID1A ablation leads to multiple drug resistance in ovarian cancer via transcriptional activation of MRP2.
Cancer Lett. 2018; 427:9-17 [PubMed] Related Publications
Multiple Drug Resistance (MDR) of ovarian cancer is a severe trouble for clinical treatment and always contributes to a bad prognosis. AT-rich interaction domain 1 A (ARID1A) has been recognized as a bona fide tumor suppressor gene in recent years, with the highest mutation rate in ovarian cancer. Previous study illustrated that ARID1A expression is negatively correlated with chemoresistance of ovarian cancer cases. However, the specific role of ARID1A in chemoresistance of ovarian cancer remains elusive. In this study, we showed that ARID1A knockdown in ovarian cancer cells significantly reduced their apoptosis rate and led to MDR, while ectopic expression of ARID1A showed opposite effects. ARID1A depletion transcriptionally activates the expression of multidrug resistance-associated protein 2 (MRP2) following chromatin remodeling. Furthermore, IHC analysis of ovarian cancer samples confirmed that ARID1A expression was strong negatively correlated with MRP2 expression. Both ARID1A and MRP2 expression levels are correlated with sensitivity to platinum. Collectively, our results illustrated that ARID1A loss in ovarian cancer leads to MDR through upregulation of MRP2, providing an opportunity to overcome the ARID1A loss induced chemoresistance of ovarian cancer by targeting MRP2.

Gao B, Lu Y, Nieuweboer AJM, et al.
Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer.
Sci Rep. 2018; 8(1):1508 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 10

Falkowski S, Woillard JB, Postil D, et al.
Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study.
BMC Cancer. 2017; 17(1):901 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC.
METHODS: Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6-9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and "environmental" risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with "environmental" risk factors.
RESULTS: No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29-8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10-3.39], p = 0.0257) in the "never alcohol consumption subgroup" (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70-10.9], p < 0.0001), living or working in rural or mix area (OR = 2.50[1.48-4.23], p = 0.0006 and OR = 2.99[1.63-5.48], p = 0.004, respectively) and tobacco exposure >30 years (3.37[1.63-6.96], p = 0.0010).
CONCLUSIONS: Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup.
TRIAL REGISTRATION: Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008-0144.

Maruhashi R, Akizuki R, Sato T, et al.
Elevation of sensitivity to anticancer agents of human lung adenocarcinoma A549 cells by knockdown of claudin-2 expression in monolayer and spheroid culture models.
Biochim Biophys Acta Mol Cell Res. 2018; 1865(3):470-479 [PubMed] Related Publications
Claudins, tight junctional proteins, regulate the paracellular permeability of ions and small molecules. Claudin-2 is highly expressed in human lung adenocarcinoma cells and is involved in the up-regulation of cell proliferation. However, the effect of claudin-2 on cellular sensitivity to anticancer agents has not been clarified. The cytotoxicity of anticancer agents such as cisplatin, gefitinib and doxorubicin (DXR) was increased by claudin-2 knockdown in A549 cells. Claudin-2 knockdown also significantly decreased the expression level of multidrug resistance-associated protein/ABCC2. The expression levels of other drug efflux transporters were unchanged. The intracellular accumulation of 5-chloromethylfluorescein diacetate (CMFDA) and DXR, substrates of ABCC2, was increased by claudin-2 knockdown, whereas the efflux was decreased. MK-571, an inhibitor of ABCC2, enhanced the cytotoxicity of anticancer agents. Claudin-2 knockdown decreased the levels of p-c-Jun and nuclear Sp1. SP600125, an inhibitor of c-Jun, and mithramycin, an inhibitor of Sp1, decreased the level of ABCC2. The promoter activity of ABCC2 was decreased by claudin-2 knockdown, SP600125 and mithramycin treatments, suggesting that claudin-2 is involved in the up-regulation of ABCC2 expression at the transcriptional level. Claudin-2 knockdown increased the paracellular permeability of DXR in a 2D monolayer culture model. In addition, the accumulation of DXR into spheroids was enhanced by claudin-2 knockdown, resulting in a reduction in cell viability. We suggest that claudin-2 may be a novel therapeutic target in lung adenocarcinoma, because claudin-2 knockdown increased the accumulation of anticancer agents in cancer cells and spheroids.

Zhou YY, Kang YT, Chen C, et al.
Combination of TNM staging and pathway based risk score models in patients with gastric cancer.
J Cell Biochem. 2018; 119(4):3608-3617 [PubMed] Related Publications
Due to the complexity and heterogeneity of gastric cancer (GC) in individual patient, current staging system is inadequate for predicting outcome of GC. Comprehensive computational and bioinformatics approach may triumph for the prediction. In this study, GC patients were devided according to stage and treatment: curative surgery plus chemoradiotherapy in stage II, curative surgery plus chemoradiotherapy in stages III, and IV, unresectable metastatic gastric cancer. The training sets were downloaded from GEO datasets (GSE26253 and GSE14208). Gene set enrichment analysis (GSEA) was performed to explore enriched difference between recurrence and nonrecurrence. The core enrichment genes of enriched pathways significantly associated with recurrence or progression were identified using Cox proportional hazards analysis. Thereafter, the risk score models were externally validated in independent datasets-GSE15081 and The Cancer Genome Atlas (TCGA). We generated respective risk score models of patients in different stages and treatment. A five-gene signature comprising FARP1, SGCE, SGCA, LAMA4, and COL9A2 was strongly associated with recurrence of patients with curative surgery plus chemoradiotherapy in stage II. A six-gene signature consisting of SHH, NF1, AP4B1, COMP, MATN3, and CCL8 was correlated with recurrence of patients with curative surgery plus chemoradiotherapy in stages III and IV. And a four-gene signature composing of ABCC2, AHNAK2, RNF43, and GSPT2 was highly related to progression of patients with unresectable metastatic GC. Taking into consideration TNM stage and gene signature reflecting recurrence or progression, the risk score models significantly improved the accuracy in predicting outcome of GC.

Zhang Y, Yang SH, Guo XL
New insights into Vinca alkaloids resistance mechanism and circumvention in lung cancer.
Biomed Pharmacother. 2017; 96:659-666 [PubMed] Related Publications
Nowadays, lung cancer, as a health problem in worldwide, has high mortality both in men and women. Despite advances in diagnosis and surgical techniques of lung cancer in recent decades, chemotherapy is still a fundamentally and extensively useful strategy. Vinca alkaloids are a class of important and widely used drugs in the treatment of lung cancer, targeting on the Vinca binding site at the exterior of microtubule plus ends. Either intrinsic or acquired resistance to chemotherapy of Vinca alkaloids has been a major obstacle to the treatment of lung cancer, which arose great interests in studies of understanding and overcoming resistance. In this review, we focused on the application and resistance mechanisms of the Vinca alkaloids such as vinblastine, vincristine, vinorelbine and vinflunine in lung cancer. We reviewed characteristic resistance mechanisms in lung cancer including over-expression of ATP-binding cassette (ABC) transporters P-glycoprotein and structural, functional or expression alterations of β-tubulin (βII, βIII, βIV) which may devote to the development of acquired resistance to the Vinca alkaloids; multidrug-resistance proteins (MRP1, MRP2, MRP3) and RLIP76 protein have also been identified that probably play a significant role in intrinsic resistance. Lung resistance-related protein (LRP) is contributed to lung cancer therapy resistance, but is not deal with the Vinca alkaloids resistance in lung cancer. Understanding the principle of the Vinca alkaloids in clinical application and mechanisms of drug resistance will support individualized lung cancer therapy and improve future therapies.

Świerczewska M, Klejewski A, Wojtowicz K, et al.
New and Old Genes Associated with Primary and Established Responses to Cisplatin and Topotecan Treatment in Ovarian Cancer Cell Lines.
Molecules. 2017; 22(10) [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Low efficiency of chemotherapy in ovarian cancer results from the development of drug resistance. Cisplatin (CIS) and topotecan (TOP) are drugs used in chemotherapy of this cancer. We analyzed the development of CIS and TOP resistance in ovarian cancer cell lines. Incubation of drug sensitive cell lines (W1 and A2780) with cytostatic drugs was used to determine the primary response to CIS and TOP. Quantitative polymerase chain reaction (Q-PCR) was performed to measure the expression levels of the genes. We observed decreased expression of the

Kishimoto S, Yasuda M, Fukushima S
Changes in the Expression of Various Transporters as Influencing Factors of Resistance to Cisplatin.
Anticancer Res. 2017; 37(10):5477-5484 [PubMed] Related Publications
BACKGROUND: Changes in the expression of transporters have been reported as factors in resistance to cisplatin (CDDP). This study was designed to clarify whether CDDP-resistant strains isolated from a cell line had the same characteristics, and whether these characteristics could be therapeutic targets.
MATERIALS AND METHODS: Intracellular platinum levels were determined by the inductively-coupled plasma method. mRNA expression levels were determined using the real-time polymerase chain reaction.
RESULTS: Some CDDP-resistant HepG2 cell lines exhibited changes in the expression of copper transporter 1, multidrug resistant protein (MRP)2, and/or MRP3, resulting in decreased intracellular platinum amounts, while others showed no change in platinum accumulation. Expression of these transporters was not necessarily maintained in a constant direction within the cell population isolated from the same origin.
CONCLUSION: These results suggest that the CDDP-resistant tumors caused by a decrease in intracellular platinum content consist of a heterogeneous cell population showing expression changes of several transporters.

Lin GL, Ting HJ, Tseng TC, et al.
Modulation of the mRNA-binding protein HuR as a novel reversal mechanism of epirubicin-triggered multidrug resistance in colorectal cancer cells.
PLoS One. 2017; 12(10):e0185625 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
HuR (ELAVL1), a RNA-binding protein, plays a key role in posttranscriptional regulation of multidrug resistance (MDR)-related genes. Among various HuR-regulated oncogenic transcripts, the activation of galectin-3/β-catenin survival pathway is critical to induce transcription of cyclin D1, P-glycoprotein (P-gp) and/or multidrug resistance-associated proteins (MRPs). In this study, we aim to elucidate the HuR-regulating pathways related to epirubicin-mediated resistance in human colorectal carcinoma cells. The effects and mechanisms of epirubicin treatment on the expressions of upstream survival signals (e.g., β-catenin) and downstream MDR transporters (e.g., P-gp) and anti-apoptotic pathways (e.g., Bcl-2) were assessed with or without HuR knockdown (siHuR) or overexpression (overHuR; ectopic HuR or pcDNA3/HA-HuR). Our results showed that siHuR decreased transcriptional expressions of galectin-3, β-catenin, cyclin D1, Bcl-2, P-gp, MRP1, and MRP2 in epirubicin-treated colon cancer cells. Consistently, the co-treatment of epirubicin and siHuR diminished the expressions of galectin-3, ß-catenin, c-Myc, P-gp and MRP1. HuR silencing enhanced the intracellular accumulation of epirubicin in colon cancer cells. On the other hand, overHuR abolished such effects. Furthermore, siHuR significantly intensified epirubicin-mediated apoptosis via increasing reactive oxygen species and thus promoted the cytotoxic effect of epirubicin. The combined treatments of siHuR and epirubicin significantly reduced the expression of Bcl-2, but increased the expression of Bax, as well as activity and expression levels of caspase-3 and -9. In contrast, overHuR abrogated these effects. Our findings provide insight into the mechanisms by which siHuR potentiated epirubicin-induced cytotoxicity via inhibiting galectin-3/β-catenin signaling, suppressing MDR transporters and provoking apoptosis. To our best knowledge, this is an innovative investigation linking the post-transcriptional control by HuR silencing to survival signaling repression, efflux transporter reversal and apoptosis induction. Our study thus provides a powerful regimen for circumventing MDR in colon cancer cells.

Saleeb RM, Plant P, Tawedrous E, et al.
Integrated Phenotypic/Genotypic Analysis of Papillary Renal Cell Carcinoma Subtypes: Identification of Prognostic Markers, Cancer-related Pathways, and Implications for Therapy.
Eur Urol Focus. 2018; 4(5):740-748 [PubMed] Related Publications
BACKGROUND: Two histologic subtypes are recognized for papillary renal cell carcinoma (PRCC). Studies have shown that the subtypes differ in characteristic genetic alterations and clinical behavior. Clinically, the subtypes are managed similarly.
OBJECTIVES: To analyze the biological differences between the two PRCC histological subtypes, in order to further guide their clinical management.
DESIGN, SETTING, AND PARTICIPANTS: PRCC cohort consisting of 317 patients from the Cancer Genome Atlas database and our institution. Patients were stratified according to histologic criteria as type 1, type 2, or not otherwise specified (NOS). Gene and miRNA expression data for the cohort were examined via unsupervised and supervised clustering.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Significant molecular signatures for each subtype were used to unravel the implicated molecular pathways via bioinformatics analysis. Survival was compared between the subtypes. Newly discovered biomarkers were used to further stratify survival of patients in the NOS category.
RESULTS AND LIMITATIONS: Tumor genotyping revealed two distinct PRCC subtypes. The top molecular pathways enriched in PRCC1 were WNT, Hedgehog, and Notch signaling (p=0.001-0.01); highlighting an embryonic developmental theme to the pathogenesis of this subtype. PRCC2 showed enrichment in the mTOR, VEGF (p=7.49E-09) and HIF (p=7.63E-05) signaling pathways. Overall survival and disease-free survival significantly differed between the types. ABCC2 expression was identified as a significant prognostic biomarker for the NOS group in univariate (log rank p<0.0001; hazard ratio [HR] >11.63) and multivariate analysis (p=0.003; HR >2.12). ABCC2 expression and its effect on survival should be further validated at the protein level.
CONCLUSIONS: The classical PRCC types 1 and 2 have two distinct genotypes. We unraveled pathways that indicate that the two types could potentially respond differently to current therapies. We also identified biomarkers that stratify tumors within the PRCC NOS category into prognostic subgroups. Our findings highlight the need for molecular markers to accurately subtype PRCC and guide clinical management.
PATIENT SUMMARY: The two types of papillary renal cancer are treated similarly. We show that the two types have a different genetic makeup, and hence they should be considered two different tumors. There is a different biology underlying each tumor type that can potentially affect the way they respond to treatment. We uncovered genes that can be tested for to guide therapy in some problematic cases for which it hard to define the tumor type.

Gervasini G, de Murillo SG, Jiménez M, et al.
Effect of polymorphisms in transporter genes on dosing, efficacy and toxicity of maintenance therapy in children with acute lymphoblastic leukemia.
Gene. 2017; 628:72-77 [PubMed] Related Publications
The aim of the present work was to assess whether polymorphisms in genes coding for drug transport proteins may influence dosing, efficacy and toxicity of maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6MP) in childhood acute lymphoblastic leukemia (ALL). A total of 41 children with ALL were screened for 10 SNPs in the SLC19A1, ABCB1, ABCC2, ABCC4 and ABCG2 transporter genes by means of direct sequencing. Carriers of the ABCC4 934CC and ABCB1 1236TT genotypes received a lower percentage of the protocol-recommended starting dose of MTX (62.1 vs. 81.3% for 934CA carriers, p=0.001) and 6MP (73.1 vs. 87.7% for 1236CC/CT carriers; p=0.026), respectively. The C1236T SNP also increased the efficiency of myelosuppression. Median (and interquartile) number of blood tests with leukocytes levels <310

Tsyganov MM, Freidin MB, Ibragimova MK, et al.
Genetic variability in the regulation of the expression cluster of MDR genes in patients with breast cancer.
Cancer Chemother Pharmacol. 2017; 80(2):251-260 [PubMed] Related Publications
PURPOSE: We aimed to investigate the association between the polymorphism and expression patterns of multiple drug resistance genes (MDR) in breast cancer (BC).
MATERIALS AND METHODS: The MDR gene expression levels were measured in tumor tissues of 106 breast cancer patients using quantitative real-time PCR. Affymetrix CytoScan™ HD Array chips were used to assess genotypes. Pairwise correlation analysis for ABCB1, ABCC1, ABCC2 and ABCG2 gene expression levels was carried out to reveal co-expression clusters. Associations between SNPs of MDR genes and their preoperative expression levels were assessed using analysis of covariance adjusting for covariates.
RESULTS: The SNPs associated with the expression of the ABCB1, ABCC1, ABCC2 and ABCG2 genes before NAC were detected. In addition, 21 SNPs associated with the expression of four ABC-transporter genes and involved in the expression regulation were identified. Validation in an independent sample confirmed the association between the MDR cluster genes and 11 SNPs.
CONCLUSIONS: Four MDR genes: ABCB1, ABCC1, ABCC2 and ABCG2 were shown to form the functional expression cluster in breast tumor. Further studies are required to discover precise mechanisms of the cluster regulation, thereby providing new approaches and targets to combat the development of the MDR phenotype during chemotherapy.

Sun Y, Jin L, Sui YX, et al.
Circadian Gene CLOCK Affects Drug-Resistant Gene Expression and Cell Proliferation in Ovarian Cancer SKOV3/DDP Cell Lines Through Autophagy.
Cancer Biother Radiopharm. 2017; 32(4):139-146 [PubMed] Related Publications
Abnormal autophagy regulation affects the chemoresistance of ovarian cancer, during which the circadian gene clock may play a major role. In this study, RNA interference plasmid pSUPER-Clock and overexpression plasmid pcDNA3.1-Clock of CLOCK were used to stably transfect the SKOV3/DDP cells by lipofection. Upon screening, the in vitro transfected cell lines with pSUPER-Clock, the autophagy level, and G

Han ZG, Tao J, Yu TT, Shan L
Effect of GSTP1 and ABCC2 Polymorphisms on Treatment Response in Patients with Advanced Non-Small Cell Lung Cancer Undergoing Platinum-Based Chemotherapy: A Study in a Chinese Uygur Population.
Med Sci Monit. 2017; 23:1999-2006 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND Gene polymorphisms are associated with sensitivity to platinum drugs. This study aimed to investigate the polymorphisms of GSTP1 rs1695 locus and ABCC2 rs717620 locus, and the sensitivity of patients with advanced non-small cell lung cancer (NSCLC) to platinum drugs in a Xinjiang Uygur population. MATERIAL AND METHODS The gene polymorphisms of GSTP1 rs1695 and ABCC2 rs717620 of Uygur NSCLC patients were assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The relationship between the prognosis of advanced NSCLC Uygur patients and the gene polymorphisms of GSTP1 rs1695 and ABCC2 rs717620 was analyzed using progression-free survival (PFS) and overall survival (OS) as the major outcome indicators. RESULTS The median PFS of patients with advanced NSCLC was 6.9 months and the OS of Uygur patients with advanced NSCLC was 10.8 months. Kaplan-Meier survival analysis indicated that survival time of patients with GSTP1 AG + GG was significantly longer than in patients with AA gene (P<0.05), and survival time of patients with ABCC2 CT + TT was significantly longer than in patients with the CC gene (P<0.05). CONCLUSIONS Polymorphisms of GSTP1 rs1695 and ABCC2 rs717620 can be used to predict the outcomes of Uygur patients with advanced NSCLC who have received platinum-based chemotherapy. Additionally, this information could be used to guide the individualized treatment of Uygur patients with advanced NSCLC.

Herraez E, Sanchez-Vicente L, Macias RIR, et al.
Usefulness of the MRP2 promoter to overcome the chemoresistance of gastrointestinal and liver tumors by enhancing the expression of the drug transporter OATP1B1.
Oncotarget. 2017; 8(21):34617-34629 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Tumor response to chemotherapy is often limited by drug export through ABC proteins. To overcome this problem, here we have investigated the usefulness of inducing the expression of the multidrug uptake transporter OATP1B1 under the control of the MRP2 promoter (MRP2pr). Human hepatoma cells (Alexander) were transfected with MRP2pr fragments of different length fused to the firefly luciferase ORF in order to select the shortest fragment with the highest response to dexamethasone, which was subsequently used to generate the chimeric construct MRP2pr-OATP1B1-V5. Hepatoma cells transduced with MRP2pr-OATP1B1-V5 resulted in dexamethasone-sensitive inducible OATP1B1 expression and enhanced selective antitumor response to OATP1B1 substrates (paclitaxel, Bamet-R2 and Bamet-UD2). In human colon cancer cells LS174T/R, used as a model of endogenous chemoresistance due to MRP2 overexpression, MRP2pr-OATP1B1 induced OATP1B1 expression together with chemosensitivity to OATP1B1 substrates. In nude mice, xenografted tumors formed by LS174T/R cells transduced with MRP2pr-OATP1B1 plus treatment with dexamethasone were markedly sensitized to Bamet-UD2. In conclusion, the induced expression of anticancer drug uptake transporters, under the control of promoters of ABC proteins involved in chemoresistance, constitutes an interesting approach to overcome the poor response of cancer to chemotherapy due to reduced drug uptake and/or enhanced drug export.

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