Gene Summary

Gene:MSH3; mutS homolog 3
Aliases: DUP, FAP4, MRP1
Summary:The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA mismatch repair protein Msh3
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (27)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • DNA Mismatch Repair
  • Loss of Heterozygosity
  • DNA Repair
  • Signal Transducing Adaptor Proteins
  • Single Nucleotide Polymorphism
  • Base Pair Mismatch
  • Neoplasm Proteins
  • Frameshift Mutation
  • Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
  • Transcription Factors
  • Genetic Predisposition
  • Colorectal Cancer
  • Protein-Serine-Threonine Kinases
  • Immunohistochemistry
  • Transcription
  • Xenobiotics
  • Phenotype
  • Microsatellite Instability
  • Trinucleotide Repeat Expansion
  • MutS Homolog 3 Protein
  • Prostate Cancer
  • DNA-Binding Proteins
  • DNA Methylation
  • Autologous Transplantat
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • Survival Rate
  • Skin Cancer
  • Receptor, Transforming Growth Factor-beta Type II
  • Precancerous Conditions
  • Carrier Proteins
  • Polymerase Chain Reaction
  • MutL Protein Homolog 1
  • Thyroid Cancer
  • Cancer DNA
  • Sensitivity and Specificity
  • DNA Mutational Analysis
  • Multidrug Resistance-Associated Proteins
  • MutS Homolog 2 Protein
  • Sex Factors
  • Chromosome 5
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: MSH3 (cancer-related)

Zarei S, Reza JZ, Jaliani HZ, et al.
Effects of carfilzomib alone and in combination with cisplatin on the cell death in cisplatin-sensitive and cisplatin-resistant ovarian carcinoma cell lines.
Bratisl Lek Listy. 2019; 120(6):468-475 [PubMed] Related Publications
BACKGROUND: Previous studies on the efficacy of platinum-based drugs and selective inhibitors of proteasome have revealed promising outcomes. This study is aimed to evaluate the effects of the combination of cisplatin and carfilzomib on the cell death induction and drug efflux transporters expression in cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) ovarian cancer cells lines.
METHODS: MTT cytotoxic assay was conducted to determine the cytotoxicity. Drug interactions were analyzed based on Chou-Talalay's principles and real-time PCR analysis was performed to determine possible alterations in mRNA levels of MRP1 and BCRP.
RESULTS: A2780s cells were more susceptible to both cisplatin and carfilzomib while analyses of drug interactions between the two agents showed synergistic effects in all affected fractions of drug-treated A2780s and A2780cp cells (CI<0.9) with the combination indices being significantly lower in A2780cp cells (p < 0.01). We also found that although mRNA levels of BCRP and MRP1 were significantly altered in both cells exposed to each drug alone, only the combination regimen was able to significantly reduce the mRNA levels of these genes in A2780cp cells (p<0.001).
CONCLUSION: This combination might be a potential strategy for suppressing cell growth via downregulating the drug efflux transporters expression, especially in cisplatin-resistant ovarian cancer cells (Fig. 3, Ref. 45).

Mai L, Luo M, Wu JJ, et al.
The combination therapy of HIF1α inhibitor LW6 and cisplatin plays an effective role on anti-tumor function in A549 cells.
Neoplasma. 2019; 2019 [PubMed] Related Publications
Hypoxia-inducible factor 1α (HIF1α) has been demonstrated to be involved in the resistance of various human cancer cells to chemotherapies. However, the correlation between HIF1α and the sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin has not been illuminated. The aim of the present study was to investigate the effects of HIF1α on drug resistance in NSCLC cells. A549 cells were incubated in 21% or 0.5% O2 followed by the assessment of the level of HIF1α with qRT-PCR and western blot and ROS level by DCFH-DA assays. Effects of hypoxia or HIF1α inhibitor LW6 on the proliferation and apoptosis of A549 cells were evaluated via CCK-8 and flow cytometry assays. IC50 of A549 cells to cisplatin was determined by MTT assay. The mitochondrial membrane potential (MMP) was measured via JC-1 staining. Moreover, the expression of apoptosis related protein (Bcl-2, Bax) and drug resistance related proteins (MDR1, MRP1) were measured by western blotting. Exposure of A549 cells to 1% O2 significantly up-regulated HIF1α expression, maintained cell viability to cisplatin but decreased the ROS level, which promoted chemoresistance to cisplatin. LW6-treated A549 cells showed an increase in ROS level that blocked the hypoxia induced resistance to cisplatin and in addition, decreased expression of MDR1 and MRP1 in cisplatin-treated cells. This study revealed that hypoxia-improved cisplatin chemoresistance of NSCLC cells by regulated MDR1 and MRP1 expression via HIF1α/ROS pathway is reversed by LW6, suggesting that LW6 may act as effective sensitizer in chemotherapy for NSCLC.

Verma R, Agarwal AK, Sakhuja P, Sharma PC
Microsatellite instability in mismatch repair and tumor suppressor genes and their expression profiling provide important targets for the development of biomarkers in gastric cancer.
Gene. 2019; 710:48-58 [PubMed] Related Publications
We evaluated microsatellite instability (MSI) in selected mismatch repair (MMR) and tumor suppressor (TS) genes with a view to exploring genetic changes associated with the occurrence of gastric cancer (GC). Moreover, expression of MSI positive genes was measured to get insights into molecular events operating in the tumor microenvironment. We anticipated discovering new molecular targets with potential as molecular biomarkers of gastric cancer. Of the 13 genes screened, we observed 15% to 52.5% MSI at eight microsatellite loci located in 3' UTR and coding regions of six genes (TGFBR2, PDCD4, MLH3, DLC1, MSH6, and MSH3). The union probability of different combinations of unstable microsatellite loci unveiled a set of four MSI markers from TGFBR2, PDCD4, MLH3, and MSH3 genes that allows detection of up to 85% incidences of GC. Significant downregulation of MLH3, PDCD4, TGFBR2, and DLC1 genes was observed in tumor tissues. Protein structure analyses of two unexplored targets, MSH3 (TG

Wang L, Wang H, Wang T, et al.
Analysis of polymorphisms in genes associated with the FA/BRCA pathway in three patients with multiple primary malignant neoplasms.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1101-1112 [PubMed] Related Publications
Cases of more than three primary cancers are very rare. This study analyzed the genetic susceptibility of gene polymorphisms in three patients with multiple primary malignant neoplasms and examined the possible pathogenesis. The clinical data and whole genome sequence of three patients (1 with 5 primary cancers, 1 with 4 primary cancers, and 1 with 3 primary cancers) were aligned with a series of databases. We found the three patients contained a total of seven types of malignant tumours (endometrial cancer, ovarian cancer, breast cancer, colon cancer, ureter cancer, bladder cancer and kidney cancer). It was found that the varied genes in Patient 1 (5 primary cancers) were BRIP1, FANCG, NBN, AXIN2, SRD5A2, and CEBPA. Patient 2 (4 primary cancers) had variations in the following genes: BMPR1A, FANCD2, MLH3, BRCA2, and FANCM. Patient 3 (3 primary cancers) had variations in the following genes: MEN1, ATM, MSH3, BRCA1, FANCL, CEBPA, and FANCA. String software was used to analyze the KEGG pathway of the variations in these three samples, which revealed that the genes are involved in the Fanconi anaemia pathway. Defects in DNA damage repair may be one of the causes of multiple primary cancers.

Yang J, Song P, Zhou G
A study on the correlations of MRP-1 expression with the pathogenesis and prognosis of colorectal cancer.
J BUON. 2019 Jan-Feb; 24(1):84-90 [PubMed] Related Publications
PURPOSE: To investigate the expression level of multidrug resistance-associated protein 1 (MRP-1) and its correlation with prognosis in the pathogenetic process of colorectal cancer.
METHODS: 116 patients with colorectal adenocarcinoma and 50 patients with colorectal adenomas were studied. Thirty cut-end normal tissue sections were subjected to immunohistochemical staining, real-time polymerase chain reaction (RT-PCR) and Western blotting, to detect the expression levels of MRP-1 gene and protein in tissues. Besides, the correlations of the expression of MRP-1 in colorectal adenocarcinoma tissues with clinicopathological features and prognosis were analyzed.
RESULTS: MRP-1 was mainly expressed in the cell membrane and cytoplasm in colorectal adenocarcinoma. The positive expression rates of MRP-1 in colorectal adenocarcinoma tissues, colorectal adenoma tissues and normal tissues were 73.28, 46.0 and 20.0%, respectively, showing statistically significant differences (p<0.05). In adenocarcinoma tissues, MRP-1 expression level was associated with the differentiation grade, TNM staging and whether there was lymph node metastasis (p<0.05 in all comparisons). The 5-year survival rates of patients with negatively expressed MRP-1 protein, no lymph node metastasis and high/moderate grade of differentiation as well as in stage I+II were remarkably higher (p<0.01 in all comparisons).
CONCLUSION: In colorectal adenocarcinoma tissues, the expression of MRP-1 is elevated and patients with negatively expressed MRP-1 have a better prognosis. Therefore, MRP-1 can be a reference indicator for clinical diagnosis and prognosis.

Abdulkhaleq MM, Al-Ghafari AB, Yezerski A, et al.
Novel association between heterozygous genotype of single nucleotide polymorphism C218T in drug transporter ABCC1 gene and increased risk of colon cancer.
Saudi Med J. 2019; 40(3):224-229 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To determine the role of G128C and C218T variants in ABCC1 gene with the risk of developing colon cancer in Jeddah, Kingdom of Saudi Arabia. Methods: This case-control study was conducted on 51 colon cancer patients and 65 controls from King Abdulaziz University Hospital and King Abdullah Medical City in the period from January 2015 to April 2017, and was approved by the Unit of Biomedical Ethics (no: 261-15). Experiments were performed in the experimental biochemistry unit at King Fahd Medical Research Center. The genotype distributions and allele frequencies were determined by polymerase chain reaction-restriction fragments length polymorphism (PCR-RFLP) and DNA sequencing. A Chi-square test was used to determine allele and genotype distributions, odds ratio (OR), risk ratio (RR) and 95% confidence intervals (CI). P-values of less than 0.05 were considered statistically significant. Results: The results showed a novel association between heterozygous (CT) genotype for variant C218T and increased risk of colon cancer [OR=3.4, 95% CI (1.56-7.48), and RR=1.92, 95% CI (1.26-2.93), p=0.002]. These ratios were correlated with high-grade stages (III and IV). In contrast, for variant G128C, there was no significant association with the risk of developing colon cancer. Conclusion: The novel findings of the study revealed that the CT genotype of variant C218T in ABCC1 gene may increase the risk of developing colon cancer.

Roncati L
Microsatellite Instability Predicts Response to Anti-PD1 Immunotherapy in Metastatic Melanoma.
Acta Dermatovenerol Croat. 2018; 26(4):341-343 [PubMed] Related Publications
Dear Editor, Immune-checkpoint blockade is a type of passive immunotherapy aimed at enhancing preexisting anti-tumor responses of the organism, blocking self-tolerance molecular interactions between T-lymphocytes and neoplastic cells (1,2). Despite a significant increase in progression-free survival, a large proportion of patients affected by metastatic melanoma do not show durable responses even after appropriate diagnostic categorization and shared therapeutic choices (3-9). Therefore, predictive biomarkers of clinical response are urgently needed, and predictive immunohistochemistry (IHC) meets these requirements. Strong evidence suggests that DNA mismatch repair (MMR) deficiency is a frequent condition in malignant melanoma, as well as in other tumors (10). As is known, DNA MMR is a safeguard system for the detection and repair of DNA errors, which can randomly occur in the phase of DNA replication inside the cell. In humans, seven DNA MMR proteins (Mlh1, Mlh3, Msh2, Msh3, Msh6, Pms1, and Pms2) work in a coordinated and sequential manner to repair DNA mismatches. When this system is defective, the cell accumulates a series of replication errors in terms of new microsatellites; therefore, a condition of genetic hypermutability and microsatellite instability (MSI) takes place inside the cell itself (11). For this reason, my working group has started to search for MMR protein deficiency in melanoma biopsies from patients of both sexes and of all ages with metastatic spread, correlating the data with the response to pembrolizumab, the well-known anti-programmed cell death protein 1 (PD1) human monoclonal immunoglobulin G4, capable of blocking the interaction between PD1, the surface receptor of activated T-lymphocytes, and its ligand, the programmed death-ligand 1 (PD-L1), favoring melanoma cell attack by T-lymphocytes (1) rather than its depression (12). PD-L1 is highly expressed in about half of all melanomas and thus the role of PD1 in melanoma immune evasion is now well established (13). Surprisingly, the best therapeutic results to pembrolizumab, in terms of progression-free survival and overall survival, occur precisely in those patients, approximately 7% in my database, affected by deficient MMR (dMMR) melanomas. In particular, the most important benefits to pembrolizumab-based treatment have occurred in a female patient, who developed a subungual melanoma in the second finger of the left hand at the age of 41 years, together with lymph node metastases to ipsilateral axilla at the onset. The patient was promptly submitted to amputation of the first phalanx and emptying of the axillary cable. The primary tumor was a vertical growth phase melanoma with a Breslow's depth of 1.4 mm; three mitotic figures for 1 mm2 were ascertained. There was no evidence of ulceration, regression, microsatellitosis, or lymphocytic infiltration; moreover, the surgical margins tested free of disease. Further molecular analyses did not show rearrangements in B-RAF and C-KIT genes. After four years, metastases appeared in the brain and ileum; however, at present the patient is still alive and in complete pembrolizumab response with progression-free survival and overall survival of 956 days and 2546 days, respectively. The tumor was afterwards identified as a dMMR melanoma for an exclusive loss of Msh6 expression on IHC (Figure 1). This finding is in line with the fact that the U.S. Food and Drug Administration has approved the use of pembrolizumab in 2017 for unresectable or metastatic solid tumors with MMR deficiency (14). In conclusion, dMMR melanoma seems to be a particular subset of disease that can be identified with high sensibility and specificity by predictive IHC as a complete loss of one or more DNA MMR proteins and that deserves targeted therapy.

Ma G, Zhu J, Liu F, Yang Y
Long Noncoding RNA LINC00460 Promotes the Gefitinib Resistance of Nonsmall Cell Lung Cancer Through Epidermal Growth Factor Receptor by Sponging miR-769-5p.
DNA Cell Biol. 2019; 38(2):176-183 [PubMed] Free Access to Full Article Related Publications
The vital roles of long noncoding RNAs (lncRNAs) in the nonsmall cell lung cancer (NSCLC) tumorigenesis are increasingly important. This work aims to investigate the role of lncRNA LINC00460 in the gefitinib resistance of NSCLC cells and discover its relevant mechanism. Our finding reveals that the expression of lncRNA LINC00460 is upregulated in the gefitinib-resistant NSCLC tissue and cells, and closely correlated with advanced tumor stage and clinical poor prognosis outcome. Gain and loss functional assays are performed in gefitinib-resistant NSCLC cells (A549/GR), stating that LINC00460 facilitates the 50% inhibitive concentration of gefitinib for NSCLC cells, multidrug-resistant-related proteins (P-gp, MRP1, and BCRP), as well as the invasion. In vivo, LINC00460 silencing represses the tumor growth. Bioinformatics prediction tools and luciferase analysis confirm that the upregulated LINC00460 sponged miR-769-5p in NSCLC cells; moreover, epidermal growth factor receptor (EGFR) is identified as a direct target gene of miR-769-5p. Verification experiments confirm that the restoration of EGFR could weaken the sensibility of NSCLC cells toward the gefitinib. In conclusion, our result demonstrates that LINC00460 plays a pivotal role in gefitinib resistance of NSCLC cells by targeting EGFR through sponging miR-769-5p. This finding might serve as a therapeutic target for NSCLC.

Zhuang X, Wang J
Correlations of MRP1 gene with serum TGF-β1 and IL-8 in breast cancer patients during chemotherapy.
J BUON. 2018 Sep-Oct; 23(5):1302-1308 [PubMed] Related Publications
PURPOSE: To investigate the expressions of multidrug resistance-associated protein 1 (MRP1) gene, serum transforming growth factor beta-1 (TGF-β1) and interleukin-8 (IL-8) in patients with breast cancer during chemotherapy, and to analyze their correlations in chemotherapy.
METHODS: 346 breast cancer patients admitted to the Department of Surgery (Breast) of Nanjing Drum Tower Hospital from March 2015 to December 2017 were included as study subjects. All selected patients received chemotherapy in our hospital. Quantitative reverse transcription- polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were adopted to detect the expression levels of MRP1 mRNA, as well as MRP1, TGF-β1 and IL-8 proteins in patients before chemotherapy and at 1, 2, 4 and 8 weeks after chemotherapy. Correlations of MRP1 protein/mRNA with clinical features of patients were analyzed, and Pearson's correlation analysis was performed to examine correlations of MRP1 protein/mRNA with TGF-β1 and IL-8 proteins.
RESULTS: The expressions of MRP1 mRNA as well as MRP1, TGF-β1 and IL-8 proteins were increased with the prolongation of chemotherapy time, and there were statistically significant differences between the two time points (pCONCLUSION: With the prolongation of chemotherapy time in breast cancer patients, the expression level of MRP1 also increased which may affect the therapeutic effect of chemotherapy in breast cancer patients and lead to drug resistance. TGF-β1 and IL-8 may be closely associated with the mechanism of drug resistance in MRP1-guided breast cancer chemotherapy.

Mori T, Hamaya Y, Uotani T, et al.
Prevalence of elevated microsatellite alterations at selected tetranucleotide repeats in pancreatic ductal adenocarcinoma.
PLoS One. 2018; 13(12):e0208557 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDAC) prognosis remains poor even after complete resection owing to no valuable biomarkers for recurrence and chemosensitivity. Tumors not expressing MSH3 show elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). EMAST reportedly occurs in several tumors. In colorectal cancer (CRC), EMAST was reportedly correlated with 5-fluorouracil (5-FU) sensitivity. However, EMAST prevalence in PDAC and its significance as a prognostic biomarker are unknown. This study aimed to investigate EMAST prevalence in PDAC and the associations between EMAST and pathological factors, EMAST and prognosis, and EMAST and MSH3 expression via immunohistochemistry (IHC). We assessed 40 PDAC patients undergoing surgery. Genomic DNA was extracted from tumors and normal tissues. EMAST and microsatellite instability-high (MSI-H) were analyzed using five polymorphic tetranucleotide markers and five mononucleotide markers, respectively. Tumor sections were stained for MSH3, and staining intensity was evaluated via the Histoscore (H-score). Eighteen of 40 (45%) PDAC patients were EMAST-positive; however, none were MSI-H-positive. Clinicopathological characteristics including overall survival (OS) and recurrence-free survival (RFS) were not significantly different between EMAST-positive and EMAST-negative patients (P = 0.45, 0.98 respectively). IHC was performed to evaluate MSH3 protein expression levels for the PDAC tissue specimens. H-scores of EMAST-positive patients ranged from 0 to 300 (median, 40) and those of EMAST-negative patients ranged from 0 to 300 (median, 170). MSH3 protein was not significantly downregulated in EMAST-positive patients (P = 0.07). This study is a preliminary study and the number of cases investigated was small, and thus, study of a larger cohort will reveal the clinical implication of EMAST.

Taheri M, Motalebzadeh J, Mahjoubi F
Expression of LRP Gene in Breast Cancer Patients Correlated with MRP1 as Two Independent Predictive Biomarkers in Breast Cancer
Asian Pac J Cancer Prev. 2018; 19(11):3111-3115 [PubMed] Free Access to Full Article Related Publications
Background: Breast cancer is the most common malignancy in women. Multidrug resistance (MDR) is still a great obstacle of breast cancer chemotherapy. We have previously shown that multidrug resistance-associated protein 1 (MRP1) is associated with response to neoadjuvant chemotherapy. The lung resistance-related protein (LRP) is identified as a prognostic marker and response to treatment factor which has been studied mainly in hematological malignancy and leukemia. In this study, we aimed to analyze LRP expression and possible correlation between the expression level of this gene with MRP1 as a candidate marker for chemotherapy resistance. Materials and Methods: We collected 54 breast tumors and adjacent normal tissues from Iranian breast cancer patients and Real time RT-PCR was employed to measure the gene expression level in our samples. Results: MRP1 and LRP expression level were significantly lower in tumor tissues of the patients responding to chemotherapy compared to non-responding patients. No relation between the expression level of either of these genes and clinicopathology markers was found. Conclusion: Our results suggest that LRP gene expression is correlated to MRP1 in human breast cancer cells and may affect the clinical response to treatment.

Moon JY, Manh Hung LV, Unno T, Cho SK
Nobiletin Enhances Chemosensitivity to Adriamycin through Modulation of the Akt/GSK3β/β⁻Catenin/MYCN/MRP1 Signaling Pathway in A549 Human Non-Small-Cell Lung Cancer Cells.
Nutrients. 2018; 10(12) [PubMed] Free Access to Full Article Related Publications
Drug resistance is a major problem in the treatment of non-small-cell lung cancer (NSCLC). In this study, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to identify the differentially expressed genes in Adriamycin (ADR)-resistant NSCLC A549/ADR cells compared with parental A549 cells. Among the tested phytochemicals, nobiletin (NBT) is able to overcome the ADR resistance of A549/ADR cells. NBT treatment decreased the expression of a neuroblastoma-derived MYC (MYCN) and multidrug resistance-associated protein 1 (MRP1) as well as downregulating Akt, GSK3β, and β-catenin. Consistent with these results, NBT treatment resulted in the accumulation of intracellular ADR. A combination index (CI) assay confirmed the synergistic effect of combined treatment with NBT and ADR in reducing the viability of A549/ADR cells (CI = 0.152). Combined treatment with NBT and ADR enhanced apoptosis in A549/ADR cells, as evidenced by increased caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, and sub-G1 population compared to treatment with ADR alone. In vivo experiments using a mouse xenograft model revealed that combination therapy with NBT and ADR significantly reduced tumor volume by 84.15%. These data suggest that NBT can sensitize ADR-induced cytotoxicity against A549/ADR cells by inhibiting MRP1 expression, indicating that NBT could serve as an effective adjuvant agent for ADR-based chemotherapy in lung cancer.

Huang FX, Chen HJ, Zheng FX, et al.
LncRNA BLACAT1 is involved in chemoresistance of non‑small cell lung cancer cells by regulating autophagy.
Int J Oncol. 2019; 54(1):339-347 [PubMed] Related Publications
The aim of the present study was to determine the effect of the long non‑coding RNA (lncRNA) bladder cancer‑associated transcript 1 (BLACAT1) in chemoresistance of non‑small cell lung cancer (NSCLC) cells. Expression of lncRNA BLACAT1, microRNA (miR)‑17, autophagy‑related protein 7 (ATG7), multidrug‑resistance protein 1 (MRP1), and the autophagy‑associated proteins light chain 3 (LC3)‑II/LC3‑I and Beclin 1 were detected using the reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Cell viability was determined using an MTT assay. The interaction between BLACAT1 and miR‑17 was determined using RNA immunoprecipitation and RNA pull‑down assays. A cisplatin (DDP)‑resistant NSCLC cell A549/DDP xenograft model in nude mice was established to investigate the effect of BLACAT1 on the chemoresistance of NSCLC cells. Compared with in DDP‑sensitive NSCLC cells, expression of BLACAT1, ATG7, MRP1, LC3‑II/LC3‑I and Beclin 1 was significantly upregulated in DDP‑resistant NSCLC cells, whereas miR‑17 was downregulated in DDP‑resistant NSCLC cells. Short interfering RNA against BLACAT1 decreased the viability of DDP‑resistant NSCLC cells. In addition, BLACAT1 interacted with miR‑17, and negatively regulated miR‑17. BLACAT1 promoted ATG7 expression through miR‑17, and facilitated autophagy and promoted chemoresistance of NSCLC cells through miR‑17/ATG7. Finally, in vivo experiments indicated that inhibition of BLACAT1 ameliorated the chemoresistance of NSCLC. BLACAT1 was upregulated in DDP‑resistant NSCLC cells, and promoted autophagy and chemoresistance of NSCLC cells through the miR‑17/ATG7 signaling pathway.

Zhang Z, Feng L, Liu P, Duan W
ANRIL promotes chemoresistance via disturbing expression of ABCC1 by regulating the expression of Let-7a in colorectal cancer.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Increasing evidence indicates that long non-coding RNAs (lncRNAs) antisense non-coding RNA in the INK4 locus (ANRIL) has been involved in various diseases and promotes tumorigenesis and cancer progression as an oncogenic gene. However, the effect of ANRIL on chemoresistance remains still unknown in colorectal cancer (CRC). Here, we investigated ANRIL expression in 63 cases of colorectal cancer specimens and matched normal tissues. Results revealed that ANRIL was up-regulated in tumor tissues samples from patients with CRC and CRC cell lines. Increased ANRIL expression in CRC was associated with poor clinical prognosis. Kaplan-Meier analysis showed that ANRIL was associated with overall survival of patients with colorectal cancer, and patients with high ANRIL expression tended to have unfavorable outcome.

Lin H, Yang G, Yu J, et al.
KDM5c inhibits multidrug resistance of colon cancer cell line by down-regulating ABCC1.
Biomed Pharmacother. 2018; 107:1205-1209 [PubMed] Related Publications
OBJECTIVE: The study aimed to study the effect of histone methyltransferase KDM5c (Lysine(K)-specific demethylase 5C) on drug resistance in colon cancer cells.
METHODS: KDM5c expression interference was performed using empty plasmids, SMCV-dGFP-KDM5c plasmids and siControl, siKDM5c transfected human colon cancer HCT-8, RKO cell lines, and then grouped into NC, KDM5c-OE, siControl, siKDM5c groups.0.625 μg /ml, 1.25 μg/ml, 2.5 μg/ml, 5 μg/ml, 10 μg/ml, and 20 μg/ml oxaliplatin (L-OHP), and 0.25 mmol/ml, 0.5 mmol/ml, 1 mmol/ml, 2 mmol /ml, 5 mmol/ml, and 10 mmol/ml irinotecan (CPT-11) were dosed in all colon cancer cell groups. The MTT assay was used to detect growth inhibition of differentially-expressed KDM5c colon cancer cells, for which L-OHP or CPT-11 were added. ABCC1 expression in qPCR and WB was detected in all four cell groups. The H3K4me3 peak distribution in the TSS region of the ABCC1 gene was detected with the Encode database. CHIP-qPCR was used to detect the location of the H3K4me3 peak and KDM5c binding to TSS region DNA fragments of the ABCC1 gene.
RESULTS: KDM5c expression upregulation in colon cancer cells had significantly reduced L-OHP and CPT-11½ inhibitory concentrations (IC50 s) and decreased the ABCC1mRNA and protein expression. The IC50 s of L-OHP and CPT-11 were significantly increased in colon cancer cells with downregulated KDM5c expression. And, ABCC1 mRNA and protein expression increased (P < 0.05). The Encode database suggested that the H3K4me3 peak was located in the TSS region of the ABCC1 gene. CHIP-qPCR indicated that both H3K4me3 and KDM5c act on the TSS region of the ABCC1 gene and have the same site of action.
CONCLUSIONS: KDM5c might downregulate ABCC1 expression by demethylating the ABCC1 H3K4me3 in the TSS region, which can promote multidrug resistance, such that inhibiting KDM5c could decrease multidrug cancer cell resistance.

Zhang L, Jean SR, Li X, et al.
Programmable Metal/Semiconductor Nanostructures for mRNA-Modulated Molecular Delivery.
Nano Lett. 2018; 18(10):6222-6228 [PubMed] Related Publications
Cytotoxic chemotherapeutics are important tools for the clinical treatment of a variety of solid tumors. However, their use is often complicated by multidrug resistance that can develop in patients, limiting the potencies of these agents. New strategies are needed to provide versatile systems that can respond to and disable resistance mechanisms. We demonstrate the use of a new family of materials, programmable metal/semiconductor nanostructures, for drug delivery and mRNA sensing in drug-resistant cells. These materials are composed of a central core gold nanoparticle surrounded by a layer of DNA-capped quantum dots. The modularity of these "core-satellite" assemblies allows for the construction of superstructures with controlled size and the incorporation of multiple functionalities for drug delivery. The DNA sequence within the nanoparticle specifically binds to an mRNA encoding an important drug resistance factor, MRP1, inside cancer cells, releasing a potent anticancer drug doxorubicin. This event triggers a turn-on fluorescence emission along with a downregulation of the MRP1 drug efflux pump, a main resistance factor for doxorubicin, yielding a remarkable improvement in therapeutic efficacy against drug-resistant cancer cells. This work paves the way for the development of programmable materials with multiple synergistic functionalities for biomedical applications.

Hu P, Wong PT, Zhou Q, et al.
Clinical relevance of the multidrug resistance‑associated protein 1 gene in non‑small cell lung cancer: A systematic review and meta‑analysis.
Oncol Rep. 2018; 40(5):3078-3091 [PubMed] Related Publications
The multidrug resistance‑associated protein 1 (MRP1) gene has been found to be consistently overexpressed in the majority of patients with non‑small cell lung cancer (NSCLC). MRP1 is known for its ability to actively decrease intracellular drug concentration, limiting the efficacy of cancer chemotherapy; however, data on the clinical relevance of MRP1 is inconclusive. In the present meta‑analysis, all available published data were combined to provide an updated view on the clinicopathological relevance of MRP1 in patients with NSCLC. A systematic search was conducted to obtain relevant studies published in English, Chinese and Japanese databases. All data from patients with NSCLC who underwent testing for MRP1, by either immunohistochemistry or reverse transcription‑polymerase chain reaction, were extracted and combined for further analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each selected study, with either the fixed‑effects model or the random‑effects model where appropriate. The quality of methodology, heterogeneities and publication bias of the included articles were also analyzed. A total of 36 clinical studies involving 3,278 patients were included in the study. It was found that the increased expression of the MRP1 gene was associated with the following subgroups of patients: Non‑smokers vs. smokers (OR, 2.54; 95% CI, 1.17‑5.54; P=0.019); adenocarcinoma vs. squamous cell carcinoma (OR, 1.58; 95% CI, 1.16‑2.17; P=0.004); clinical stage III‑IV vs. stage I‑II (OR, 1.36; 95% CI, 1.11‑1.66; P=0.003); lymph node metastases (OR, 1.32; 95% CI, 1.09‑1.61; P=0.005); poor response to chemotherapy (OR, 0.41; 95% CI, 0.23‑0.72; P=0.002) and reduced 3‑year survival rate (OR, 0.40; 95% CI, 0.23‑0.68; P=0.001). In conclusion, the findings from this study suggest that increase in MRP1 gene expression is associated with being a non‑smoker, adenocarcinoma, advanced clinical stages and a poor response to chemotherapy in patients with NSCLC. The results from the most extensive and updated data on MRP1 support the requirement for continued investigation into the potential use of MRP1 as a biomarker/clinical indicator for NSCLC.

Chang L, Hu Z, Zhou Z, Zhang H
Linc00518 Contributes to Multidrug Resistance Through Regulating the MiR-199a/MRP1 Axis in Breast Cancer.
Cell Physiol Biochem. 2018; 48(1):16-28 [PubMed] Related Publications
BACKGROUND/AIMS: Long non-coding RNAs (LncRNAs) have been validated to be pivotal mediators in multidrug resistance (MDR) of various cancers. This study aims to explore the roles and molecular mechanisms of linc00518 implicated in chemoresistance in breast cancer.
METHODS: Expressions of linc00518, miR-199a and MRP1 were evaluated by RT-qPCR or western blot. IC50 values of adriamycin (ADR), vincristine (VCR) and paclitaxel (PTX) were determined by XTT assays and cell apoptosis was assessed by flow cytometry. Luciferase reporter and RIP assays were employed to detect the interaction of linc00518, miR-199a and MRP-1.
RESULTS: linc00518 expression increased nearly 2 fold and MRP1 level elevated about 2.5 fold in breast cancer tissues as compared to that in adjacent normal tissues. Also, almost 2 fold upregulation of linc00518 and MRP-1 expressions was observed in MCF-7 cells than in MCF-10A cells. Additionally, linc00518 level was almost 2.5 fold higher and MRP1 level was about 2 fold increased in ADR-resistant MCF-7 cells (MCF-7/ADR) than in parental cell line MCF-7. Linc00518 knockdown enhanced chemosensitivity to ADR, VCR and PTX, and boosted ADR-, VCR- and PTX-induced apoptosis in MCF-7/ADR cells. miR-199a inhibitor conferred chemoresistance to ADR, VCR and PTX in MCF-7/ADR cells, and suppressing miR-199a reversed multi-drug susceptibility induced by linc00518 knockdown. Furthermore, linc00518 could act as a molecular sponge of miR-199a to repress MRP1 expression. MRP1 depletion increased the sensitivity of MCF-7/ADR cells to ADR, VCR and PTX, and this effect was attenuated following miR-199a inhibition or linc00518 overexpression. Also, linc00518 silencing increased ADR-mediated anti-tumor effect in vivo.
CONCLUSIONS: linc00518 downregulation reduced MDR by regulating miR-199a/MRP1 axis in breast cancer.

Fernandes E Silva E, Figueira FS, Cañedo AD, et al.
C-phycocyanin to overcome the multidrug resistance phenotype in human erythroleukemias with or without interaction with ABC transporters.
Biomed Pharmacother. 2018; 106:532-542 [PubMed] Related Publications
The phenotype of multidrug resistance (MDR) is one of the main causes of chemotherapy failure. Our study investigated the effect of C-phycocyanin (C-PC) in three human erythroleukemia cell lines with or without the MDR phenotype: K562 (non-MDR; no overexpression of drug efflux proteins), K562-Lucena (MDR; overexpression of ATP-binding cassette, sub-family B/ABCB1), and FEPS (MDR; overexpression of ABCB1 and ATP-binding cassette, sub-family C/ABCC1). Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, we showed that 20 and 200 μg/mL C-PC decreased K562 viable cells after 24 h and 200 μg/mL C-PC decreased K562-Lucena cell proliferation after 48 h. C-PC did not decrease viable cells of FEPS cells. On the other hand, the MTT assay showed that exposure of 2, 20, and 200 μg/mL C-PC for 24 or 48 h was not cytotoxic to peritoneal macrophages. At 72 h, the trypan blue exclusion assay showed that 20 μg/mL C-PC decreased K562 and K562-Lucena cell proliferation and in FEPS cells, only 200 μg/mL C-PC decreased proliferation. In addition, protein-protein docking showed differences in energy and binding sites of ABCB1 and ABCC1 for C-PC, and these results were confirmed by the efflux protein activity assay. Only ABCC1 activity was altered in the presence of C-PC and FEPS cells showed lower C-PC accumulation, suggesting C-PC extrusion by ABCC1, conferring C-PC resistance. In combination with chemotherapy (vincristine [VCR] and daunorubicin [DNR]), the sensitivity of K562-Lucena cells for C-PC + VCR did not increase, whereas FEPS cell sensitivity for C-PC + DNR was increased. In molecular docking experiments, the estimated free energies of binding for C-PC associated with chemotherapy were similar (VCR: -6.9 kcal/mol and DNR: -7.2 kcal/mol) and these drugs were located within the C-PC cavity. However, C-PC exhibited specificity for tumor cells and K562 cells were more sensitive than K562-Lucena cells, followed by FEPS cells. Thus, C-PC is a possible chemotherapeutic agent for cells with the MDR phenotype, both alone in K562-Lucena cells (resistance due to ABCB1), or in combination with other drugs for cells similar to FEPS (resistance due to ABCC1). Moreover, C-PC did not damage healthy cells (peritoneal macrophages of Mus musculus).

Hu H, Yang L, Li L, Zeng C
Long non-coding RNA KCNQ1OT1 modulates oxaliplatin resistance in hepatocellular carcinoma through miR-7-5p/ ABCC1 axis.
Biochem Biophys Res Commun. 2018; 503(4):2400-2406 [PubMed] Related Publications
The underlying functions of long non-coding RNAs (lncRNAs) on chemoresistance in multiple cancers have been testified. However, the function and mechanism of lncRNAs on chemoresistance in hepatocellular carcinoma are still confused. In this study, we concentrated on the function and mechanism of KCNQ1OT1 on oxaliplatin resistance in hepatocellular carcinoma. Results showed that KCNQ1OT1 was significantly up-regulated in oxaliplatin-resistant HepG2 and Huh7 cells. Moreover, knockdown of KCNQ1OT1 inhibited the cell proliferation, migration, invasion and reduced the expression of drug-resistant gene (MRP5, MDR1, LRP1). Additionally, bioinformatics analysis and dual-luciferase reporter assay showed that miR-7-5p directly targeted the 3'-UTR of miR-7-5p and ABCC1 mRNA, indicating that KCNQ1OT1 regulated the expression of ABCC1 via endogenous sponging miR-7-5p. Conclusively, KCNQ1OT1 modulated oxaliplatin resistance in hepatocellular carcinoma through miR-7-5p/ABCC1 axis, indicating a novel approach for the treatment of hepatocellular carcinoma.

Nie H, Mu J, Wang J, Li Y
miR‑195‑5p regulates multi‑drug resistance of gastric cancer cells via targeting ZNF139.
Oncol Rep. 2018; 40(3):1370-1378 [PubMed] Free Access to Full Article Related Publications
Gastric cancer (GC) is one of the most common malignant tumors with a high mortality rate. Reversing the multi‑drug resistance (MDR) of GC offers the potential for significant enhancement of the effect of chemotherapy and improvement of prognosis. Aberrant microRNA expression can attribute to the pathogenesis of GC. However, the effects of microRNA (miR)‑195‑5p on the MDR of GC cells remains to be fully elucidated. In the present study, the effect of miR‑195‑5p in regulating the MDR of GC cells was investigated. Reverse transcription quantitative‑polymerase chain reaction was used to analyze the levels of miR‑195‑5p in GC cells. Western blot analysis was performed to analyze the protein levels of ZNF139, P‑gp, BCL‑2 and MRP1. The chemosensitivity of GC cells was determined by MTT. The results showed that the expression of miR‑195‑5p was decreased in poorly differentiated GC tissues with a higher chemosensitivity. The overexpression of miR‑195‑5p promoted the chemosensitivity of GC cells. Bioinformatics analysis indicated that Zing finger 139 (ZNF139) was a target of miR‑195‑5p. miR‑195‑5p negatively regulated the expression of ZNF139 by binding to its 3'‑untranslated region. The silencing of ZNF139 promoted the chemosensitivity of GC cells, and the downregulation of ZNF139 reversed the effect of miR‑195‑5p inhibitor on the chemosensitivity of GC cells. In conclusion, miR‑195‑5p regulated the MDR of GC cells via targeting ZNF139.

Yang T, Cheng J, You J, et al.
S100B promotes chemoresistance in ovarian cancer stem cells by regulating p53.
Oncol Rep. 2018; 40(3):1574-1582 [PubMed] Related Publications
Chemoresistance is one of the most important causes of ovarian cancer‑related deaths. Recently, cancer stem cells (CSCs) have been recognized as the source of chemoresistance in ovarian cancer. However, the underlying mechanisms that regulate the chemoresistance of ovarian CSCs (OCSCs) remain unclear. The aim of the present study was to investigate the roles of S100B in the regulation of OCSC chemoresistance, which provides a novel therapeutic target. We observed high expression of S100B in CD133+ OCSCs derived from ovarian cancer cell lines and primary tumors and in cisplatin‑resistant patient samples. Then, we determined that S100B knockdown promoted the apoptosis of OCSCs after treatment with different concentrations of cisplatin. The underlying mechanism of S100B‑mediated chemoresistance in OCSCs may be through p53 inhibition. Furthermore, drug‑resistance genes, including MDR1 and MRP1, were involved in the process of S100B‑mediated OCSC chemoresistance. In conclusion, our results elucidated the importance of S100B in the maintenance of OCSC chemoresistance, which may provide a promising therapeutic target for ovarian cancer.

Zhang C, Wang M, Shi C, et al.
Long non-coding RNA Linc00312 modulates the sensitivity of ovarian cancer to cisplatin via the Bcl-2/Caspase-3 signaling pathway.
Biosci Trends. 2018; 12(3):309-316 [PubMed] Related Publications
Chemotherapy is one of the main treatments for ovarian cancer (OC). Cisplatin combined with paclitaxel is a commonly used chemotherapy regimen. However, effective cancer therapy is hindered by a patient's resistance to cisplatin. The mechanism that potentially leads to that resistance is unclear. The current study examined the mechanism by which Linc00312 is involved in resistance to cisplatin in OC. Quantitative real-time PCR (RT-qPCR) was used to test for expression of Linc00312 in freshly frozen tissue samples of OC and in SKOV3 and SKOV3/DDP cells. In situ hybridization was performed to examine the distribution of Linc00312 expression in paraffin-embedded histological sections that were sensitive or resistant to cisplatin. The cell counting kit-8 assay was used to detect cell viability. Flow cytometry was used to measure cell apoptosis. RT-qPCR was performed to confirm changes in expression of MDR1, MRP1, Bcl-2, Bax, Caspase-3, and Caspase-9 mRNA. Levels of MDR1, Bcl-2, Bax, Caspase-3, and Caspase-9 protein were detected with Western blotting. Experiments indicated that the expression of Linc00312 decreased significantly in SKOV3/DDP cells compared to that in SKOV3 cells. Upregulation of Linc00312 can considerably increase the sensitivity of SKOV3/DDP cells to cisplatin, while down-regulation of Linc00312 has the exact opposite effect in SKOV3 cells. Linc00312 enhanced the sensitivity of SKOV3/DDP cells to cisplatin by promoting cell apoptosis via the Bcl-2/Caspase-3 signaling pathway. These findings suggest that Linc00312 may be a promising clinical strategy for the treatment of drug-resistant OC.

Zheng X, Li H
TKTL1 modulates the response of paclitaxel-resistant human ovarian cancer cells to paclitaxel.
Biochem Biophys Res Commun. 2018; 503(2):572-579 [PubMed] Related Publications
Transketolase-like 1 (TKTL1) plays an important role in the pentose phosphate pathway (PPP) branch. The main obstacle of ovarian cancer treatment is chemotherapeutic resistance. We investigated whether inhibiting TKTL1 in OC3/TAX300 cells could re-sensitize paclitaxel-resistant cells to paclitaxel and proposed a mechanism of action. Western blotting revealed that TKTL1 expression levels in OC3/Tax300 cells were significantly higher than those in OC3 cells. Inhibition of TKTL1 significantly decreased the cellular proliferation rate and IC50 for paclitaxel. Metabolomics revealed that NADPH levels were reduced in the si-TKTL1 group, whereas NADP

Li Y, Liu Y, Ren J, et al.
miR-1268a regulates ABCC1 expression to mediate temozolomide resistance in glioblastoma.
J Neurooncol. 2018; 138(3):499-508 [PubMed] Related Publications
INTRODUCTION: Temozolomide (TMZ) is the preferred chemotherapeutic drug approved for the Glioblastoma multiforme (GBM) treatment. However, resistance to TMZ is the most intractable challenge for treatment of GBM. Screening of miRNAs is becoming a novel strategy to reveal underlying mechanism of drug-resistance of human tumors.
MATERIALS AND METHODS: We conducted RNA sequencing (RNA-seq) for GBM cells treated continuously with TMZ 1 or 2 week or not. Bioinformatic analysis was used to predict targets of these altered miRNAs. Subsequently, we studied the potential role of miR-1268a in TMZ-resistance of GBM cells.
RESULTS: Expression levels of 55 miRNAs were identified altering both after 1 and 2 weeks TMZ treatment. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to illuminate the biological implication and related pathways of predicted target genes. We showed that miR-1268a was downregulated after TMZ treatment and targeted ABCC1/MRP1, a membrane transporter contributing to drug resistance, using dual-luciferase assay. Furthermore, we confirmed overexpression of miR-1268a inhibited protein translation of ABCC1 and restored upregulated expression of ABCC1 due to TMZ. Inversely, knockdown of miR-1268a increased ABCC1 at protein level and enhanced upregulation of ABCC1 with TMZ treatment. In addition, our data indicated that miR-1268a enhanced TMZ sensitivity in GBM cells.
CONCLUSION: Through RNA-seq analysis, we discovered miR-1268a and elucidated its role in modulating TMZ-resistance of GBM cells by targeting ABCC1.

Hashimoto Y, Penas-Prado M, Zhou S, et al.
Rethinking medulloblastoma from a targeted therapeutics perspective.
J Neurooncol. 2018; 139(3):713-720 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents.
METHODS: Using multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications.
RESULTS: High expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472). PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her2 or EGFR were not found. Several unique mutations were identified, but their rarity indicates large-scale screening efforts would be necessary to identify sufficient patients for clinical trial inclusion.
CONCLUSIONS: Therapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.

Everson RG, Hashimoto Y, Freeman JL, et al.
Multiplatform profiling of meningioma provides molecular insight and prioritization of drug targets for rational clinical trial design.
J Neurooncol. 2018; 139(2):469-478 [PubMed] Related Publications
INTRODUCTION: Surgery and radiation therapy are the standard treatment options for meningiomas, but these treatments are not always feasible. Expression profiling was performed to determine the presence of therapeutic actionable biomarkers for prioritization and selection of agents.
METHODS: Meningiomas (n = 115) were profiled using a variety of strategies including next-generation sequencing (592-gene panel: n = 14; 47-gene panel: n = 94), immunohistochemistry (n = 8-110), and fluorescent and chromogenic in situ hybridization (n = 5-70) to determine mutational and expression status.
RESULTS: The median age of patients in the cohort was 60 years, with a range spanning 6-90 years; 52% were female. The most frequently expressed protein markers were EGFR (93%; n = 44), followed by PTEN (77%; n = 110), BCRP (75%; n = 8), MRP1 (65%, n = 23), PGP (62%; n = 84), and MGMT (55%; n = 97). The most frequent mutation among all meningioma grades occurred in the NF2 gene at 85% (11/13). Recurring mutations in SMO and AKT1 were also occasionally detected. PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1 + T cells were present in 46% (24/52) of meningiomas. TOP2A and thymidylate synthase expression increased with grade (I = 5%, II = 22%, III = 62% and I = 5%, II = 23%, III = 47%, respectively), whereas progesterone receptor expression decreased with grade (I = 79%, II = 41%, III = 29%).
CONCLUSION: If predicated on tumor expression, our data suggest that therapeutics directed toward NF2 and TOP2A could be considered for most meningioma patients.

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

Tang CY, Zhu LX, Yu JD, et al.
Effect of β-elemene on the kinetics of intracellular transport of d-luciferin potassium salt (ABC substrate) in doxorubicin-resistant breast cancer cells and the associated molecular mechanism.
Eur J Pharm Sci. 2018; 120:20-29 [PubMed] Related Publications
In order to explore the mechanism of the reversing multidrug resistance (MDR) phenotypes by β-elemene (β-ELE) in doxorubicin (DOX)-resistant breast cancer cells (MCF-7/DOX), both the functionality and quantity of the ABC transporters in MCF-7/DOX were studied. Bioluminescence imaging (BLI) was used to study the efflux of d-luciferin potassium salt, the substrate of ATP-binding cassette transporters (ABC transporters), in MCF-7/DOX cells treated by β-ELE. At the same time three major ABC transport proteins and genes-related MDR, P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated protein 1 (MRP, ABCC1) as well as breast cancer resistance protein (BCRP, ABCG2) were analyzed by q-PCR and Western blot. To investigate the efflux functionality of ABC transporters, MCF-7/DOX

Du J, He Y, Li P, et al.
IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1).
Cancer Chemother Pharmacol. 2018; 81(6):1111-1119 [PubMed] Related Publications
Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.

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