Gene Summary

Gene:MDM4; MDM4 regulator of p53
Aliases: HDMX, MDMX, MRP1
Summary:This gene encodes a nuclear protein that contains a p53 binding domain at the N-terminus and a RING finger domain at the C-terminus, and shows structural similarity to p53-binding protein MDM2. Both proteins bind the p53 tumor suppressor protein and inhibit its activity, and have been shown to be overexpressed in a variety of human cancers. However, unlike MDM2 which degrades p53, this protein inhibits p53 by binding its transcriptional activation domain. This protein also interacts with MDM2 protein via the RING finger domain, and inhibits the latter's degradation. So this protein can reverse MDM2-targeted degradation of p53, while maintaining suppression of p53 transactivation and apoptotic functions. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Feb 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein Mdm4
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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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.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

Entity Topic PubMed Papers
Breast CancerMDM4 and Breast Cancer View Publications40
Soft Tissue SarcomaMDM4 and Soft Tissue Sarcoma View Publications24
Brain Tumours, ChildhoodMDM4 and Brain Tumours View Publications20
RetinoblastomaMDM4 and Retinoblastoma
The penetrance of the RB1 mutation in retinoblastoma is thought to be dependent on concurrent genetic modifiers, in particular MDM2 and MDM4. de Oliveira Reis AH et al, 2012 reported findings that suggest that MDM2 and MDM4 polymorphisms may influence development and survival in Retinoblastoma.
View Publications15

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

Latest Publications: MDM4 (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.

Huang J, Luo J
The Achilles Heel of Malignant Rhabdoid Tumors.
Cancer Res. 2019; 79(11):2808-2809 [PubMed] Related Publications
Malignant rhabdoid tumors (MRT) are rare but deadly pediatric tumors characterized by mutations in the

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.

Mao S, Zhang J, Guo Y, et al.
Hyperprogression after anti-programmed cell death ligand-1 therapy in a patient with recurrent metastatic urothelial bladder carcinoma following first-line cisplatin-based chemotherapy: a case report.
Drug Des Devel Ther. 2019; 13:291-300 [PubMed] Free Access to Full Article Related Publications
Background: Immune checkpoint blockade targeting programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) signaling was approved recently for locally advanced and metastatic urothelial bladder carcinoma (UBC). Some patients experience a very rapid tumor progression, rather than clinical benefit, from anti-PD-L1/PD-1 therapy.
Case presentation: A 58-year-old male diagnosed with non-muscle-invasive bladder cancer 3 years ago received transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy. TURBT was repeated a year later for recurrent and progressive UBC. Following further disease progression, he received a radical cystectomy (RC), pathologically staged as T2bN2M0, and adjuvant cisplatin-containing combination chemotherapy. When his disease progressed to metastatic UBC, he was started on anti-PD-L1 monotherapy and experienced ultrarapid disease progression within 2 months; imaging scans ruled out pseudoprogression. We observed a fourfold increase in tumor growth rate, defined as the ratio of post- to pretreatment rates. Next-generation sequencing of formalin-fixed paraffin-embedded RC tissues showed
Conclusion: Even in cases with PD-L1-positive tumors,

Gao C, Xiao G, Piersigilli A, et al.
Context-dependent roles of MDMX (MDM4) and MDM2 in breast cancer proliferation and circulating tumor cells.
Breast Cancer Res. 2019; 21(1):5 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Many human breast cancers overexpress the E3 ubiquitin ligase MDM2 and its homolog MDMX. Expression of MDM2 and MDMX occurs in estrogen receptor α-positive (ERα
METHODS: To assess the context-dependent roles, we carried out MDM2 and MDMX knockdown in orthotopic tumors of TNBC MDA-MB-231 cells expressing mtp53 R280K and MDM2 knockdown in ERα
RESULTS: Knocking down MDMX or MDM2 in MDA-MB-231 cells reduced cell migration and CTC detection, but only MDMX knockdown reduced tumor volumes at early time points. This is the first report of MDMX overexpression in TNBC enhancing the CTC phenotype with correlated upregulation of CXCR4. Experiments were carried out to compare MDM2-knockdown outcomes in nonmetastatic ERα
CONCLUSIONS: This is the first report showing that the expression of MDM2 in ERα

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.

Park DE, Cheng J, Berrios C, et al.
Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response.
Proc Natl Acad Sci U S A. 2019; 116(3):1027-1032 [PubMed] Free Access to Full Article Related Publications
Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative MCC contains inactivating mutations in TP53 and RB1. While the MCV-truncated LT can bind and inhibit RB, it does not bind p53. We report here that MCV LT binds to RB, leading to increased levels of ARF, an inhibitor of MDM2, and activation of p53. However, coexpression of ST reduced p53 activation. MCV ST recruits the MYC homologue MYCL (L-Myc) to the EP400 chromatin remodeler complex and transactivates specific target genes. We observed that depletion of EP400 in MCV-positive MCC cell lines led to increased p53 target gene expression. We suspected that the MCV ST-MYCL-EP400 complex could functionally inactivate p53, but the underlying mechanism was not known. Integrated ChIP and RNA-sequencing analysis following EP400 depletion identified MDM2 as well as CK1α, an activator of MDM4, as target genes of the ST-MYCL-EP400 complex. In addition, MCV-positive MCC cells expressed high levels of MDM4. Combining MDM2 inhibitors with lenalidomide targeting CK1α or an MDM4 inhibitor caused synergistic activation of p53, leading to an apoptotic response in MCV-positive MCC cells and MCC-derived xenografts in mice. These results support dual targeting of MDM2 and MDM4 in virus-positive MCC and other p53 wild-type tumors.

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.

Imanishi M, Yamamoto Y, Wang X, et al.
Augmented antitumor activity of 5-fluorouracil by double knockdown of MDM4 and MDM2 in colon and gastric cancer cells.
Cancer Sci. 2019; 110(2):639-649 [PubMed] Free Access to Full Article Related Publications
Inactivation of the TP53 tumor suppressor gene is essential during cancer development and progression. Mutations of TP53 are often missense and occur in various human cancers. In some fraction of wild-type (wt) TP53 tumors, p53 is inactivated by upregulated murine double minute homolog 2 (MDM2) and MDM4. We previously reported that simultaneous knockdown of MDM4 and MDM2 using synthetic DNA-modified siRNAs revived p53 activity and synergistically inhibited in vitro cell growth in cancer cells with wt TP53 and high MDM4 expression (wtTP53/highMDM4). In the present study, MDM4/MDM2 double knockdown with the siRNAs enhanced 5-fluorouracil (5-FU)-induced p53 activation, arrested the cell cycle at G

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.

Ding H, Wen Z, Sun G
Silencing of Xeroderma Pigmentosum Group D Gene Promotes Hepatoma Cell Growth by Reducing P53 Expression.
Med Sci Monit. 2018; 24:8015-8021 [PubMed] Free Access to Full Article Related Publications
BACKGROUND This study investigated the effect of xeroderma pigmentosum group D (XPD) silencing on the growth of hepatoma cells and assessed the mechanisms. MATERIAL AND METHODS XPD gene was silenced by siRNA in hepatoma cells. The experiments were randomly divided into a control group, a liposome control group, a negative control (NC) group, an XPD siRNA group, and an XPD siRNA + P53 inhibitor group. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) was used to detect cell viability 24 h after gene silencing and treatments. Terminal deoxynucleotidyl transferases (TdT)-mediated dUTP nick-end labeling (TUNEL) and flow cytometry were used to detect apoptosis. Invasive ability was detected by Transwell assay. Additionally, the expression of mouse double-minute 2 homolog (Mdm2), mouse double-minute 4 homolog (Mdm4), CyclinD1, P21, Bax, P53, C-sis, and Bcl-2 was detected by real-time polymerase chain reaction and Western blotting. RESULTS Compared with the NC group, XPD siRNA significantly reduced XPD expression at both mRNA and protein levels. XPD siRNA significantly promoted cell proliferation, reduced apoptosis, and promoted cell invasive ability. Expression of CyclinD1, Bcl-2, and C-sis increased significantly after XPD silencing, while the expression of P21, Mdm2, Mdm4, Bax, and P53 significantly decreased (vs. NC, P<0.05). Importantly, P53 inhibitor (1 μM bpV) further enhanced the effect of XPD silencing (vs. XPD silencing, P<0.05). CONCLUSIONS Our data revealed that XPD silencing promoted growth of hepatoma cells by reducing P53 expression.

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.

Ling ZA, Xiong DD, Meng RM, et al.
LncRNA NEAT1 Promotes Deterioration of Hepatocellular Carcinoma Based on In Vitro Experiments, Data Mining, and RT-qPCR Analysis.
Cell Physiol Biochem. 2018; 48(2):540-555 [PubMed] Related Publications
BACKGROUND/AIMS: Accumulated evidence indicates that lncRNA NEAT1 has important roles in various malignant tumors. In this study, we conducted a comprehensive analysis to explore the exact role of NEAT1 in hepatocellular carcinoma (HCC).
METHODS: The effects of NEAT1 on cell proliferation, apoptosis, migration, and invasion were measured by in vitro experiments. The expression level and clinical value of NEAT1 in HCC was evaluated based on data from The Cancer Genome Atlas (TCGA), Oncomine, and in-house real-time quantitative (RT-qPCR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network analyses were conducted to investigate the potential molecular mechanisms of NEAT1.
RESULTS: NEAT1 siRNA not only inhibited proliferation, migration, and invasion of HCC cells but also induced HCC cell apoptosis. A total of four records from TCGA, Oncomine, and RT-qPCR analysis were combined to assess the expression level of NEAT1 in HCC. The pooled standard mean deviation (SMD) indicated that NEAT1 was up-regulated in HCC (SMD = 0.54; 95% CI, 0.36-0.73; P < 0.0001). The area under the curve value of the summary receiver operating characteristic curve was 0.71. NEAT1 expression was also related to race (P = 0.025) and distant metastasis (P = 0.002). Additionally, the results of GO, KEGG pathway, and PPI network analyses suggest that NEAT1 may promote the progression of HCC by interacting with several tumor-related genes (SP1, MDM4, CREBBP, TRAF5, CASP8, TRAF1, KAT2A, and HIST4H4).
CONCLUSIONS: NEAT1 contributes to the deterioration of HCC and provides a potential biomarker for the diagnosis and therapy of HCC.

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).

Leighton X, Bera A, Eidelman O, et al.
High ANXA7 Potentiates Eucalyptol Toxicity in Hormone-refractory Prostate Cancer.
Anticancer Res. 2018; 38(7):3831-3842 [PubMed] Related Publications
BACKGROUND/AIM: Our studies showed that ANXA7 is a novel tumor suppressor gene that is lost in various aggressive forms of prostate cancer. However, little is known about the role of ANXA7 in the anticancer drug treatment towards different cancers.
MATERIALS AND METHODS: The expression of ANXA7 was measured in the 60 cancer cell lines of the NCI-60 ADS project and correlated with the enhanced sensitivity to over 30,000 natural and synthetic compounds.
RESULTS: Eucalyptol showed a high positive correlation with ANXA7 expression and castration-resistant prostate cancer cell death occurred very effectively in response to the combination of eucalyptol and overexpressed wt-ANXA7 than either agent alone. The synergistic effects of ANXA7 and eucalyptol resulted in concordant changes in gene expression profiles particularly of Ras family members, MDM4, NF-ĸB and VEGF.
CONCLUSION: Overexpression of ANXA7 enhances eucalyptol cytotoxicity in prostate cancer cell lines.

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.

Further References

de Oliveira Reis AH, de Carvalho IN, de Sousa Damasceno PB, et al.
Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma.
Pediatr Blood Cancer. 2012; 59(1):39-43 [PubMed] Related Publications
BACKGROUND: Retinoblastoma (RB) accounts for 3% of all childhood malignancies, with different incidences around the world. This malignancy results from loss-of-function of both RB1 alleles although other genes, like MDM2 and MDM4, have been proposed to be involved in tumor development.
PROCEDURE: We genotyped rs2279744T>G and rs937283A>G in MDM2, and rs4252668T>C and rs116197192G>A in MDM4, in 104 unrelated RB patients and 104 controls. Sixty-month survival Kaplan-Meier curves and χ(2)-tests were performed for estimating the putative effect of MDM2 and MDM4 alleles on disease progression and survival of RB patients.
RESULTS: MDM2 rs2279744G was significantly more frequent in controls, indicating an apparently protective effect on RB development. However, survival of patients who carried a constitutional RB1 mutation was significantly lower with rs2279744TG or GG than with rs2279744TT. Presence of rs2279744G and a constitutional RB1 mutation was sixfold more frequent in the 0-12 month age group than other age groups at onset of symptoms (P = 0.0401). MDM4 rs4252668C was present at a significantly higher frequency in controls while the frequency of MDM4 rs116197192G was significantly higher in RB patients, suggesting that this allele might increase the risk of developing RB.
CONCLUSION: Our results indicate that MDM2 and MDM4 polymorphisms may influence development and/or survival in RB.

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