Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (12)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MDM2 (cancer-related)
Chrysovergis A, Papanikolaou V, Tsiambas E, et al.P53/MDM2 Co-Expression in Laryngeal Squamous Cell Carcinoma Based on Digital Image Analysis.
Anticancer Res. 2019; 39(8):4137-4142 [PubMed
] Related Publications
BACKGROUND: P53 is a key regulator of genomic stability and function, acting as a tumor suppressor protein. Our aim was to correlate P53 expression with murine double minute 2 (MDM2), a proto-oncogene that interacts with P53 and forms an auto-regulatory pathway, in laryngeal squamous cell carcinoma (LSCC).
MATERIALS AND METHODS: A total of 50 LSCC cases were included in the study. Immunohistochemistry was applied by using antibodies to P53 and MDM2 in the corresponding tissue sections. Protein expression levels for both molecules were measured by implementing a digital image analysis assay (immunostaining intensity levels, densitometric evaluation).
RESULTS: Overexpression of P53 protein was observed in 16/50 (32%) LSCC cases, while 22/50 (44%) cases strongly expressed MDM2 protein. Interestingly, in 13/50 (26%) cases, combined overexpression of P53/MDM2 was detected. Overall P53 was strongly positively correlated with MDM2 expression (p=0.001). Both P53 and MDM2 overexpression were significantly correlated with advanced stage of LSCC (p=0.032 and p=0.001, respectively). Additionally, MDM2 was found to be associated with poorer survival of patients (p=0.046).
CONCLUSION: Aberrant co-expression of P53 and MDM2 is associated with advanced stage in LSCC. Furthermore, MDM2 overexpression is a frequent and critical genetic event in LSCC and seems to negatively affect survival.
Yari K, Jalilvand AComment on: 'A 40-bp insertion/deletion polymorphism in the constitutive promoter of MDM2 confers risk for hepatocellular carcinoma in a Chinese population'.
Gene. 2019; 712:143965 [PubMed
] Related Publications
Recently, we read the published article in GENE. Dong et al. presented the evaluation of the MDM2 40-bp insertion/deletion status in Hepatocellular carcinoma patients (Dong et al., 2012). The authors stated that the insertion allele showed a 521-bp band and the deletion allele showed a 481-bp band on agarose gel electrophoresis. While it seems that these reported sizes for insertion and deletion alleles of MDM2 are incorrect. Our analysis using the primers indicated that the length of insertion and deletion fragments will be 481 and 441 bps, respectively. Actually, 40-bp is added to the fragment length instead of reducing the 40-bp. In the 'UCSC In-Silico PCR' tool, the length of the amplified fragment using mentioned primers is 481-bp including the sequence of 40-bp insertion allele (5'-(A)
Dusek J, Skoda J, Holas O, et al.Stilbene compound trans-3,4,5,4´-tetramethoxystilbene, a potential anticancer drug, regulates constitutive androstane receptor (Car) target genes, but does not possess proliferative activity in mouse liver.
Toxicol Lett. 2019; 313:1-10 [PubMed
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The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.
Malignant rhabdoid tumors (MRT) are rare but deadly pediatric tumors characterized by mutations in the
Jia H, Xu M, Bo Y, et al.Ras-ERK1/2 signaling accelerates the progression of colorectal cancer via mediation of H2BK5ac.
Life Sci. 2019; 230:89-96 [PubMed
] Related Publications
AIMS: Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) is a key downstream gene of Ras pathway. Activation of Ras-ERK1/2 has been testified to be linked to the progression of diverse cancers. Nonetheless, whether Ras-ERK1/2-tumorigenic pathway is mediated by epigenetic factors remains indistinct. The purpose of the research attempted to disclose the functions of H2BK5ac in Ras-ERK1/2-evoked CRC cell phenotypes.
MATERIALS AND METHODS: Western blot assay was implemented for exploration of the relevancy between Ras-ERK1/2 and H2BK5ac. H2BK5Q was established and its functions in cell viability, colony formation and migration were appraised via utilizing MTT, soft-agar colony formation and Transwell assays. The mRNA and transcription of ERK1/2 downstream genes were estimated via RT-qPCR and ChIP assays. HDAC2 functions in SW48 cell phenotypes were evaluated after co-transfection with pEGFP-Ras
KEY FINDINGS: H2BK5ac expression was evidently repressed by Ras-ERK1/2 pathway in SW48 cells. Moreover, Ras-ERK1/2-elevated cell viability, the number of colonies and migration were both impeded by H2BK5ac. The mRNA and transcriptions of CYR61, IGFBP3, WNT16B, NT5E, GDF15 and CARD16 were both mediated by H2BK5ac. Additionally, HDAC2 silence overtly recovered H2BK5ac expression inhibited by Ras-ERK1/2, meanwhile abated Ras-ERK1/2-affected SW48 cell phenotypes. Beyond that, restrained H2BK5ac induced by Ras-ERK1/2 was concerned with MDM2-mediated ATF2 degradation.
SIGNIFICANCE: These investigations testified that Ras-ERK1/2 pathway affected SW48 cell phenotypes through repressing H2BK5ac expression. Otherwise, declined H2BK5ac might be linked to MDM2-mediated ATF2 degradation.
BACKGROUND/AIM: The aim of this study was to determine the joint effect of single nucleotide polymorphisms (SNPs) of MDM2, TP53, and CDKN2A (P14ARF) genes on the onset and course of endometrial cancer (EC) in postmenopausal women.
MATERIALS AND METHODS: The study group consisted of 144 EC women and 50 non-cancer controls. MDM2 rs22279744, TP53 rs1042522, and P14ARF rs3088440, rs3731217, and rs3731245 SNPs were analysed.
RESULTS: The double-SNP combinations T-C, T-T, or T-G in MDM2 SNP 309 and P14ARF polymorphisms decreased EC risk. The triple-SNP combinations T-C-T, T-C-G, or T-T-G in MDM2 SNP and two P14ARF polymorphisms decreased EC risk. The multiple-SNP combination T-C-T-G in MDM2 and three P14ARF polymorphisms decreased EC risk. The G-Arg-C-T-G carriers were at increased EC risk, while the T-Arg-C-T-G carriers were at decreased EC risk.
CONCLUSION: MDM2 SNP309 plays a role in EC onset in postmenopausal women.
BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the most lethal of all gynecological malignancies. Patients often suffer from chemoresistance. Several studies have reported that Fn14 could regulate migration, invasion, and angiogenesis in cancer cells. However, its functional role in chemoresistance of HGSOC is still unknown.
METHODS: The expression of Fn14 in tissue specimens was detected by IHC. CCK-8 assay was performed to determine changes in cell viability. Apoptosis was measured by flow cytometry. The potential molecular mechanism of Fn14-regulated cisplatin resistance in HGSOC was investigated using qRT-PCR, western blotting, and Co-IP assays. The role of Fn14 in HGSOC was also investigated in a xenograft mouse model.
RESULTS: In this study, we found that Fn14 was significantly downregulated in patients with cisplatin resistance. Patients with low Fn14 expression were associated with shorter progression-free survival and overall survival. Overexpression of Fn14 suppressed cisplatin resistance in OVCAR-3 cells, whereas knockdown of Fn14 did not affect cisplatin resistance in SKOV-3 cells. Interestingly, Fn14 could exert anti-chemoresistance effect only in OVCAR-3 cells harboring a p53-R248Q mutation, but not in SKOV-3 cells with a p53-null mutation. We isolated and identified primary cells from two patients with the p53-R248Q mutation from HGSOC patients and the anti-chemoresistance effect of Fn14 was observed in both primary cells. Mechanistic studies demonstrated that overexpression of Fn14 could reduce the formation of a Mdm2-p53-R248Q-Hsp90 complex by downregulating Hsp90 expression, indicating that degradation of p53-R248Q was accelerated via Mdm2-mediated ubiquitin-proteasomal pathway.
CONCLUSION: Our findings demonstrate for the first time that Fn14 overcomes cisplatin resistance through modulation of the degradation of p53-R248Q and restoration of Fn14 expression might be a novel strategy for the treatment of HGSOC.
Wei Y, Wang F, Sang B, et al.Activation of KRas-ERK1/2 signaling drives the initiation and progression of glioma by suppressing the acetylation of histone H4 at lysine 16.
Life Sci. 2019; 225:55-63 [PubMed
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BACKGROUND/AIMS: Acetylation of H4 at lysine 16 (H4K16ac) has been well-characterized as an acetylated mark, and the expression of which is closely associated with the tumorigenesis of human cancers. This study aimed to reveal whether KRas mutation drives the initiation and progression of glioma via modulation of H4 acetylation.
METHODS: Changes of H4K16 acetylation in human glioblastoma A172 cells following transfection with a plasmid for expression of mutant KRas were tested by western blot analysis. MTT assay, transwell assay, soft-agar colony formation assay, RT-PCR and chromatin immunoprecipitation were carried out to evaluate the effect of H4K16ac on A172 cells growth and migration. Furthermore, the enzymes participating in the deacetylation of H4K16ac were studied by using RT-PCR and western blot analysis.
RESULTS: H4K16ac was found to be deacetylated by KRas-ERK1/2 activation. H4K16Q (a plasmid for mimicking H4K16ac) repressed A172 cells viability, colony formation, and migratory capacity. Besides, H4K16ac was capable of regulating the transcription of several ERK1/2 pathway downstream genes. KRas-ERK1/2 signaling repressed H4 acetylation at K16 via modulation of a histone deacetylase Sirt2, as well as a histone acetyl-transferase TIP60. Moreover, KRas-ERK1/2 inhibited TIP60 via an MDM2-dependnet fashion.
CONCLUSION: Our results suggest that activation of KRas-ERK1/2 signaling participates in the onset and progression of glioma at least partially through modulating acetylation of H4 at K16. KRas-ERK1/2 signaling mediates the acetylation of H4K16 via Sirt2 and MDM2-dependnet degeneration of TIP60.
BACKGROUND: To evaluate the diagnostic value of MR imaging for the differentiation of lipomas and atypical lipomatous tumors (ALT) in comparison with histology and MDM2 amplification status.
METHODS: Patients with well-differentiated lipomatous tumors (n = 113), of which 66 were diagnosed as lipoma (mean age 53 years (range, 13-82); 47% women) and 47 as atypical lipomatous tumor (ALT; mean age 60 years (range, 28-88); 64% women), were included into this study using histology and MDM2 amplification status by fluorescence in situ hybridization (FISH) as standard of reference. Preoperative MR images were retrospectively assessed by two radiologists for the following imaging features: maximum tumor diameter (mm) as well as the affected compartment (intramuscular, intermuscular or subcutaneous), septa (absent, thin (< 2 mm) or thick septa (> 2 mm) with nodular components); contrast enhancing areas within the lipomatous tumor (< 1/3 of the tumor volume, > 1/3 of the tumor volume); RESULTS: Of the 47 patients with ALT, 40 (85.1%) presented thick septa (> 2 mm) and this finding significantly increased the likelihood of ALT (OR 6.24, 95% CI 3.36-11.59; P < 0.001). The likelihood of ALT was increased if the tumor exceeded a maximum diameter of 130.0 mm (OR 2.74, 95% CI 1.82-4.11, P < 0.001). The presence of contrast enhancement in lipomatous tumors significantly increased the likelihood of ALT (Odds ratio (OR) 2.95, 95% confidence interval (CI) 2.01-4.31; P < 0.001). Of the lipomas, 21.1% were located subcutaneously, 63.6% intramuscularly and 15.2% intermuscularly. On the other hand, none of the ALTs were located subcutaneously, the majority was located intermuscularly (87.3%) and a small number of ALTs was located intramuscularly (12.7%).
CONCLUSIONS: Our results suggest that using specific morphological MR imaging characteristics (maximum tumor diameter, thick septa and contrast enhancement) and the information on the localization of the lipomatous tumor, a high sensitivity and substantial specificity can be achieved for the diagnosis of lipomas and ALTs.
Zhang J, Liu M, Liu W, Wang WRas-ERK1/2 signalling promotes the development of osteosarcoma through regulation of H4K12ac through HAT1.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1207-1215 [PubMed
] Related Publications
Histone H4 acetylation at lysine 12 (H4K12ac) has been reported to be associated with the poor prognosis of pancreatic cancer. The study intends to study whether H4K12ac participates in regulating the carcinogenic effect of Ras-ERK1/2 on osteosarcoma (OS). The plasmids of pEGFP-N1, pEGFP-Ras
Adipocytic neoplasms include a diversity of both benign tumors (lipomas) and malignancies (liposarcomas), and each tumor type is characterized by its own unique molecular alterations driving tumorigenesis. Work over the past 30 years has established the diagnostic utility of several of these characteristic molecular alterations (e.g. MDM2 amplification in well- and dedifferentiated liposarcoma, FUS/EWSR1-DDIT3 gene fusions in myxoid liposarcoma, RB1 loss in spindle cell/pleomorphic lipoma). More recent studies have focused on additional molecular alterations which may have therapeutic or prognostic impact. This review will summarize several of the important molecular findings in adipocytic tumors that have been described over the past 10 years.
Thway KWell-differentiated liposarcoma and dedifferentiated liposarcoma: An updated review.
Semin Diagn Pathol. 2019; 36(2):112-121 [PubMed
] Related Publications
Well-differentiated liposarcoma (WDL)/atypical lipomatous tumor and dedifferentiated liposarcoma (DDL) together comprise the largest subgroup of liposarcomas, and constitute a histologic and behavioral spectrum of one disease. WDL and DDL typically occur in middle-aged to older adults, particularly within the retroperitoneum or extremities. WDL closely resembles mature adipose tissue, but typically shows fibrous septation with variable nuclear atypia and enlargement. WDL does not metastasize, but can dedifferentiate to DDL, which is associated with more aggressive clinical behavior, with a greater propensity for local recurrence and the capacity for metastasis. Although distant metastasis is rarer in DDL compared with other pleomorphic sarcomas, behavior is related to location, with a significantly worse outcome in retroperitoneal tumors. DDL typically has the appearance of undifferentiated pleomorphic or spindle cell sarcoma, and is usually a non-lipogenic sarcoma that is adjacent to WDL, occurs as a recurrence of WDL or which can arise de novo. WDL and DDL share similar background genetic aberrations; both are associated with high-level amplifications in the chromosomal 12q13-15 region, which includes the CDK4 and MDM2 cell cycle oncogenes. In addition, DDL harbor further genetic changes, particularly 6q23 and 1p32 coamplifications. While surgical excision remains the treatment mainstay with limited medical options for patients with aggressive recurrent disease or metastases, novel targeted therapies towards the gene products of chromosome 12 are being evaluated. This review summarizes the pathology of WDL and DDL, discussing morphology, immunohistochemistry, genetics and the differential diagnosis.
Zhou R, Shi C, Tao W, et al.Analysis of Mucosal Melanoma Whole-Genome Landscapes Reveals Clinically Relevant Genomic Aberrations.
Clin Cancer Res. 2019; 25(12):3548-3560 [PubMed
] Related Publications
PURPOSE: Unlike advances in the genomics-driven precision treatment of cutaneous melanomas, the current poor understanding of the molecular basis of mucosal melanomas (MM) has hindered such progress for MM patients. Thus, we sought to characterize the genomic landscape of MM to identify genomic alterations with prognostic and/or therapeutic implications.
EXPERIMENTAL DESIGN: Whole-genome sequencing (WGS) was performed on 65 MM samples, including 63 paired tumor blood samples and 2 matched lymph node metastases, with a further droplet digital PCR-based validation study of an independent MM cohort (
RESULTS: Besides the identification of well-recognized driver mutations of
CONCLUSIONS: Our largest-to-date cohort WGS analysis of MMs defines the genomic landscape of this deadly cancer at unprecedented resolution and identifies genomic aberrations that could facilitate the delivery of precision cancer treatments.
BACKGROUND AND OBJECTIVE: Alterations in gene expressions are often due to epigenetic modifications that can have a significant influence on cancer development, growth, and progression. Lately, histone deacetylase inhibitors (HDACi) such as suberoylanilide hydroxamic acid (SAHA, or vorinostat, MK0683) have been emerging as a new class of drugs with promising therapeutic benefits in controlling cancer growth and metastasis. The small molecule RG7388 (idasanutlin, R05503781) is a newly developed inhibitor that is specific for an oncogene-derived protein called MDM2, which is also in clinical trials for the treatment of various types of cancers. These two drugs have shown the ability to induce p21 expression through distinct mechanisms in MCF-7 and LNCaP cells, which are reported to have wild-type TP53. Our understanding of the molecular mechanism whereby SAHA and RG7388 can induce cell cycle arrest and trigger cell death is still evolving. In this study, we performed experiments to measure the cell cycle arrest effects of SAHA and RG7388 using MCF-7 and LNCaP cells.
MATERIALS AND METHODS: The cytotoxicity, cell cycle arrest, and apoptosis/necroptosis effects of the SAHA and RG7388 treatments were assessed using the Trypan Blue dye exclusion (TBDE) method, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescence assay with DEVD-amc substrate, and immunoblotting methods.
RESULTS: The RG7388 treatment was able to induce cell death by elevating p21
CONCLUSION: Our results from MCF-7 and LNCaP cells confirmed that SAHA and RG7388 treatments were able to induce cell death via a combination of cell cycle arrest and cytotoxic mechanisms. We speculate that our findings could lead to the development of newer treatments for breast and prostate cancers with drug combinations including HDACi.
SNP309T>G (rs2279744) and SNP285G>C (rs117039649) in the
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the USA. However, the underlying molecular mechanisms that drive CRC tumorigenesis are still not clear. Several studies have reported that long noncoding RNAs (lncRNAs) have important roles in tumor development. Here, we undertook a transcriptome microarray analysis in 6 pairs of CRC tissues and their corresponding adjacent normal tissues. A total of 1705 differentially expressed lncRNAs were detected in CRC tissues at stages I/II and III/IV (fold change greater than or equal to 2 or less than or equal to 0.5). Among them, we found that the lncRNA lung cancer-associated transcript 1 (LUCAT1) was upregulated in CRC tissues and was closely associated with poor overall survival of CRC patients, through analysis of clinical data and The Cancer Genome Atlas. Functional studies indicated that LUCAT1 promoted CRC cell proliferation, apoptosis, migration, and invasion in vitro and in vivo. Furthermore, knockdown of LUCAT1 rendered CRC cells hypersensitive to oxaliplatin treatment. Mechanistically, bioinformatic analysis indicated that low expression of LUCAT1 was associated with the p53 signaling pathway. Chromatin isolation by RNA purification followed by mass spectrometry and RNA immunoprecipitation revealed that LUCAT1 bound with UBA52, which encodes ubiquitin and 60S ribosomal protein L40 (RPL40). We found that RPL40 functions in the ribosomal protein-MDM2-p53 pathway to regulate p53 expression. Taken together, our findings indicate that suppression of LUCAT1 induces CRC cell cycle arrest and apoptosis by binding UBA52 and activating the RPL40-MDM2-p53 pathway. These results implicate LUCAT1 as a potential prognostic biomarker and therapeutic target for CRC.
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,
Mucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.
OBJECTIVES: The aim of the study is to explore the relationship between CCDC69 expression and resistance of ovarian cancer cells to cisplatin and reveal the underlying mechanism.
METHODS: One hundred thirty five ovarian cancer patients with intact chemo-response information from The Cancer Genome Atlas (TCGA) database were included and analyzed. Stable CCDC69 overexpressing 293 and ovarian cancer A2780 cell lines were established and subjected to examine cell apoptosis and cell cycle distribution using CCK-8 assay and flow cytometry. Cell cycle and apoptosis pathway were evaluated by immunoblots. Stability of p14
RESULTS: We found that CCDC69 expression was significantly higher in chemo-sensitive groups compared with chemo-resistant groups from TCGA database. High CCDC69 expression was associated longer survival. CCDC69 overexpressing 293 and A2780 cells with wildtype p53 and contributes to cisplatin sensitivity following treatment with cisplatin. We further found over-expression of CCDC69 activated p14
CONCLUSIONS: It is tempting to conclude that targeting CCDC69 may play a role in cisplatin resistance.
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
Endometrial cancer (EC) is one of the most common malignancies of the female reproductive system, and metastasis is a major cause of mortality. In this study, we aimed to explore the role of CP‑31398 in the migration, invasion and apoptosis of EC cells by its regulation of the expression of the murine double minute 2 (MDM2) gene. For this purpose, EC tissues and adjacent normal tissues were collected, and the positive expression rate of MDM2 in these tissues was assessed. Subsequently, the cellular 50% inhibitory concentration (IC50) of CP‑31398 was measured. The EC RL95‑2 and KLE cell lines had a higher MDM2 expression and were thus selected for use in subsequent experiments. The EC cells were then treated with CP‑31398 (2 µg/ml), and were transfected with siRNA against MDM2 or an MDM2 overexpression plasmid in order to examine the effects of CP‑31398 and MDM2 on EC cell activities. The expression of p53, p21, Bad, Bax, B‑cell lymphoma‑2 (Bcl‑2), cytochrome c (Cyt‑c), caspase‑3, Cox‑2, matrix metalloproteinase (MMP)‑2 and MMP‑9 was measured to further confirm the effects of CP‑31398 on cell migration, invasion and apoptosis. Our results indicated that MDM2 was highly expressed in EC tissues. Notably, EC cell viability decreased with the increasing concentrations of CP‑31398. The EC cells treated with CP‑31398 or siRNA against MDM2 exhibited an increased apoptosis and a suppressed migration and invasion, corresponding to an increased expression of p53, p21, Bad, Bax, Cyt‑c and caspase‑3, as well as to a decreased expression of Bcl‑2, Cox‑2, MMP‑2 and MMP‑9. Moreover, treatment with CP‑31398 and siRNA against MDM2 further enhanced these effects. Taken together, the findings of this study indicate that the CP‑31398‑mediated downregulation of MDM2 may suppress EC progression via its inhibitory role in EC cell migration, invasion and resistance to apoptosis. Therefore, treatment with CP‑31398 may prove to be possible therapeutic strategy for EC.
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.
Cisplatin is a platinum-containing chemotherapeutic drug, which is widely used and highly effective. While effective against tumors, its use is limited by severe side effects such as nephrotoxicity and bone marrow suppression. Murine double minute 2 (MDM2) is the E3 ubiquitin ligase of the tumor suppressor gene, p53, and inhibition of MDM2 can suppress tumor cell growth. However, independent of p53, MDM2 acts as a co-transcription factor for nuclear factor-κB (NFκB), whose signaling can be involved in cisplatin-induced tubular injury. We therefore examined the effects of MDM2 inhibitor on cisplatin cytotoxicity. In order to induce acute kidney injury and to investigate MDM2 inhibitory effects, we injected cisplatin into rats with or without the MDM2 inhibitor, DS-5272, and analyzed kidney physiology/histology and NFκB signaling. Serum creatinine was significantly lower in the DS-5272 group than in the vehicle group on day 3 (0.55 ± 0.069 vs 0.70 ± 0.072 mg/dL,
Gupta A, Shah K, Oza MJ, Behl TReactivation of p53 gene by MDM2 inhibitors: A novel therapy for cancer treatment.
Biomed Pharmacother. 2019; 109:484-492 [PubMed
] Related Publications
Cancer is an uncontrolled and abnormal growth of cells in the body. Gene that guards the cell cycle and function as tumor suppressor is p53 (also called as the guardian of the genome) which is encoded by the TP53 gene. Various events like DNA damage, heat shock, hypoxia and oncogene over expression, results in activation of p53.Thus, it plays a major role as a regulatory protein which regulates various diverse biological responses, responsible for genetic stability by preventing genome mutation. More than 50% mutations in human cancers along with the increase in expression of murine double minute 2 gene (mdm2), has been found as one of the reason for cancer progression. Murine double minute 2 (MDM2) is the negative regulator of p53 gene forming an autoregulatory feedback loop controlling each other cellular levels. Murine double minute 2 is unique E3 ubiquitin ligase protein which is responsible for ubiquitination and degradation of p53 gene. Many drugs/compounds have been developed for reactivation of p53 gene by inhibiting MDM2 interaction with p53, using MDM2 antagonism, inhibiting E3 ubiquitination of p53. Many compounds have entered clinical trials in haematological malignancies. This review will throw some light on reactivation of p53 gene by MDM2 and its homologues.
Retinoblastoma (Rb) is the most common intra-ocular malignancy in children. The association of rs2279744, and rs937283 in MDM2 gene, and p21 rs1801270 polymorphism and RB development have been demonstrated. To provide a comprehensive assessment of and to clarify associations between the 3 SNPs (MDM2 rs2279744, MDM2 rs937283, and p21 rs1801270) and the risk of RB, we performed a meta-analysis of all the eligible case-control studies. We searched English databases include PubMed, Embase, Google Scholar, and Cochrane Library, using an upper date limit of January 1, 2018. The association between MDM2 rs2279744, MDM2 rs937283, and p21 rs1801270 polymorphisms and the risk of RB were estimated by calculating a pooled OR and 95% CI under a homozygote comparison, heterozygote comparison, dominant model, and recessive model. The statistical power analysis was performed using G*Power. Our meta-analysis showed a significant association between RB susceptibility and MDM2 rs2279744 recessive model (OR = 1.427, 95%CI: 1.107-1.840, P = .006, I = 0%). Moreover, a significant link was observed between RB risk and MDM2 rs937283 homozygote comparison (OR = 0.471, 95%CI: 0.259-0.858, P = .014, I = 0%) and recessive model (OR = 0.587, 95%CI: 0.410-0.840, P = .004, I = 0%). However, no significant relationship between the p21 rs1801270 polymorphism and RB susceptibility was detected in any of the 4 models (P > .05). In conclusion, we found that significant association between the MDM2 rs2279744 polymorphism and increased RB risk, while MDM2 rs937283 polymorphism was associated with significantly decreased RB risk. However, as to the P21 rs1801270 polymorphism, a statistically significant association was not identified for RB.
BACKGROUND: Murine double minute 2 homolog (MDM2) plays an important role in the downregulation of P53 tumor suppressor gene. MDM2 inhibits P53 transcriptional activity and thereby results in accelerated tumor formation. Overexpression of MDM2 has been found in several cancer types including endometrial cancer. SNP309 is located in the promoter region of MDM2 and contributes to the overexpression of MDM2. The association between MDM2 SNP309 polymorphism and endometrial cancer risk has been investigated in several studies; however, the conclusion remains controversial.
OBJECTIVES: We performed the present meta-analysis to give a comprehensive conclusion of the association between MDM2 SNP309 polymorphism and endometrial cancer susceptibility.
METHODS: We conducted a literature research on PubMed, Embase, Cochrane Library, OVID, Web of Science, Wan Fang, CNKI, and CQVIP databases up to July 31, 2018. Newcastle-Ottawa scale was used to assess the quality of studies. We evaluated the strength of association by combining odds ratios (ORs) and 95% confidence intervals (CIs) in 5 different genetic models under a fixed-effect model or random-effect model. We further conducted subgroup analysis by ethnicity, source of control, histological type, clinical type, grade, and stage of tumor. Sensitivity analysis and publication bias were also performed.
RESULTS: Nine eligible studies were finally included in our meta-analysis. We found MDM2 SNP309 polymorphism increased the risk of endometrial cancer under allele model (OR: 1.23, 95% CI: 1.06-1.41, P = .005), homozygote model (OR: 1.43, 95% CI: 1.13-1.81, P = .003) and recessive model (OR: 1.55, 95% CI: 1.17-2.04, P = .002). Subgroup analysis suggested a similar elevated risk in both Asians and Caucasians. We identified a strong association of enhanced susceptibility to endometrial cancer in endometrioid group (OR: 2.13, 95% CI: 1.28-3.54, P = .004) and Type I group (OR: 1.89, 95% CI: 1.25-2.86, P = .002) under dominant model. We identified no significant publication bias according to Egger's test.
CONCLUSIONS: Our meta-analysis suggested that MDM2 SNP309 polymorphism increased the risk of endometrial cancer significantly, especially in endometrioid and Type I endometrial cancer, indicating MDM2 could serve as a potential diagnostic factor marker for endometrial cancer.
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
The role of long non-coding RNAs (lncRNAs) in regulating endothelial function through the DNA damage response (DDR) remains poorly understood. In this study, we demonstrate that lncRNA maternally expressed gene 3 (Meg3) interacts with the RNA binding protein polypyrimidine tract binding protein 3 (PTBP3) to regulate gene expression and endothelial function through p53 signaling ─ a major coordinator of apoptosis and cell proliferation triggered by the DDR. Meg3 expression is induced in endothelial cells (ECs) upon p53 activation. Meg3 silencing induces DNA damage, activates p53 signaling, increases the expression of p53 target genes, promotes EC apoptosis, and inhibits EC proliferation. Mechanistically, Meg3 silencing reduces the interaction of p53 with Mdm2, induces p53 expression, and promotes the association of p53 with the promoters of a subset of p53 target genes. PTBP3 silencing recapitulates the effects of Meg3 deficiency on the expression of p53 target genes, EC apoptosis and proliferation. The Meg3-dependent association of PTBP3 with the promoters of p53 target genes suggests that Meg3 and PTBP3 restrain p53 activation. Our studies reveal a novel role of Meg3 and PTBP3 in regulating p53 signaling and endothelial function, which may serve as novel targets for therapies to restore endothelial homeostasis.
Liu W, Xiao H, Wu S, et al.MAP9 single nucleotide polymorphism rs1058992 is a risk of EBV-associated gastric carcinoma in Chinese population.
Acta Virol. 2018; 62(4):435-440 [PubMed
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Microtubule-associated protein 9 (MAP9) is a mitosis-associated protein involved in bipolar spindle assembly. Following DNA damage, MAP9 stabilizes p53 via p300 and MDM2 (mouse double minute-2 homolog). The dysregulation of MAP9 was considered to be associated with tumorigenesis. Single nucleotide polymorphisms (SNPs) in key genes governing mitosis may particularly increase susceptibility to gastric carcinoma (GC). Our study demonstrated that the CC homozygous genotype of SNP rs1058992 located in the MAP9 gene was significantly correlated with EBV-associated GC (EBVaGC) in a recessive genetic model (OR = 2.558, 95% CI = 1.306-5.010, P = 0.043), and the C allele frequency of rs1058992 also showed significant correlation with EBVaGC (OR = 1.904, 95% CI = 1.141-3.179, P = 0.013). These results suggest that the MAP9 rs1058992 polymorphism is associated with risk of EBVaGC. The conversion of lysine to arginine caused by rs1058992 may affect development of EBVaGC; however, further studies in larger populations are needed to fully elucidate its role in EBVaGC. Keywords: SNP; EBV; gastric carcinoma; MAP9.
Since 2013 next-generation sequencing (NGS) targeting genes mutated in diffuse gliomas is part of routine diagnostics in our institute. In the present report, we evaluate the use of this custom tailored NGS platform on 434 samples. The NGS panel assesses mutations in ATRX, CIC, EGFR, FUBP1, NOTCH1, PTEN; H3F3A, IDH1/2, PIK3CA, and BRAF, amplifications in EGFR or MDM2 and copy number alterations (CNA) of chromosome 1p, 7, 10 and 19q. TERT promoter mutations were assessed separately when indicated. Of the 433 samples of individual tumors with NGS data available, 176 cases were diagnosed as grade 2 or 3 glioma (40.6) and in 201 patients a glioblastoma (46.4%). Of the remaining 56 patients, 22 had inconclusive histology. In 378 cases (87.1%) a diagnosis solely based on glioma-targeted NGS could be established and resulted in a different diagnosis in ~ 1/4 of the cases. In 17 out of 22 cases without a conclusive histological diagnosis NGS resulted in a molecular diagnosis.The current study on a large cohort of patients confirms the diagnostic strength of the platform we developed, with a clear separation of glioma subgroups with different outcomes. It demonstrates the diagnostic value and the efficiency of glioma-targeted NGS for routine glioma diagnostics allowing with a single assay a glioma diagnosis in the large majority of cases. It allows in one run the molecular assessments required for the WHO classification of diffuse gliomas, including the recent recommendations to assess copy number alterations of chromosome 7 and 10, and of the TERT promoter region in IDHwt lower grade glioma.
Castéra L, Sabbagh A, Dehainault C, et al.MDM2 as a modifier gene in retinoblastoma.
J Natl Cancer Inst. 2010; 102(23):1805-8 [PubMed
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Variability in the age of onset and number of tumors is occasionally described among retinoblastoma patients, and possible genetic modifiers might lie in the pRB or p53 pathways, both of which are involved in the development of retinoblastoma. MDM2, which increases p53 and pRB catabolism, is therefore a prominent candidate. The minor allele of MDM2 that includes a 309T>G transversion (single-nucleotide polymorphism rs2279744) in the MDM2 promoter is known to enhance MDM2 expression. Its genetic transmission was studied in 326 individuals including 212 RB1 mutation carriers in 70 retinoblastoma families, and the marker genotype was tested for association with age at diagnosis and disease phenotype. In family-based association analyses, the MDM2 309G allele was found to be statistically significantly associated with incidence of bilateral or unilateral retinoblastoma among members of retinoblastoma families (Z = 3.305, two-sided exact P = .001) under a recessive model (ie, affected patients tend to be homozygous for the G allele); in transmission disequilibrium analyses using the recessive model, the association was also observed (estimated odds ratio = 4.0, 95% confidence interval = 1.3 to 12.0). The strong association of this genotype with retinoblastoma development designates MDM2 as the first modifier gene to be identified among retinoblastoma patients and suggests that enhancement of pRB haploinsufficiency and/or resistance to p53-mediated apoptosis is critical to tumor formation.
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
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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.