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 (5)
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: APEX1 (cancer-related)
STAT3 is an oncoprotein overexpressed in different types of tumors, including prostate cancer (PCa), and its activity is modulated by a variety of post-translational modifications (PTMs). Prostate cancer represents the most common cancer diagnosed in men, and each phase of tumor progression displays specific cellular conditions: inflammation is predominant in tumor's early stage, whereas oxidative stress is typical of clinically advanced PCa. The aim of this research is to assess the correspondence between the stimulus-specificity of STAT3 PTMs and definite STAT3-mediated transcriptional programs, in order to identify new suitable pharmacological targets for PCa treatment. Experiments were performed on less-aggressive LNCaP and more aggressive DU-145 cell lines, simulating inflammatory and oxidative-stress conditions. Cellular studies confirmed pY705-STAT3 as common denominator of all STAT3-mediated signaling. In addition, acK685-STAT3 was found in response to IL-6, whereas glutC328/542-STAT3 and pS727-STAT3 occurred upon tert-butyl hydroperoxyde (tBHP) treatment. Obtained results also provided evidence of an interplay between STAT3 PTMs and specific protein interactors such as P300 and APE1/Ref-1. In accordance with these outcomes, mRNA levels of STAT3-target genes seemed to follow the differing STAT3 PTMs. These results highlighted the role of STAT3 and its PTMs as drivers in the progression of PCa.
Mengwasser KE, Adeyemi RO, Leng Y, et al.Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets.
Mol Cell. 2019; 73(5):885-899.e6 [PubMed
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BRCA1 or BRCA2 inactivation drives breast and ovarian cancer but also creates vulnerability to poly(ADP-ribose) polymerase (PARP) inhibitors. To search for additional targets whose inhibition is synthetically lethal in BRCA2-deficient backgrounds, we screened two pairs of BRCA2 isogenic cell lines with DNA-repair-focused small hairpin RNA (shRNA) and CRISPR (clustered regularly interspaced short palindromic repeats)-based libraries. We found that BRCA2-deficient cells are selectively dependent on multiple pathways including base excision repair, ATR signaling, and splicing. We identified APEX2 and FEN1 as synthetic lethal genes with both BRCA1 and BRCA2 loss of function. BRCA2-deficient cells require the apurinic endonuclease activity and the PCNA-binding domain of Ape2 (APEX2), but not Ape1 (APEX1). Furthermore, BRCA2-deficient cells require the 5' flap endonuclease but not the 5'-3' exonuclease activity of Fen1, and chemically inhibiting Fen1 selectively targets BRCA-deficient cells. Finally, we developed a microhomology-mediated end-joining (MMEJ) reporter and showed that Fen1 participates in MMEJ, underscoring the importance of MMEJ as a collateral repair pathway in the context of homologous recombination (HR) deficiency.
Dumitrache LC, Shimada M, Downing SM, et al.Apurinic endonuclease-1 preserves neural genome integrity to maintain homeostasis and thermoregulation and prevent brain tumors.
Proc Natl Acad Sci U S A. 2018; 115(52):E12285-E12294 [PubMed
] Free Access to Full Article Related Publications
Frequent oxidative modification of the neural genome is a by-product of the high oxygen consumption of the nervous system. Rapid correction of oxidative DNA lesions is essential, as genome stability is a paramount determinant of neural homeostasis. Apurinic/apyrimidinic endonuclease 1 (APE1; also known as "APEX1" or "REF1") is a key enzyme for the repair of oxidative DNA damage, although the specific role(s) for this enzyme in the development and maintenance of the nervous system is largely unknown. Here, using conditional inactivation of murine
Sun Z, Zhu Y, Aminbuhe, et al.Differential expression of APE1 in hepatocellular carcinoma and the effects on proliferation and apoptosis of cancer cells.
Biosci Trends. 2018; 12(5):456-462 [PubMed
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This research aimed to investigate the differential expression of apurinic-apyrimidinic endonuclease 1 (APE1) in hepatocellular carcinoma (HCC) tissues and cells and the effects on proliferation and apoptosis of cancer cells. Immunohistochemical techniques were used to detect the expression of APE1 in 80 cases of HCC and the corresponding paracancerous tissue microarrays; meanwhile, Western blots were used to detect the expression of APE1 in both human HCC BEL-7402, BEL-7405, HCC-9204, Hep3B, HepG2, SMMC-7721 and Huh-7 cells, and normal hepatocyte L-02 cells. The relationship between APE1 expression and clinical pathological characteristics of HCC was statistically analyzed. APE1 shRNA vector was constructed in Hep 3B cells to establish a stably transfected cell line, using Western blots to determine the interference efficiency. Cell proliferation activity was detected with MTT assays, while apoptosis was detected with the Annexin V-FITC/PI double-labeling technique. The expression of APE1 in HCC tissues and cells was significantly up-regulated, and its expression was significantly different from TNM staging and histopathological grading. Down-regulation of APE1 expression significantly reduced the proliferative activity and increased the apoptosis rate of Hep 3B cells. In conclusion, APE1 demonstrates cancer progression potential at the clinical, tissue and cell level. It provides a new idea and theoretical basis for APE1-based clinical diagnosis, prognosis determination and molecular targeted therapy in treatment of HCC.
Zavadil JA, Herzig MCS, Hildreth K, et al.C3HeB/FeJ Mice mimic many aspects of gene expression and pathobiological features of human hepatocellular carcinoma.
Mol Carcinog. 2019; 58(3):309-320 [PubMed
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Hepatocellular carcinoma (HCC) remains a deadly cancer, underscoring the need for relevant preclinical models. Male C3HeB/FeJ mice model spontaneous HCC with some hepatocarcinogenesis susceptibility loci corresponding to syntenic regions of human chromosomes altered in HCC. We tested other properties of C3HeB/FeJ tumors for similarity to human HCC. C3HeB/FeJ tumors were grossly visible at 4 months of age, with prevalence and size increasing until about 11 months of age. Histologic features shared with human HCC include hepatosteatosis, tumor progression from dysplasia to poorly differentiated, vascular invasion, and trabecular, oncocytic, vacuolar, and clear cell variants. More tumor cells displayed cytoplasmic APE1 staining versus normal liver. Ultrasound effectively detected and monitored tumors, with 85.7% sensitivity. Over 5000 genes were differentially expressed based on the GSE62232 and GSE63898 human HCC datasets. Of these, 158 and 198 genes, respectively, were also differentially expressed in C3HeB/FeJ. Common cancer pathways, cell cycle, p53 signaling and other molecular aspects, were shared between human and mouse differentially expressed genes. We established eigengenes that distinguish HCC from normal liver in the C3HeB/FeJ model and a subset of human HCC. These features extend the relevance and improve the utility of the C3HeB/FeJ line for HCC studies.
We have previously reported that homologous recombination (HR) is dysregulated in multiple myeloma (MM) and contributes to genomic instability and development of drug resistance. We now demonstrate that base excision repair (BER) associated apurinic/apyrimidinic (AP) nucleases (APEX1 and APEX2) contribute to regulation of HR in MM cells. Transgenic as well as chemical inhibition of APEX1 and/or APEX2 inhibits HR activity in MM cells, whereas the overexpression of either nuclease in normal human cells, increases HR activity. Regulation of HR by AP nucleases could be attributed, at least in part, to their ability to regulate recombinase (RAD51) expression. We also show that both nucleases interact with major HR regulators and that APEX1 is involved in P73-mediated regulation of RAD51 expression in MM cells. Consistent with the role in HR, we also show that AP-knockdown or treatment with inhibitor of AP nuclease activity increases sensitivity of MM cells to melphalan and PARP inhibitor. Importantly, although inhibition of AP nuclease activity increases cytotoxicity, it reduces genomic instability caused by melphalan. In summary, we show that APEX1 and APEX2, major BER proteins, also contribute to regulation of HR in MM. These data provide basis for potential use of AP nuclease inhibitors in combination with chemotherapeutics such as melphalan for synergistic cytotoxicity in MM.
There has been enormous recent progress in understanding how human cells respond to oxidative stress, such as that caused by exposure to ionizing radiation. We have witnessed a significant deciphering of the events that underlie how antioxidant responses counter pro-oxidant damage to key biological targets in all cellular compartments, including the genome and mitochondria. These cytoprotective responses include: 1. The basal cellular repertoire of antioxidant capabilities and its supporting cast of facilitator enzymes; and 2. The inducible phase of the antioxidant response, notably that mediated by the Nrf2 transcription factor. There has also been frenetic progress in defining how reactive electrophilic species swamp existing protective mechanisms to augment DNA damage, events that are embodied in the cellular "DNA-damage response", including cell cycle checkpoint activation and DNA repair, which occur on a time scale of hours to days, as well as the implementation of cellular responses such as apoptosis, autophagy, senescence and reprograming that extend the time period of damage sensing and response into weeks, months and years. It has become apparent that, in addition to the initial oxidative insult, cells typically undergo further waves of secondary reactive oxygen/nitrogen species generation, DNA damage and signaling and that these may reemerge long after the initial events have subsided, probably being driven, at least in part, by persisting DNA damage. These reactive oxygen/nitrogen species are an integral part of the pathological consequences of radiation exposure and may persist across multiple cell divisions. Because of the pervasive nature of oxidative stress, a cell will manifest different responses in different subcellular compartments and to different levels of stress injury. Aspects of these compartmentalized responses can involve the same proteins (such as ATM, p53 and p21) but in different functional guises, e.g., in cytoplasmic versus nuclear responses or in early- versus late-phase events. Many of these responses involve gene activation and new protein synthesis as well as a plethora of post-translational modifications of both basal and induced response proteins. It is these responses that we focus on in this review.
The development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC) is highly linked to exposure to acidic bile salts due to chronic gastroesophageal reflux disease (GERD). In this study, we investigated the role of Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) in STAT3 activation in response to acidic bile salts. Our results indicate that APE1 is constitutively overexpressed in EAC, whereas its expression is transiently induced in response to acidic bile salts in non-neoplastic BE. Using overexpression or shRNA knockdown of APE1, we found that APE1 is required for phosphorylation, nuclear localization, and transcriptional activation of STAT3. By using an APE1 redox-specific mutant (C65A) and APE1 redox inhibitor (E3330), we demonstrate that APE1 activates STAT3 in a redox-dependent manner. By using pharmacologic inhibitors and genetic knockdown systems, we found that EGFR is a required link between APE1 and STAT3. EGFR phosphorylation (Y1068) was directly associated with APE1 levels and redox function. Co-immunoprecipitation and proximity ligation assays indicated that APE1 coexists and interacts with the EGFR-STAT3 protein complex. Consistent with these findings, we demonstrated a significant induction in mRNA expression levels of STAT3 target genes (IL-6, IL-17A, BCL-xL, Survivin, and c-MYC) in BE and EAC cells, following acidic bile salts treatment. ChIP assays indicated that acidic bile salts treatment enhances binding of STAT3 to the promoter of its target genes, Survivin and BCL-xL. Inhibition of APE1/REF-1 redox activity using E3330 abrogated STAT3 DNA binding and transcriptional activity. The induction of APE1-STAT3 axis in acidic bile salts conditions provided a survival advantage and promoted cellular proliferation. In summary, our study provides multiple pieces of evidence supporting a critical role for APE1 induction in activating the EGFR-STAT3 signaling axis in response to acidic bile salts, the main risk factor for Barrett's carcinogenesis.
Mattar MM, Zekri AN, Hussein N, et al.Polymorphisms of base-excision repair genes and the hepatocarcinogenesis.
Gene. 2018; 675:62-68 [PubMed
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AIM: To determine the possible association between polymorphisms of DNA repair genes, including XRCC1 Arg194Tryp, Arg280His, and Arg399Glu, APE1 Asp148Glu, and NEIL2 Arg257Leu, and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
METHODS: A total of 264 subjects were recruited in this retrospective case-control study and were categorized into four groups: 88 control subjects (CR), 53 chronic hepatitis C patients (CHC), 36 liver cirrhotic patients (LC), and 87 HCC patients. The XRCC1 Arg194Tryp, Arg280His, and Arg399Glu polymorphisms were detected using PCR-RFLP, while real-time PCR was used to genotype APE1 Asp148Glu and NEIL2 Arg257Leu.
RESULTS: Our data revealed that, compared with the healthy controls, for those subjects with the XRCC1 Arg194Trp genotype, the risk of developing CHC, LC, and HCC was increased by 6.66- (odds ratio (OR) = 6.667; 95% confidence interval (CI) = 3.244-13.701; P > 0.01), 3.85- (OR = 3.852; 95% CI = 1.797-8.256; P > 0.01), and 2.14-fold (OR = 2.14; 95% CI = 1.13-4.06; P > 0.05), respectively. There was no association between the risk of HCC development and the XRCC1 Arg280His or XRCC1 Arg399Gln genotypes. Moreover, the analysis showed a lack of association between APE1 Asp148Glu and the risk of HCC development. The analysis of clinicopathological parameters showed that the HCC patients with the XRCC1 Arg280His polymorphism were 2.9 fold more likely to have hepatic lesions in both hepatic lobes (OR: 2.9; 95% CI: 1.15-7.29). Notably, in the HCC patients, the prevalence of the APE1 polymorphism in the males was four times higher than that in the females (OR = 4; 95% CI = 1.129-14.175; P > 0.05).
CONCLUSION: Our results indicate that the XRCC1 Arg194Trp polymorphism could be a risk factor for HCV-related HCC development in Egypt.
Jin S, Qian Z, Liang T, et al.Identification of a DNA Repair-Related Multigene Signature as a Novel Prognostic Predictor of Glioblastoma.
World Neurosurg. 2018; 117:e34-e41 [PubMed
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BACKGROUND: Glioblastoma (GBM) is an extremely challenging malignancy to treat. Although temozolomide (TMZ) is a standard treatment regimen, many patients with GBM develop chemoresistance. The aim of this study was to identify a DNA repair-related gene signature to better stratify patients treated with TMZ.
METHODS: We selected 89 cases of primary GBM (pGBM) from the Chinese Glioma Genome Atlas RNA-seq dataset as the training cohort, whereas The Cancer Genome Atlas RNA-seq and Gene Set Enrichment (GSE) 16011 mRNA array sets were used as validation cohorts. Regression analysis and linear risk score assessment were performed to build a DNA repair-related signature. We used Kaplan-Meier analysis to evaluate the predictive value of the signature for overall survival (OS) in the different groups. Multivariate Cox regression analysis was used to determine whether the 5-gene signature could independently predict OS.
RESULTS: Using our 5-gene signature panel of APEX1, APRT, PARP2, PMS2L2, and POLR2L, we divided patients with pGBM into high- and low-risk groups. Patients with a low-risk score were predicted to have favorable survival and greater benefit from TMZ therapy compared with patients from the high-risk group (P < 0.05). Moreover, receiver operating characteristic curves showed that the multigene signature was the most sensitive and specific model for survival prediction (P < 0.05).
CONCLUSIONS: Among patients with pGBM, classification based on a risk score determined using a 5-gene panel indicated different OS and reaction to TMZ. The findings in this study demonstrate that this unique 5-gene signature could be a novel model to predict OS and provide accurate therapy for patients with pGBM.
Guida M, Tommasi S, Strippoli S, et al.The search for a melanoma-tailored chemotherapy in the new era of personalized therapy: a phase II study of chemo-modulating temozolomide followed by fotemustine and a cooperative study of GOIM (Gruppo Oncologico Italia Meridionale).
BMC Cancer. 2018; 18(1):552 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients.
METHODS: A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21-81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m
RESULTS: We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status.
CONCLUSION: This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed.
TRIAL REGISTRATION: EUDRACT 2009-016487-36l ; date of registration 23 June 2010.
Gotoh N, Saitoh T, Takahashi N, et al.Association between OGG1 S326C CC genotype and elevated relapse risk in acute myeloid leukemia.
Int J Hematol. 2018; 108(3):246-253 [PubMed
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Recent studies have shown that tumors of relapsed acute myeloid leukemia (AML) present additional genetic mutations compared to the primary tumors. The base excision repair (BER) pathway corrects oxidatively damaged mutagenic bases and plays an important role in maintaining genetic stability. The purpose of the present study was to investigate the relationship between BER functional polymorphisms and AML relapse. We focused on five major polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W, and XRCC1 R399Q. Ninety-four adults with AML who achieved first complete remission were recruited. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The OGG1 S326C CC genotype (associated with lower OGG1 activity) was observed more frequently in patients with AML relapse [28.9 vs. 8.9%, odds ratio (OR) = 4.10, 95% confidence interval (CI) = 1.35-12.70, P = 0.01]. Patients with the CC genotype exhibited shorter relapse-free survival (RFS). Moreover, the TCGA database suggested that low OGG1 expression in AML cells is associated with a higher frequency of mutations. The present findings suggest that the OGG1 S326C polymorphism increased the probability of AML relapse and may be useful as a prognostic factor for AML relapse risk.
BACKGROUND: Genetic variations in key DNA repair genes may influence DNA repair capacity, DNA damage and breast carcinogenesis. The current study aimed to estimate the association of APEX1 and OGG1 polymorphisms with the risk of breast cancer development.
METHODS: A total of 518 patients with histopathologically confirmed breast cancer and 921 region- and age-matched cancer-free controls were genotyped for the APEX1 polymorphisms rs3136817 and rs1130409 and the OGG1 polymorphisms rs1052133 and rs2072668 using a QuantStudio™ 12 K Flex Real-Time PCR System.
RESULTS: The rs3136817 heterozygous TC genotype along with the rs3136817 dominant model (TC + CC) was strongly associated with breast cancer susceptibility (odds ratio [OR] = 0.670, 95% confidence interval [95% CI]: 0.513 - 0.873, P = 0.003; OR = 0.682, 95% CI: 0.526 - 0.883, P = 0.004, respectively). No significant associations were observed among rs1130409, rs1052133, rs2072668 and breast cancer risk. Furthermore, an allele combination analysis revealed that APEX1 haplotypes containing C-T (alleles rs3136817 and rs1130409) conferred a significantly lower risk (corrected P < 0.001).
CONCLUSION: This research is the latest report showing that an APEX1 rs3136817 heterozygous genotype may have a positive influence on DNA repair capacity in patients with breast cancer and thus may have a potential protective effect for Chinese Han women.
Hernández-Franco P, Silva M, Franco R, et al.Lead facilitates foci formation in a Balb/c-3T3 two-step cell transformation model: role of Ape1 function.
Environ Sci Pollut Res Int. 2018; 25(12):12150-12158 [PubMed
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Several possible mechanisms have been examined to gain an understanding on the carcinogenic properties of lead, which include among others, mitogenesis, alteration of gene expression, oxidative damage, and inhibition of DNA repair. The aim of the present study was to explore if low concentrations of lead, relevant for human exposure, interfere with Ape1 function, a base excision repair enzyme, and its role in cell transformation in Balb/c-3T3. Lead acetate 5 and 30 μM induced APE1 mRNA and upregulation of protein expression. This increase in mRNA expression is consistent throughout the chronic exposure. Additionally, we also found an impaired function of Ape1 through molecular beacon-based assay. To evaluate the impact of lead on foci formation, a Balb/c-3T3 two-step transformation model was used. Balb/c-3T3 cells were pretreated 1 week with low concentrations of lead before induction of transformation with n-methyl-n-nitrosoguanidine (MNNG) (0.5 μg/mL) and 12-O-tetradecanoylphorbol-13-acetate (TPA) (0.1 μg/mL) (a classical two-step protocol). Morphological cell transformation increased in response to lead pretreatment that was paralleled with an increase in Ape1 mRNA and protein overexpression and an impairment of Ape1 activity and correlating with foci number. In addition, we found that lead pretreatment and MNNG (transformation initiator) increased DNA damage, determined by comet assay. Our data suggest that low lead concentrations (5, 30 μM) could play a facilitating role in cellular transformation, probably through the impaired function of housekeeping genes such as Ape1, leading to DNA damage accumulation and chromosomal instability, one of the most important hallmarks of cancer induced by chronic exposures.
Kalitin NN, Chernykh YB, Buravtsova IVComparative Analysis of Quantitative Parameters of Expression of the Retinoic Acid Nuclear Receptor RARα Gene and APE1/YB-1/MDR1 Pattern Genes in Patients with Newly Detected Multiple Myeloma.
Bull Exp Biol Med. 2017; 164(1):90-94 [PubMed
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The expression of retinoic acid nuclear receptor gene RARα and its relationship with expression of APE1, YB-1, and MDR1 genes was studied in bone marrow aspiration biopsy specimens from 22 patients with newly detected multiple myeloma. The expression of RARα directly correlated with the expression of APE1/YB-1/MDR1 pattern genes. Groups differing by expression of RARα exhibited significant differences in the overall survival of patients; concordant and simultaneous changes in the expression of all genes of the APE1/YB-1/MDR1 pattern suggested the level of RARα gene expression as a potential prognostic factor in the pathogenesis of multiple myeloma.
Liu W, Wang L, Zheng C, et al.Microcystin-LR increases genotoxicity induced by aflatoxin B1 through oxidative stress and DNA base excision repair genes in human hepatic cell lines.
Environ Pollut. 2018; 233:455-463 [PubMed
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Aflatoxin B1 (AFB1) and microcystin-LR (MC-LR) simultaneously exist in polluted food and water in humid and warm areas, and each has been reported to be genotoxic to liver and associated with hepatocellular carcinoma (HCC). However, the genotoxic effects of the two biotoxins in combination and potential mechanism remain unknown. We treated the human hepatic cell line HL7702 with AFB1 and MC-LR together at different ratios, examined their genotoxic effects using micronuclei and comet assays, and evaluated the possible mechanism by measuring oxidative stress markers and DNA base excision repair (BER) genes. Our data show that co-exposure to AFB1 and MC-LR significantly increased DNA damage compared with AFB1 or MC-LR alone as measured by the levels of both micronuclei and tail DNA. Meanwhile, AFB1 and MC-LR co-exposure showed biphasic effects on ROS production, and a gradual trend towards increased Glutathione (GSH) levels and activity of Catalase (CAT) and Superoxide Dismutase (SOD). Furthermore, MC-LR, with or without AFB1, significantly down-regulated the expression of the base excision repair (BER) genes 8-oxoguanine glycosylase-1 (OGG1) and X-ray repair cross complementing group 1 (XRCC1). AFB1 and MC-LR in combination upregulated the expression of the BER gene apurinic/apyrimidinic endonuclease 1 (APE1), whereas either agent alone had no effect. In conclusion, our studies show that MC-LR exacerbates AFB1-induced genotoxicity and we report for the first time that this occurs through effects on oxidative stress and the deregulation of DNA base excision repair genes.
Chen T, Liu C, Lu H, et al.The expression of APE1 in triple-negative breast cancer and its effect on drug sensitivity of olaparib.
Tumour Biol. 2017; 39(10):1010428317713390 [PubMed
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Triple-negative breast cancer is a kind of breast cancer with poor prognosis and special biological behavior, which lacked endocrine therapy and targeted therapy. We investigate the effect of human APE1 (apurinic/apyrimidyl endonuclease 1), a rate-limiting enzyme of base excision repair, on the prognosis in triple-negative breast cancer and drug sensitivity of olaparib. The expression of APE1 was detected by immunohistochemistry in the triple-negative breast cancer tissues and its effect on survival of triple-negative breast cancer patients was followed. To find whether APE1 effect the drug sensitivity in triple-negative breast cancer cells, the APE1-knockout HCC1937 cell line (triple-negative breast cancer cell line) was established by CRISPR/Cas9 system. Then, we use the wild-type and knockout one to test the drug sensitivity of olaparib. The expression of APE1 in triple-negative breast cancer tissues was significantly higher than that in the adjacent tissues (85.6% vs 14.4%) and its expression was related to tumor size (p < 0.05). We also found that it is an independent prognostic factor in patients with triple-negative breast cancer (overall survival, p = 0.01). In vitro assay, the half maximal inhibitory concentration of olaparib in HCC1937-APE1-KO was significantly increased (17.22 vs 91.85 μM) compared to the wild type. The growth curve showed that olaparib had a stronger lethality on HCC1937 compared to HCC1937- APE1-KO (p < 0.05 on day 3). HCC1937 resulted in more mitotic G2/M arrest and increased apoptosis rate after treatment with 40 μM of olaparib, while HCC1937-APE1-KO did not change significantly. When HCC1937 was treated with different concentrations of olaparib, it was found that APE1 expression decreased more significantly at 15 μM of olaparib was. In HCC1937-APE1-KO, the expression of endogenous poly (ADP-ribose) polymerase 1 was also less than that of HCC1937. These results suggested that the expression of APE1 was an important basis for the maintenance of poly (ADP-ribose) polymerase 1, and the deletion of APE1 may be related to the resistance of olaparib.
Mammalian apurinic/apyrimidinic endonuclease 1 is a DNA repair enzyme involved in genome stability and expression of genes involved in oxidative stress responses, tumor progression and chemoresistance. However, the molecular mechanisms underlying the role of apurinic/apyrimidinic endonuclease 1 in these processes are still unclear. Recent findings point to a novel role of apurinic/apyrimidinic endonuclease 1 in RNA metabolism. Through the characterization of the interactomes of apurinic/apyrimidinic endonuclease 1 with RNA and other proteins, we demonstrate here a role for apurinic/apyrimidinic endonuclease 1 in pri-miRNA processing and stability via association with the DROSHA-processing complex during genotoxic stress. We also show that endonuclease activity of apurinic/apyrimidinic endonuclease 1 is required for the processing of miR-221/222 in regulating expression of the tumor suppressor PTEN. Analysis of a cohort of different cancers supports the relevance of our findings for tumor biology. We also show that apurinic/apyrimidinic endonuclease 1 participates in RNA-interactomes and protein-interactomes involved in cancer development, thus indicating an unsuspected post-transcriptional effect on cancer genes.APE1 plays an important role in the cellular response to oxidative stress, and mutations are linked to tumor progression and chemoresistance. Here, the authors characterize the interactions of APE1 with RNA and demonstrate a role in microRNA processing.
Shah F, Goossens E, Atallah NM, et al.APE1/Ref-1 knockdown in pancreatic ductal adenocarcinoma - characterizing gene expression changes and identifying novel pathways using single-cell RNA sequencing.
Mol Oncol. 2017; 11(12):1711-1732 [PubMed
] Free Access to Full Article Related Publications
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer-related pathways. Because APE1 is essential for cell viability, generation of APE1-knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single-cell RNA sequencing to identify differentially expressed genes (DEGs) in relation to APE1 protein levels within the cell. Using a straightforward yet novel statistical design, we identified 2837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mechanistic target of Rapamycin pathways and a number of mitochondrial-related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the DEGs along with siRNA knockdown and qRT-PCR. Testing additional patient-derived pancreatic cancer cells reveals particular genes (ITGA1, TNFAIP2, COMMD7, RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox-specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor subtype specificity. These findings will allow for hypothesis-driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.
Purpose: Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients.
Materials and Methods: Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients.
Results: Using bioinformatics tools and genetic data, four functionally interesting variants were selected (ABCC4, APEX1, CYP1A1, and CYP4F2). Including four variants, 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 185 patients. Ultimately, a variant allele in APEX1 rs2307486was found to be strongly associated with MP-induced neutropenia that occurred within 28 days of initiating MP (odds ratio, 3.44; p=0.02). Moreover, the cumulative incidence of MP-related neutropenia was significantly higher in patients with APEX1 rs2307486 variants, as GG genotypes were associated with the highest cumulative incidence (p < 0.01). NUDT15 rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01).
Conclusion: We have identified that APEX1 rs2307486 variants conferred an increased risk of MP-related early onset neutropenia. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia.
Wang J, Liu Q, Yuan S, et al.Genetic predisposition to lung cancer: comprehensive literature integration, meta-analysis, and multiple evidence assessment of candidate-gene association studies.
Sci Rep. 2017; 7(1):8371 [PubMed
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More than 1000 candidate-gene association studies on genetic susceptibility to lung cancer have been published over the last two decades but with few consensuses for the likely culprits. We conducted a comprehensive review, meta-analysis and evidence strength evaluation of published candidate-gene association studies in lung cancer up to November 1, 2015. The epidemiological credibility of cumulative evidence was assessed using the Venice criteria. A total of 1018 publications with 2910 genetic variants in 754 different genes or chromosomal loci were eligible for inclusion. Main meta-analyses were performed on 246 variants in 138 different genes. Twenty-two variants from 21 genes (APEX1 rs1130409 and rs1760944, ATM rs664677, AXIN2 rs2240308, CHRNA3 rs6495309, CHRNA5 rs16969968, CLPTM1L rs402710, CXCR2 rs1126579, CYP1A1 rs4646903, CYP2E1 rs6413432, ERCC1 rs11615, ERCC2 rs13181, FGFR4 rs351855, HYKK rs931794, MIR146A rs2910164, MIR196A2 rs11614913, OGG1 rs1052133, PON1 rs662, REV3L rs462779, SOD2 rs4880, TERT rs2736098, and TP53 rs1042522) showed significant associations with lung cancer susceptibility with strong cumulative epidemiological evidence. No significant associations with lung cancer risk were found for other 150 variants in 98 genes; however, seven variants demonstrated strong cumulative evidence. Our findings provided the most updated summary of genetic risk effects on lung cancer and would help inform future research direction.
Fan X, Wen L, Li Y, et al.The expression profile and prognostic value of APE/Ref-1 and NPM1 in high-grade serous ovarian adenocarcinoma.
APMIS. 2017; 125(10):857-862 [PubMed
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To analyze the expression trends and clinical significance of Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1/Ref-1) and Nucleophosmin (NPM1) proteins in high-grade serous ovarian adenocarcinoma (HGSC). The expressions of APE1/Ref-1 and NPM1 proteins in 94 patients with HGSC were determined using the immunohistochemical (IHC) method, and their relationships with clinicopathological features were analyzed by the χ
Krupa R, Czarny P, Wigner P, et al.The Relationship Between Single-Nucleotide Polymorphisms, the Expression of DNA Damage Response Genes, and Hepatocellular Carcinoma in a Polish Population.
DNA Cell Biol. 2017; 36(8):693-708 [PubMed
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The molecular mechanism of hepatocellular carcinoma (HCC) is related to DNA damage caused by oxidative stress products induced by hepatitis B virus (HBV) or C (HCV) infection and exposure to environmental pollutants. Single-nucleotide polymorphisms (SNPs) of DNA damage response (DDR) genes may influence individual susceptibility to environmental risk factors and affect DNA repair efficacy, which, in turn, can influence the risk of HCC. The study evaluates a panel of 15 SNPs in 11 DDR genes (XRCC1, XRCC3, XPD, MUTYH, LIG1, LIG3, hOGG1, PARP1, NFIL1, FEN1, and APEX1) in 65 HCC patients, 50 HBV- and 50 HCV-infected non-cancerous patients, and 50 healthy controls. It also estimates the mRNA expression of nine DDR genes in cancerous and adjacent healthy liver tissues. Two of the investigated polymorphisms (rs1052133 and rs13181) were associated with HCC risk. For all investigated genes, the level of mRNA was significantly lower in HCC cancer tissue than in non-cancerous liver tissue. Seven of the investigated polymorphisms were statistically related to gene expression in cancer tissues. The disruption of DDR genes may be responsible for hepatocellular transformation in HCV-infected patients.
Silva LP, Santana T, Sedassari BT, et al.Apurinic/apyrimidinic endonuclease 1 (APE1) is overexpressed in malignant transformation of salivary gland pleomorphic adenoma.
Eur Arch Otorhinolaryngol. 2017; 274(8):3203-3209 [PubMed
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DNA repair systems play a critical role in protecting the human genome against cumulative damage. The apurinic/apyrimidinic endonuclease 1 is a protein involved in DNA base excision repair and its expression still needs to be investigated in salivary gland tumors. The objective of this study is to analyze the immunoexpression of apurinic/apyrimidinic endonuclease 1 in pleomorphic adenomas and carcinomas ex pleomorphic adenomas of the salivary glands. A total of 33 pleomorphic adenomas and 16 carcinomas ex pleomorphic adenomas of the salivary glands underwent immunohistochemical study by the polymeric biotin-free technique. Immunopositive cells were analyzed quantitatively. For statistical analysis, Mann-Whitney test was performed and a significance level was set at p ≤ 0.05. All analyzed tumors (n = 49) were positive for apurinic/apyrimidinic endonuclease 1. However, there was a higher median expression in carcinomas ex pleomorphic adenomas (p < 0.001). There was no difference between this protein immunoexpression and tumors of major or minor salivary gland. Overexpression was found mainly in cases of carcinomas ex pleomorphic adenomas with lymph node metastasis (p = 0.002) and invasive growth (p = 0.003), when compared to cases without metastasis and without capsular invasion (intracapsular pattern). Our findings revealed that apurinic/apyrimidinic endonuclease 1 is downregulated in pleomorphic adenomas and overexpressed in carcinomas ex pleomorphic adenomas, suggesting that this protein is possibly deregulated in pleomorphic adenoma malignant transformation. Furthermore, the increased expression of this protein is associated with a more aggressive behavior in carcinomas ex pleomorphic adenomas, which suggests that this protein may represent a prognostic biomarker in the studied salivary gland tumors.
Yu SN, Liu GF, Li XF, et al.Evaluation of Prediction of Polymorphisms of DNA Repair Genes on the Efficacy of Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer: A Network Meta-Analysis.
J Cell Biochem. 2017; 118(12):4782-4791 [PubMed
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This network meta-analysis (NMA) was conducted to compare the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). These included ERCC1 (rs11615, rs3212986, rs3212948), XRCC1 (rs25487, rs25489, rs1799782), XPD (rs13181, rs1799793), XPG (rs1047768, rs17655), XPA (rs1800975), XRCC3 (rs861539), APE1 (rs3136820), and RRM1 (rs1042858). The PubMed and Cochrane library databases were reviewed from their inception to February 2017 and studies which met our inclusion criteria were included in our investigation. This network meta-analysis combines direct and indirect evidence to assess the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC. We evaluated the predictive value through the use of the odd ratios (OR) and drawing surface under the cumulative ranking curves (SUCRA). A total of 26 eligible cohort studies were enrolled in this NMA. The pairwise meta-analysis indicated that in terms of overall response ratio (ORR), ERCC1 (rs11615), XRCC1 (rs25487, rs1799782), and XPD (rs13181) polymorphisms are associated with the efficacy of platinum-based chemotherapy in NSCLC. The result of this NMA suggests that there is no significant difference in predictive value of 8 DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC patients. The rank of SUCRA values of the 14 SNPs in the eight DNA repair genes were: XPD (rs1799793)→ERCC1 (rs3212986)→XPA(rs1800975)→ERCC1(rs3212948)→XRCC1(rs25487)→XRCC3(rs861539)→APE1(rs3136820)→ERCC1(rs11615)→XRCC1(rs1799782)→RRM1(rs1042858)→XPD(rs13181)→XPG (rs1047768)→XPG(rs17655)→XRCC1(rs25489). ERCC1(rs11615), XRCC1(rs25487, rs1799782) and XPD(rs13181) polymorphisms were better predictors in evaluating the efficacy of platinum-based chemotherapy in NSCLC patients. J. Cell. Biochem. 118: 4782-4791, 2017. © 2017 Wiley Periodicals, Inc.
Juhnke M, Heumann A, Chirico V, et al.Apurinic/apyrimidinic endonuclease 1 (APE1/Ref-1) overexpression is an independent prognostic marker in prostate cancer without TMPRSS2:ERG fusion.
Mol Carcinog. 2017; 56(9):2135-2145 [PubMed
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Polymorphisms of the base excision repair gene APE1 may be associated with an increased risk for developing prostate cancer. In other cancer types, altered APE1 protein expression is a candidate prognostic marker. Using immunohistochemistry, we thus analyzed APE1 expression in 9763 prostate cancers in a tissue microarray (TMA) with attached clinical and molecular data. The comparison with normal prostate tissue revealed an upregulation of APE1 in cancer samples. APE1 immunostaining was considered weak in 20.2%, moderate in 36.7%, and strong in 33.4% of cancers. Strong APE1 expression was markedly more frequent in prostate cancers harboring the TMPRSS2:ERG fusion (52.9%) than in ERG-negative cancers (19.1%, P < 0.0001). Significant associations with Gleason grade, tumor stage, tumor grade, and early biochemical recurrence (P < 0.0001 each) were largely limited to ERG-negative tumors. Multivariable analysis revealed that the prognostic value of APE1 upregulation in ERG-negative prostate cancers was independent from established histopathological and clinical parameters. In conclusion, the results of our study demonstrate that APE1 overexpression is an independent prognostic marker, but exclusively in ERG-negative prostate cancers.
Lu Z, Li S, Ning S, et al.Association of the rs1760944 polymorphism in the APEX1 base excision repair gene with risk of nasopharyngeal carcinoma in a population from an endemic area in South China.
J Clin Lab Anal. 2018; 32(2) [PubMed
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BACKGROUND: Apurinic/apyrimidinic endonuclease 1 (APEX1) plays a central role in the repair of oxidative DNA lesions via base excision repair, and polymorphism in the APEX1 gene may affect susceptibility to carcinogenesis.
METHODS: Here, we assessed possible relationships between single-nucleotide polymorphism at APEX1 rs1760944 and risk of nasopharyngeal carcinoma (NPC) in 477 NPC patients and 558 healthy controls from Guangxi province, which is the second largest NPC endemic area in South China.
RESULTS: Genotype frequencies in controls were in Hardy-Weinberg equilibrium. Logistic regression analysis identified the genotypes GT or GG as associated with significantly lower risk than the genotype TT (adjusted odds ratio [OR] 0.745, 95% confidence interval [CI] 0.573-0.970). This apparent protective effect of GT/GG was even greater among those with no smoking history (adjusted OR 0.679, 95%CI 0.494-0.934).
CONCLUSION: Our results suggest that APEX1 rs1760944 polymorphism may correlate with NPC susceptibility in a population from an endemic area in South China.
The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets but has yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multifunctional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T cells, including in patient biopsies. Ref-1 redox function is active in leukemia T cells, regulating the Ref-1 target NF-κB, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and downregulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small-molecule inhibitor for leukemia.
Changes in mitochondrial DNA (mtDNA) integrity have been reported in many cancers; however, the contribution of mtDNA integrity to tumorigenesis is not well understood. We used a transgenic mouse model that is haploinsufficient for the apurinic/apyrimidinic endonuclease 1 (
Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts. Overexpression of wild-type APE1 or the R237C variant in the nontransformed C127I mouse cell line had no effect on proliferation, cell cycle status, steady-state DNA damage levels, mitochondrial function, or cellular transformation. A human cell line heterozygous for an APE1 knockout allele had lower levels of endogenous APE1, increased cellular sensitivity to DNA-damaging agents, impaired proliferation with time, and a distinct global gene expression pattern consistent with a stress phenotype. Our results indicate that: (i) the tumor-associated R237C variant is a possible susceptibility factor, but not likely a driver of cancer cell phenotypes, (ii) overexpression of APE1 does not readily promote cellular transformation, and (iii) haploinsufficiency at the APE1 locus can have profound cellular consequences, consistent with BER playing a critical role in proliferating cells. Environ. Mol. Mutagen. 58:84-98, 2017. © 2017 Wiley Periodicals, Inc.