Research IndicatorsGraph generated 29 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 29 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: SOD1 (cancer-related)
Multiple signaling pathways including ERK, PI3K-Akt, and NF-
There are seven ligands for the epidermal growth factor receptor (EGFR) ErbB1 and two ligands for ErbB3. EGFR can form a homodimer or a heterodimer with ErbB3. In this study, we investigated whether homodimers or heterodimers, and which ligand, play a major role in cancer development, with the goal of ultimately identifying therapeutic targets. We demonstrated that the ErbB3 ligand heregulin1 is the strongest mitogenic factor for non-small cell lung cancer cells and is more potent in activating EGFRmut-ErbB3 heterodimers than EGFRwt-ErbB3 heterodimers. We discovered that four of the seven EGFR ligands inhibited heregulin1-induced EGFRwt-ErbB3 activation and cell proliferation by promoting dephosphorylation of heregulin1-induced ErbB3 phosphorylation, whereas the other three did not exhibit such inhibition. Importantly, those four EGFR ligands did not inhibit heregulin1-induced EGFRmut-ErbB3 activation and proliferation of cells with EGFR mutants. We demonstrated that ErbB3 was overexpressed in the lung cancer cells but not in the adjacent normal alveoli or stromal tissue. EGFR and heregulin1 were also highly expressed in lung cancer cells. We conclude that the overexpression of heregulin1, ErbB3, and EGFR mutant renders uncontrolled cell proliferation.
Zhang L, Guo Y, Wang H, et al.Edaravone reduces Aβ-induced oxidative damage in SH-SY5Y cells by activating the Nrf2/ARE signaling pathway.
Life Sci. 2019; 221:259-266 [PubMed
] Related Publications
AIMS: Edaravone potentially alleviates cognitive deficits in a mouse model of Alzheimer's disease (AD). However, the mechanism of edaravone in suppressing AD progression remains unclear. We aim to investigate the mechanism of edaravone in suppressing oxidative stress-mediated AD progression in vitro.
MAIN METHODS: Human neuroblastoma SH-SY5Y cells were pretreated with different concentrations of edaravone prior to the induction by Aβ
KEY FINDINGS: The results showed that apoptosis and reactive oxygen species levels significantly increased in Aβ
SIGNIFICANCE: Activation of the Nrf2/ARE signaling pathway may underlie the protective effects of edaravone against the oxidative damage associated with Alzheimer's disease.
Gurunathan S, Kang MH, Jeyaraj M, Kim JHDifferential Immunomodulatory Effect of Graphene Oxide and Vanillin-Functionalized Graphene Oxide Nanoparticles in Human Acute Monocytic Leukemia Cell Line (THP-1).
Int J Mol Sci. 2019; 20(2) [PubMed
] Free Access to Full Article Related Publications
Graphene and its derivatives are emerging as attractive materials for biomedical applications, including antibacterial, gene delivery, contrast imaging, and anticancer therapy applications. It is of fundamental importance to study the cytotoxicity and biocompatibility of these materials as well as how they interact with the immune system. The present study was conducted to assess the immunotoxicity of graphene oxide (GO) and vanillin-functionalized GO (V-rGO) on THP-1 cells, a human acute monocytic leukemia cell line. The synthesized GO and V-rGO were characterized by using various analytical techniques. Various concentrations of GO and V-rGO showed toxic effects on THP-1 cells such as the loss of cell viability and proliferation in a dose-dependent manner. Cytotoxicity was further demonstrated as an increased level of lactate dehydrogenase (LDH), loss of mitochondrial membrane potential (MMP), decreased level of ATP content, and cell death. Increased levels of reactive oxygen species (ROS) and lipid peroxidation caused redox imbalance in THP-1 cells, leading to increased levels of malondialdehyde (MDA) and decreased levels of anti-oxidants such as glutathione (GSH), glutathione peroxidase (GPX), super oxide dismutase (SOD), and catalase (CAT). Increased generation of ROS and reduced MMP with simultaneous increases in the expression of pro-apoptotic genes and downregulation of anti-apoptotic genes suggest that the mitochondria-mediated pathway is involved in GO and V-rGO-induced apoptosis. Apoptosis was induced consistently with the significant DNA damage caused by increased levels of 8-oxo-dG and upregulation of various key DNA-regulating genes in THP-1 cells, indicating that GO and V-rGO induce cell death through oxidative stress. As a result of these events, GO and V-rGO stimulated the secretion of various cytokines and chemokines, indicating that the graphene materials induced potent inflammatory responses to THP-1 cells. The harshness of V-rGO in all assays tested occurred because of better charge transfer, various carbon to oxygen ratios, and chemical compositions in the rGO. Overall, these findings suggest that it is essential to better understand the parameters governing GO and functionalized GO in immunotoxicity and inflammation. Rational design of safe GO-based formulations for various applications, including nanomedicine, may result in the development of risk management methods for people exposed to graphene and graphene family materials, as these nanoparticles can be used as delivery agents in various biomedical applications.
DE Moura CFG, Soares GR, Ribeiro FAP, et al.Evaluation of the Chemopreventive Activity of Grape Skin Extract Using Medium-term Oral Carcinogenesis Assay Induced by 4-Nitroquinoline 1-Oxide.
Anticancer Res. 2019; 39(1):177-182 [PubMed
] Related Publications
BACKGROUND/AIM: The aim of this study was to evaluate the chemoprotective potential of grape skin extract following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide (4NQO).
MATERIALS AND METHODS: Male Wistar rats were distributed into four groups (n=5, per group): Control Group: free access to commercial diet and drinking water for 12 weeks; 4NQO Group: received 4NQO diluted in drinking water daily, for 12 weeks; Grape Skin Extract Group: free access to water and received grape skin extract incorporated with diet for 12 weeks; 4NQO + Grape Skin Extract Group: received 4NQO in drinking water daily and grape extract incorporated with diet for 12 weeks.
RESULTS: Animals treated with grape skin extract revealed a significant reduction in epithelial dysplasia. Also, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and ki-67 immunoexpression was reduced in animals treated with grape skin extract. Western blot analysis showed a significant decrease of p-NFκB p50 and MyD88 protein expression in the groups treated with grape skin extract. Copper-zinc superoxide dismutase, manganese superoxide dismutase, and catalase gene expression did not present any statistically significant differences (p>0.05).
CONCLUSION: Grape skin extract displayed chemopreventive activity in oral carcinogenesis assays as depicted by its antioxidant, anti-proliferative and anti-inflammatory properties.
NAD(P)H quinone oxidoreductase 1 (NQO1) catalyses the two electron reduction of quinones and a wide range of other organic compounds. Its physiological role is believed to be partly the reduction of free radical load in cells and the detoxification of xenobiotics. It also has non-enzymatic functions stabilising a number of cellular regulators including p53. Functionally, NQO1 is a homodimer with two active sites formed from residues from both polypeptide chains. Catalysis proceeds via a substituted enzyme mechanism involving a tightly bound FAD cofactor. Dicoumarol and some structurally related compounds act as competitive inhibitors of NQO1. There is some evidence for negative cooperativity in quinine oxidoreductases which is most likely to be mediated at least in part by alterations to the mobility of the protein. Human NQO1 is implicated in cancer. It is often over-expressed in cancer cells and as such is considered as a possible drug target. Interestingly, a common polymorphic form of human NQO1, p.P187S, is associated with an increased risk of several forms of cancer. This variant has much lower activity than the wild-type, primarily due to its substantially reduced affinity for FAD which results from lower stability. This lower stability results from inappropriate mobility of key parts of the protein. Thus, NQO1 relies on correct mobility for normal function, but inappropriate mobility results in dysfunction and may cause disease.
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the
PURPOSE: To investigate the effect and mechanism of phospholipase C epsilon gene 1 (
MATERIALS AND METHODS: The esophageal carcinoma cell lines Eca109 and EC9706 and normal esophageal epithelial cell line HEEC were cultured. The expression of PLCE1, protein kinase C alpha (PKCα), and nuclear factor kappa B (NF-κB) p50/p65 homodimer in cells were comparatively analyzed. The esophageal cancer cells were divided into si-PLCE1, control siRNA (scramble), and mock groups that were transfected with specific siRNA for PLCE1, control siRNA, and blank controls, respectively. Expression of PLCE1, PKCα, p50, and p65 was detected by Western blotting. Transwell assay was used to detect migration and invasion of Eca109 and EC9706 cells.
RESULTS: Compared with HEEC, the expression of PLCE1, PKCα, p50, and p65 was increased in Eca109 and EC9706 cells. The expression of PLCE1 was positively correlated with the expression of PKCα and p50 (PKCα: r=0.6328,
CONCLUSION: PLCE1 activated NF-κB signaling by up-regulating PKCα, which could promote invasion and migration of esophageal cancer cells.
Mohammed A, Zhang C, Zhang S, et al.Inhibition of cell proliferation and migration in non‑small cell lung cancer cells through the suppression of LYPLA1.
Oncol Rep. 2019; 41(2):973-980 [PubMed
] Related Publications
Lysophospholipase1 (LYPLA1) also known as acyl‑protein thioesterase1 (APT1) belongs to the superfamily of α/β hydrolase. It has been found to have the properties of a homodimer by manifesting depalmitoylation as well as lysophospholipase activity. LYPLAs are under the control of both microRNAs, miR‑138 and miR‑424. They were observed to be significantly overexpressed in chronic lymphocytic leukemia cells. To date, LYPLAs are the sole enzymes recognized to activate depalmitoylation. In this study, we provide the expression pattern of LYPLA1 in non‑small cell lung cancer (NSCLC) using four different NSCLC cell lines. Western blot analysis and RT‑PCR were performed to detect the protein expression and mRNA expression of LYPLA1 in NSCLC cell lines. We detected the highest LYPLA1 protein expression level in SPC‑A‑1 cells followed by A549 cells, and the highest LYPLA1 mRNA expression level was detected in the SPC‑A‑1 cells followed by the H1299 cell line. We found that suppression of LYPLA1 expression using small‑interfering RNA significantly inhibited proliferation, migration and invasion of the LYPLA1‑transfected NSCLC cells. Furthermore, we explored the involvement of LYPLA1 in the regulation of epithelial‑mesenchymal transition (EMT). The epithelial marker E‑cadherin was significantly increased, while mesenchymal markers N‑cadherin, vimentin and SNAIL were markedly decreased in the LYPLA1‑silenced cells. Collectively the results of the present study suggest that the LYPLA1 gene plays a tumor‑promotor role in NSCLC cells in vitro.
Manganese(III) porphyrins (MnPs) are superoxide dismutase (SOD) mimics with demonstrated beneficial effects in cancer treatment in combination with chemo- and radiotherapy regimens. Despite the ongoing clinical trials, little is known about the effect of MnPs on metastasis, being therefore essential to understand how MnPs affect this process. In the present work, the impact of the MnP MnTnHex-2-PyP
Ahamed M, Akhtar MJ, Khan MAM, et al.Oxidative stress mediated cytotoxicity and apoptosis response of bismuth oxide (Bi
Chemosphere. 2019; 216:823-831 [PubMed
] Related Publications
Bismuth oxide nanoparticles (Bi
Hassanein EHM, Shalkami AS, Khalaf MM, et al.The impact of Keap1/Nrf2, P
Biomed Pharmacother. 2019; 109:47-56 [PubMed
] Related Publications
Berberine (BBR) is a natural compound of plant origin belonging to isoquinoline type of alkaloid. Methotrexate (MTX) is an anti-metabolite used widely for a variety of tumors and autoimmune conditions. Clinical uses of MTX were severely limited by its concomitant renal intoxication. The current study was designed to investigate the efficacy of BBR against MTX-induced nephrotoxicity and for exploring the underlying molecular mechanisms through examining the Keap1/Nrf2, NF-κB/P
Estrogen receptors promote target gene transcription when they form a dimer, in which two identical (homodimer) or different (heterodimer) proteins are bound to each other. In hormone-dependent cancers, hormone receptor dimerization plays pivotal roles, not only in the pathogenesis or development of the tumors, but also in the development of therapeutic resistance. Protein⁻protein interactions (PPIs), including dimerization and complex formation, have been also well-known to be required for proteins to exert their functions. The methods which could detect PPIs are genetic engineering (i.e., resonance energy transfer) and/or antibody technology (i.e., co-immunoprecipitation) using cultured cells. In addition, visualization of the target proteins in tissues can be performed using antigen⁻antibody reactions, as in immunohistochemistry. Furthermore, development of microscopic techniques (i.e., electron microscopy and confocal laser microscopy) has made it possible to visualize intracellular and/or intranuclear organelles. We have recently reported the visualization of estrogen receptor dimers in breast cancer tissues by using the in situ proximity ligation assay (PLA). PLA was developed along the lines of antibody technology development, and this assay has made it possible to visualize PPIs in archival tissue specimens. Localization of PPI in organelles has also become possible using super-resolution microscopes exceeding the resolution limit of conventional microscopes. Therefore, in this review, we summarize the methodologies used for studying PPIs in both cells and tissues, and review the recently reported studies on PPIs of hormones.
Deng L, Jiang L, Tseng KF, et al.Aberrant NEAT1_1 expression may be a predictive marker of poor prognosis in diffuse large B cell lymphoma.
Cancer Biomark. 2018; 23(2):157-164 [PubMed
] Related Publications
BACKGROUND: Many studies have demonstrated that the long non-coding RNA (lncRNA), NEAT1_1, plays critical roles in various human tumor entities and is related to the survival of patients with malignancies. However, the role of NEAT1_1 in diffuse large B cell lymphoma (DLBCL) remains unclear. The aim of this study was to investigate the role of NEAT1_1 in DLBCL.
METHODS: The expression of NEAT1_1 was evaluated in paraffin-embedded tissues from 64 DLBCL patients and 15 lymphnoditis patients using the ISH method. The correlations between the expression levels of NEAT1_1 and clinical-pathological features and patients' survival were also analyzed. After knocking down NEAT1_1 using shRNA in the DLBCL cell lines OCI-Ly1 and SUDHL-4, cell viability, apoptosis and migration were assessed by performing CCK8 assays, annexin V-FITC/PI double staining assays and migration filter assays, respectively.
RESULTS: NEAT1_1 expression was increased in DLBCL tissue compared to lymphnoditis tissue samples (P< 0.001). The NEAT1_1 level was positively related to stage (P= 0.031), IPI (P= 0.017), extranodal site involvement (P= 0.042) and drug response (P= 0.040). Kaplan-Meier analysis showed that high expression levels of NEAT1_1 were correlated with a poor prognosis in DLBCL patients. After shRNA-NEAT1_1 was transfected into OCI-Ly1 and SUDHL-4 for 24 h, the NEAT1_1 level decreased to approximately one-third the level of the control. Moreover, the viability and migration ability of the DLBCL cell lines were significantly suppressed. shRNA-NEAT1_1 induced apoptosis in both DLBCL cell lines.
CONCLUSIONS: Our results showed that NEAT1_1 plays an oncogenic role in DLBCL. NEAT1_1 expression may serve as a predictive marker for DLBCL patients.
Sharma P, Kumar SMetformin inhibits human breast cancer cell growth by promoting apoptosis via a ROS-independent pathway involving mitochondrial dysfunction: pivotal role of superoxide dismutase (SOD).
Cell Oncol (Dordr). 2018; 41(6):637-650 [PubMed
] Related Publications
PURPOSE: Despite a growing body of evidence indicating a potential efficacy of the anti-diabetic metformin as anti-cancer agent, the exact mechanism underlying this efficacy has remained largely unknown. Here, we aimed at assessing putative mechanisms associated with the ability of metformin to reduce the proliferation and migration of breast cancer cells.
METHODS: A battery of in vitro assays including MTT, colony formation, NBT and scratch wound healing assays were performed to assess the viability, proliferation, anti-oxidative potential and migration of breast cancer-derived MCF-7, MDA-MB-231 and T47D cells, respectively. Reactive oxygen species (ROS) assays along with fluorescence microscopy were used to assess apoptotic parameters. Quantification of SOD, Bcl-2, Bax, MMPs, miR-21 and miR-155 expression was performed using qRT-PCR.
RESULTS: We found that metformin inhibited the growth, proliferation and clonogenic potential of the breast cancer-derived cells tested. ROS levels were found to be significantly reduced by metformin and, concomitantly, superoxide dismutase (SOD) isoforms were found to be upregulated. Mitochondrial dysfunction was observed in metformin treated cells, indicating apoptosis. In metastatic MDA-MB-231 cells, migration was found to be suppressed by metformin through deregulation of the matrix metalloproteinases MMP-2 and MMP-9. The oncogenic microRNAs miR-21 and miR-155 were found to be downregulated by metformin, which may be correlated with the suppression of cell proliferation and/or migration.
CONCLUSIONS: Our data indicate that metformin may play a pivotal role in modulating the anti-oxidant system, including the SOD machinery, in breast cancer-derived cells. Our observations were validated by in silico analyses, indicating a close interaction between SOD and metformin. We also found that metformin may inhibit breast cancer-derived cell proliferation through apoptosis induction via the mitochondrial pathway. Finally, we found that metformin may modulate the pro-apoptotic Bax, anti-apoptotic Bcl-2, MMP-2, MMP-9, miR-21 and miR-155 expression levels. These findings may be instrumental for the clinical management and/or (targeted) treatment of breast cancer.
Gaikwad S, Chakraborty A, Salwe S, et al.Juglone-ascorbic acid synergy inhibits metastasis and induces apoptotic cell death in poorly differentiated thyroid carcinoma by perturbing SOD and catalase activities.
J Biochem Mol Toxicol. 2018; 32(9):e22176 [PubMed
] Related Publications
Anaplastic thyroid carcinoma (ATC) requires more innovative approaches as the current regimes for therapy are inadequate, also most anticancer drugs cause general suppression of physiological functions. However, therapy with limited nontarget tissue damage is desirable. In the present study, we show prooxidant ability of ascorbic acid, which enhances cytotoxicity induced by juglone. We decipher that juglone-ascorbate combination induces reactive oxygen species-mediated apoptosis leading to cell death in ARO cell line originated from ATC. This combination also affects enzyme activity of catalase, glutathione reductase, and superoxide dismutase destabilizing redox balance in cell and thereby making juglone effective at a lower dose. We also show that juglone-ascorbate combination suppresses cell migration, invasion, and expression of tumor-promoting, and angiogenic genes in ARO cell line, thereby disrupting epithelial-mesenchymal transition ability of the cells. Overall, we show that ascorbic acid increases cytotoxic potency of juglone through redox cycling when used in synergy.
BACKGROUND/OBJECTIVES: In the Middle East, people consume camel milk regularly as it is believed to improve immunity against diseases and decrease the risk for cancer. Recently, it was noted that most of the beneficial effects of milk come from their nanoparticles, especially exosomes. Herein, we evaluated the anticancer potential of camel milk and its exosomes on MCF7 breast cancer cells (in vitro and in vivo) and investigated the possible underlying molecular mechanism of action.
METHODS/RESULTS: Administration of camel milk (orally) and its exosomes (orally and by local injection) decreased breast tumor progression as evident by ( a) higher apoptosis (indicated by higher DNA fragmentation, caspase-3 activity, Bax gene expression, and lower Bcl2 gene expression), ( b) remarkable inhibition of oxidative stress (decrease in MDA levels and iNOS gene expression); ( c) induction of antioxidant status (increased activities of SOD, CAT, and GPX), ( d) notable reduction in expression of inflammation-( IL1b, NFκB), angiogenesis-( VEGF) and metastasis-( MMP9, ICAM1) related genes; and ( e) higher immune response (high number of CD
CONCLUSIONS: Overall, administration of camel milk-derived exosomes showed better anticancer effect, but less immune response, than treatment by camel milk. Moreover, local injection of exosomes led to better improvement than oral administration. These findings suggest that camel milk and its exosomes have anticancer effect possibly through induction of apoptosis and inhibition of oxidative stress, inflammation, angiogenesis and metastasis in the tumor microenvironment. Thus, camel milk and its exosomes could be used as an anticancer agent for cancer treatment.
BACKGROUND: Fascin is a F-actin bundling protein and its overexpression is correlated with poor prognosis and increases metastatic potential in a number of cancers. But underlying function and mechanism of fascin on tumorigenesis in melanoma remain elusive.
METHODS: The melanoma cell lines WM793 and WM39 were employed for the soft agar and sphere formation assay. Quantitative RT-PCR and Western blot were performed for identifying the gene expression at mRNA and protein levels, respectively. Co-IP and in vitro GST pulldown experiments were used to test the interaction between fascin and MST2.
RESULTS: Fascin regulates tumorigenesis and cancer cell stemness in melanoma through inhibition of the Hippo pathway kinase MST2 and the activation of transcription factor TAZ. Our data showed that fascin interacts with the kinase domain of MST2 to inhibit its homodimer formation and kinase activity. Depletion of fascin led to increase of p-LATS level and decrease of TAZ, but not YAP. We also demonstrated that fascin regulates melanoma tumorigenesis independent of its actin-bundling activity.
CONCLUSIONS: Fascin is a new regulator of the MST2-LATS-TAZ pathway and plays a critical role in melanoma tumorigenesis. Inhibition of fascin reduces melanoma tumorigenesis and stemness, and thus fascin could be a potential therapeutic target for this malignancy.
Li C, Tang B, Feng Y, et al.Pinostrobin Exerts Neuroprotective Actions in Neurotoxin-Induced Parkinson's Disease Models through Nrf2 Induction.
J Agric Food Chem. 2018; 66(31):8307-8318 [PubMed
] Related Publications
The aim of the present study was to assess the neuroprotective effects of pinostrobin (PSB), a dietary bioflavonoid, and its underlying mechanisms in neurotoxin-induced Parkinson's disease (PD) models. First, PSB could attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons and improve behavior deficiency in zebrafish, supporting its potential neuroprotective actions in vivo. Next, PSB could decreased apoptosis and death in the 1-methyl-4-phenylpyridinium (MPP
BACKGROUND: SOD1 is an abundant enzyme that has been studied as a regulator of the antioxidant defence system, and this enzyme is well known for catalyzing the dismutation of superoxide into hydrogen peroxide. However the SOD1 in the progress of NPC and underlying mechanisms remain unclear.
METHODS: In NPC tissue samples, SOD1 protein levels were measured by Western blot and immunohistochemical (IHC) staining. mRNA levels and SOD1 activity were monitored by qRT-PCR and SOD activity kit, respectively. Kaplan-Meier survival analysis was performed to explore the relationship between SOD1 expression and prognosis of NPC. The biological effects of SOD1 were investigated both in vitro by CCK-8, clonogenicity and apoptosis assays and in vivo by a xenograft mice model. Western blotting, ROS assay and triglyceride assays were applied to investigate the underlying molecular mechanism of pro-survival role of SOD1 in NPC.
RESULTS: We observed a significant upregulation of SOD1 in NPC tissue and high SOD1 expression is a predictor of poor prognosis and is correlated with poor outcome. We confirmed the pro-survival role of SOD1 both in vitro and in vivo. We demonstrated that these mechanisms of SOD1 partly exist to maintain low levels of the superoxide anion and to avoid the accumulation of lipid droplets via enhanced CPT1A-mediated fatty acid oxidation.
CONCLUSIONS: The results of this study indicate that SOD1 is a potential prognostic biomarker and a promising target for NPC therapy.
Background: Alteration in the biotransformation of exogenous compounds can result in production of reactive
oxygen species (ROS), which can predispose cells to malignant transformation in the head and neck. This study aimed
to evaluate the expression of genes involved in antioxidant metabolism in the oral squamous cell carcinoma (OSCC).
Methods: The expression of eighty-four genes was evaluated in OSCC and non-tumor tissues by quantitative real-time
polymerase chain reaction using the TaqMan Gene Expression Array. The biological mechanisms related to
the differentially expressed genes were investigated using Gene – NCBI, KEGG, UNIPROT and REACTOME databases.
Results: Twenty-one genes encoding enzymes involved in antioxidant metabolism were differentially expressed in
the OSCC case. Four genes (ATOX1, PRDX4, PRNP, and SOD2) were up-regulated, and seventeen (ALOX12, CAT,
CSDE1, DHCR24, DUOX1, DUOX2, EPHX2, GLRX2, GPX3, GSR, GSTZ1, MGST3, PRDX1, OXR1, OXSR1,
SOD1, and SOD3) were down-regulated. We identified 14 possible novel biomarkers for OSCC. The differentially
expressed genes appeared related to important biological processes involved in carcinogenesis, such as inflammation,
angiogenesis, apoptosis, genomic instability, invasion, survival, and cell proliferation. Conclusions: Our study
identified novel biomarkers which might warrant further investigation regarding OSCC pathogenesis since the altered
expression in the genes can modulate biological processes related to oxidative stress and predispose cells to malignant
transformation in the oral cavity.
Conte A, Pierantoni GMUpdate on the Regulation of HIPK1, HIPK2 and HIPK3 Protein Kinases by microRNAs.
Microrna. 2018; 7(3):178-186 [PubMed
] Related Publications
The Homeodomain-Interacting Protein Kinases (HIPKs) HIPK1, HIPK2 and HIPK3 are Ser/Thr kinases which interact with homeobox proteins and other transcription factors, acting as transcriptional coactivators or corepressors. HIPKs contribute to regulate several biological processes, such as signal transduction, apoptosis, embryonic development, DNA-damage response, and cellular proliferation, in response to various extracellular stimuli. Recently it has emerged that, in addition to their role in cancer, fibrosis and diabetes, HIPKs may also be involved in other human diseases, including Amyotrophic Lateral Sclerosis (ALS), Rett syndrome, cerebellar diseases, and retinal vascular dysfunction.
METHODS: Here, we update our previous paper concerning the regulation of HIPK proteins expression by microRNAs (miRNAs), pointing out the most recent findings about new cellular mechanisms and diseases which are affected by the interplay between HIPKs and miRNAs.
CONCLUSION: Recently, it has emerged that HIPKs and their related miRNAs are involved in diabetic nephropathy, gastric cancer chemoresistance, cervical cancer progression, and recombinant protein expression in cultured cells. Interestingly, circular RNAs (circRNAs) deriving from HIPK2 and HIPK3 loci also modulate cellular proliferation and viability by sponging several miRNAs, thus emerging as new putative therapeutic targets for diabetes-associated retinal vascular dysfunction, astrogliosis and cancer.
Kusaczuk M, Krętowski R, Naumowicz M, et al.Silica nanoparticle-induced oxidative stress and mitochondrial damage is followed by activation of intrinsic apoptosis pathway in glioblastoma cells.
Int J Nanomedicine. 2018; 13:2279-2294 [PubMed
] Free Access to Full Article Related Publications
Introduction: Recently, the focus of oncological research has been on the optimization of therapeutic strategies targeted at malignant diseases. Nanomedicine utilizing silicon dioxide nanoparticles (SiNPs) is one such strategy and is rapidly developing as a promising tool for cancer diagnosis, imaging, and treatment. Nevertheless, little is known about the mechanisms of action of SiNPs in brain tumors.
Materials and methods: Here, we explored the effects of 5-15 nm SiNPs in the human glioblastoma cell line LN229. In this respect, MTT assays, microscopic observations, flow cytometry analyses, and luminescent assays were performed. Moreover, RT-qPCR and Western blot analyses were done to determine gene and protein expressions.
Results: We demonstrated that SiNPs triggered evident cytotoxicity, with microscopic observations of the nuclei, annexin V-fluorescein isothiocyanate/propidium iodide staining, and elevated caspase 3/7 activity, suggesting that SiNPs predominantly induced apoptotic death in LN229 cells. We further showed the occurrence of oxidative stress induced by enhanced reactive oxygen-species generation. This effect was followed by deregulated expression of genes encoding the antioxidant enzymes SOD1, SOD2, and CAT, and impaired mitochondria function. SiNP- induced mitochondrial dysfunction was characterized by membrane-potential collapse, ATP depletion, elevated expression of
Conclusions: Altogether, our data indicate that in LN229 cells, SiNPs evoke cell death via activation of the intrinsic apoptosis pathway and suggest that other aspects of cellular function may also be affected. As such, SiNPs represent a potentially promising agent for facilitating further progress in brain cancer therapy. However, further exploration of SiNP long-term toxicity and molecular effects is necessary prior to their widespread application.
Bulgurcuoglu Kuran S, Iplik ES, Cakmakoglu B, et al.Relation of MPO, MnSOD, NQO1 gene variants in endometrial carcinoma in the line of PCR-RFLP methods.
Cell Mol Biol (Noisy-le-grand). 2018; 64(4):78-82 [PubMed
] Related Publications
Reactive oxygen species (ROS) have been shown to be responsible for inducing DNA damage leading to mutagenesis, carcinogenesis, and cell death if the capacity of the protective antioxidant system is impaired. Endometrial carcinoma is the primary cancer type in the female genital system. The enhanced cell lipid peroxidation and impaired antioxidant enzyme activities observed in patients with endometrial cancer indicate the potential for oxidative injury to cells and cell membranes in such patients. The aim of the study was to investigate the possible association between gene variants of superoxide dismutase (SOD), myeloperoxidase (MPO), and NADPH quinone oxido reductase (NQO1), and their possible role in endometrial cancer in Turkish patients. According to results, MPO G+ genotype and AG genotype were significantly increased in patients compared with controls (P<0.001). We suggest that the MPO polymorphism might be a risk for endometrial cancer.
Castejón-Griñán M, Herraiz C, Olivares C, et al.cAMP-independent non-pigmentary actions of variant melanocortin 1 receptor: AKT-mediated activation of protective responses to oxidative DNA damage.
Oncogene. 2018; 37(27):3631-3646 [PubMed
] Related Publications
The melanocortin 1 receptor gene (MC1R), a well-established melanoma susceptibility gene, regulates the amount and type of melanin pigments formed within epidermal melanocytes. MC1R variants associated with increased melanoma risk promote the production of photosensitizing pheomelanins as opposed to photoprotective eumelanins. Wild-type (WT) MC1R activates DNA repair and antioxidant defenses in a cAMP-dependent fashion. Since melanoma-associated MC1R variants are hypomorphic in cAMP signaling, these non-pigmentary actions are thought to be defective in MC1R-variant human melanoma cells and epidermal melanocytes, consistent with a higher mutation load in MC1R-variant melanomas. We compared induction of antioxidant enzymes and DNA damage responses in melanocytic cells of defined MC1R genotype. Increased expression of catalase (CAT) and superoxide dismutase (SOD) genes following MC1R activation was cAMP-dependent and required a WT MC1R genotype. Conversely, pretreatment of melanocytic cells with an MC1R agonist before an oxidative challenge with Luperox decreased (i) accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanine, a major product of oxidative DNA damage, (ii) phosphorylation of histone H2AX, a marker of DNA double-strand breaks, and (iii) formation of DNA breaks. These responses were comparable in cells WT for MC1R or harboring hypomorphic MC1R variants without detectable cAMP signaling. In MC1R-variant melanocytic cells, the DNA-protective responses were mediated by AKT. Conversely, in MC1R-WT melanocytic cells, high cAMP production downstream of MC1R blocked AKT activation and was responsible for inducing DNA repair. Accordingly, MC1R activation could promote repair of oxidative DNA damage by a cAMP-dependent pathway downstream of WT receptor, or via AKT in cells of variant MC1R genotype.
Hashemzehi M, Behnam-Rassouli R, Hassanian SM, et al.Phytosomal-curcumin antagonizes cell growth and migration, induced by thrombin through AMP-Kinase in breast cancer.
J Cell Biochem. 2018; 119(7):5996-6007 [PubMed
] Related Publications
Here we explored the antitumor-activity of novel-formulated-form of curcumin (phytosomal-encapsulated-curcumin) or in combination with 5-FU in breast cancer. The antiproliferative activity was assessed in 2D and 3-dimensional cell-culture-model. The migratory-behaviors of the cells were determined by migration assay. The expression levels of CyclinD1,GSK3a/b, P-AMPK, MMP9, and E-cadherin were studied by qRT-PCR and/or Western blotting. The anti-inflammatory of nano-curcumin was assessed, while antioxidant activity was evaluated by malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and total thiols (T-SH). To understand dynamic behavior of genes, we reconstructed a Boolean network, while the robustness of this model was evaluated by Hamming distance. phytosomal-curcumin suppressed cell-growth followed by tumor-shrinkage in 3D model through perturbation of AMP-activated protein kinase. Curcumin reduced the invasiveness of MCF-7 through perturbation of E-cadherin. Moreover, phytosomal-curcumin inhibited the tumor growth in xerograph model. Histological staining of tumor tissues revealed vascular disruption and RBC extravasation, necrosis, tumor stroma, and inflammation. Co-treatment of curcumin and 5-FU reduced the lipid-peroxidation and increased MDA/SOD level. Of note, curcumin reduced cyclinD-expression in breast cancer cell treated with thrombin, and activates AMPK in a time-dependent manner. Also suppression of AMPK abrogated inhibitory effect of phytosomal-curcumin on thrombin-induced cyclin D1 over-expression, suggesting that AMPK is essential for anti-proliferative effect of this agent in breast cancer. Our finding demonstrated that phytosomal-curcumin antagonizes cell growth and migration, induced by thrombin through AMP-Kinase in breast cancer, supporting further-investigations on the therapeutic potential of this novel anticancer agent in treatment of breast cancer.
Nasopharyngeal carcinoma (NPC), although not very common in many parts of the world, is a major concern in
some countries, including Iran. Molecular studies are very helpful to provide essential information regarding underlying
carcinogenetic mechanisms. Here, considering NPC proteomic approaches, established biomarkers were designated for
protein-protein interaction network construction and analysis with corresponding plug-ins. A network of reported protein
markers was constructed and topological and biological process features were investigated. Centrality analysis showed
that JUN, CALM1, HSB1, and SOD1 are more important than other differentially expressed proteins in an interacting
pattern. What is more, by extending the network, Tp53, PRDM10, AKT1, ALB, HSP90AA1, and EGFR achieved the
highest values for NPC network strength. It can be concluded that these proteins as well as their contributing processes,
particularly in a second network, may be important for NPC onset and development. Targeting these candidate proteins
may allow novel treatment approaches following appropriate validation.
Saquib Q, Siddiqui MA, Ahmad J, et al.Nickel Oxide Nanoparticles Induced Transcriptomic Alterations in HEPG2 Cells.
Adv Exp Med Biol. 2018; 1048:163-174 [PubMed
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Nickel oxide nanoparticles (NiO-NPs) are increasingly used and concerns have been raised on its toxicity. Although a few studies have reported the toxicity of NiO-NPs, a comprehensive understanding of NiO-NPs toxicity in human cells is still lagging. In this study, we integrated transcriptomic approach and genotoxic evidence to depict the mechanism of NiO-NPs toxicity in human hepatocellular carcinoma (HepG2) cells. DNA damage analysis was done using comet assay, which showed 26-fold greater tail moment in HepG2 cells at the highest concentration of 100 μg/ml. Flow cytometric analysis showed concentration dependent enhancement in intracellular reactive oxygen species (ROS). Real-time PCR analysis of apoptotic (p53, bax, bcl2) and oxidative stress (SOD1) genes showed transcriptional upregulation. Transcriptome analysis using qPCR array showed over expression of mRNA transcripts related to six different cellular pathways. Our data unequivocally suggests that NiO-NPs induces oxidative stress, DNA damage, apoptosis and transcriptome alterations in HepG2 cells.
Bone morphogenetic protein-2 (BMP-2), is a potential factor to enhance osseointegration of dental implants. However, the appropriate cellular system to investigate the osteogenic effect of BMP-2 in vitro in a standardized manner still needs to be defined. The aim of this study was to examine the effect of BMP-2 on the cell proliferation and osteogenic differentiation of human osteogenic progenitors of various origins: dental pulp stem cells (DPSC), human osteosarcoma cell line (Saos-2) and human embryonic palatal mesenchymal cell line (HEPM). For induction of osteogenic differentiation, cell culture medium was supplemented with BMP-2 homodimer alone or in combination with conventionally used differentiation inducing agents. Differentiation was monitored for 6-18 days. To assess differentiation, proliferation rate, alkaline phosphatase activity, calcium deposition and the expression level of osteogenic differentiation marker genes (Runx2, BMP-2) were measured. BMP-2 inhibited cell proliferation in a concentration and time-dependent manner. In a concentration which caused maximal cell proliferation, BMP-2 did not induce osteogenic differentiation in any of the tested systems. However, it had a synergistic effect with the osteoinductive medium in both DPSC and Saos-2, but not in HEPM cells. We also found that the differentiation process was faster in Saos-2 than in DPSCs. Osteogenic differentiation could not be induced in the osteoblast progenitor HEPM cells. Our data suggest that in a concentration that inhibits proliferation the differentiation inducing effect of BMP-2 is evident only in the presence of permissive osteoinductive components. β-glycerophosphate, was identified interacting with BMP-2 in a synergistic manner.
Wang Y, Liu FT, Wang YX, et al.Autophagic Modulation by Trehalose Reduces Accumulation of TDP-43 in a Cell Model of Amyotrophic Lateral Sclerosis via TFEB Activation.
Neurotox Res. 2018; 34(1):109-120 [PubMed
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Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease characterized by the formation of protein inclusion and progressive loss of motor neurons, finally leading to muscle weakness and respiratory failure. So far, the effective drugs for ALS are yet to be developed. Impairment of transcriptional activator transcription factor EB (TFEB) has been demonstrated as a key element in the pathogenesis of ALS. Trehalose is an mechanistic target of rapamycin-independent inducer for autophagy, which showed autophagic activation and neuroprotective effect in a variety of neurodegenerative diseases. The mechanism for trehalose-induced autophagy enhancement is not clear, and its therapeutic effect on TAR DNA-binding protein-43 (TDP-43) proteinopathies has been poorly investigated. Here we examined the effect of trehalose on TDP-43 clearance in a cell culture model and identified that trehalose treatment significantly reduced TDP-43 accumulation in vitro through modulation of the autophagic degradation pathway. Further studies revealed that activation of TFEB induced by trehalose was responsible for the enhancement of autophagy and clearance of TDP-43 level. These results gave us the notion that TFEB is a central regular in trehalose-mediated autophagic clearance of TDP-43 aggregates, representing an important step forward in the treatment of TDP-43 related ALS diseases.