Research IndicatorsGraph generated 01 September 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 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
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: PRKCE (cancer-related)
BACKGROUND: MiR-182-5p, as a member of miRNA family, can be detected in lung cancer and plays an important role in lung cancer. To explore the clinical value of miR-182-5p in lung squamous cell carcinoma (LUSC) and to unveil the molecular mechanism of LUSC.
METHODS: The clinical value of miR-182-5p in LUSC was investigated by collecting and calculating data from The Cancer Genome Atlas (TCGA) database, the Gene Expression Omnibus (GEO) database, and real-time quantitative polymerase chain reaction (RT-qPCR). Twelve prediction platforms were used to predict the target genes of miR-182-5p. Protein-protein interaction (PPI) networks and gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to explore the molecular mechanism of LUSC.
RESULTS: The expression of miR-182-5p was significantly over-expressed in LUSC than in non-cancerous tissues, as evidenced by various approaches, including the TCGA database, GEO microarrays, RT-qPCR, and a comprehensive meta-analysis of 501 LUSC cases and 148 non-cancerous cases. Furthermore, a total of 81 potential target genes were chosen from the union of predicted genes and the TCGA database. GO and KEGG analyses demonstrated that the target genes are involved in pathways related to biological processes. PPIs revealed the relationships between these genes, with EPAS1, PRKCE, NR3C1, and RHOB being located in the center of the PPI network.
CONCLUSIONS: MiR-182-5p upregulation greatly contributes to LUSC and may serve as a biomarker in LUSC.
Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.
Gallbladder cancer (GBC) is one of the most common malignancy of the biliary tract characterized by its high chemoresistant tendency. Although great progresses have been made in recent decades for treating many cancers with anticancer drugs, effective therapeutics methods for anti-GBC are still lacking. Therefore, investigations into identifying the mechanisms underlying the drug resistance of GBC are greatly needed. In this study, we show that miR-218-5p plays a critical role in gemcitabine resistance of GBC. miR-218-5p levels were significantly lower in GBC than adjacent non-cancer tissues, and which were also associated with patient prognosis. While miR-218-5p overexpression abrogated gemcitabine resistance of GBC cells, silencing of which exhibited the opposite effects. Via six microRNA targets prediction algorithms, we found that PRKCE is a potential target of miR-218-5p. Moreover, miR-218-5p overexpression repressed the luciferase activity of reporter constructs containing 3'-UTR of PRKCE and also reduced PRKCE expression. Further studies revealed that miR-218-5p promotes sensitivity of gemcitabine by abolishing PRKCE-induced upregulation of MDR1/P-gp. Taken together, our results imply that an intimate correlation between miR-218-5p and PRKCE/MDR1 axis abnormal expression is a key determinant of gemcitabine tolerance, and suggest a novel miR-218-5p-based clinical intervention target for GBC patients.
Anthracycline chemotherapeutics, e.g. doxorubicin and daunorubicin, are active against a broad spectrum of cancers. Their cytotoxicity is mainly attributed to DNA intercalation, interference with topoisomerase activity, and induction of double-stranded DNA breaks. Since modification of anthracyclines can profoundly affect their pharmacological properties we attempted to elucidate the mechanism of action, and identify possible molecular targets, of bis-anthracycline WP760 which previously demonstrated anti-melanoma activity at low nanomolar concentrations. We studied the effect of WP760 on several human melanoma cell lines derived from tumors in various development stages and having different genetic backgrounds. WP760 inhibited cell proliferation (IC
Gümus M, Ozgur A, Tutar L, et al.Design, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis.
Curr Pharm Biotechnol. 2016; 17(14):1231-1245 [PubMed
] Related Publications
BACKGROUND: Despite development of novel cancer drugs, invasive ductal breast carcinoma and its metastasis are still highly morbid. Therefore, new therapeutic approaches are being developed and Hsp90 is an important target for drug design. For this purpose, a series of benzodiazepine derivatives were designed and synthesized as novel Hsp90 inhibitor.
METHODS: Benzodiazepine derivatives anticancer activities were determined by XTT cell proliferation assay against human breast cancer cell line (MCF-7). Effects of the compounds on endothelial function were monitored on human vascular endothelium (HUVEC) cell line as well. In order to determine the anti-proliferative mechanism of the compounds, in silico molecular docking studies were performed between Hsp90 ATPase domain and the benzodiazepine derivatives. Further, these compounds perturbation on Hsp90 ATPase function were tested. Fluorescence binding experiments showed that the derivatives bind Hsp90 effectively. Expression analysis of known cancer drug target genes by PCR array experiments suggest that the benzodiazepine derivatives have remarkable anticancer activity.
RESULTS: A representative Benzodiazepine derivative D5 binds Hsp90 with Kd value of 3,93 μM and with estimated free energy of binding -7.99 (kcal/mol). The compound decreases Hsp90 ATPase function and inhibit Hsp90 client protein folding activity. The compound inhibits expression of both Hsp90 isoforms and key proteins (cell cycle receptors; PLK2 and TERT, kinases; PI3KC3 and PRKCE, and growth factors; IGF1, IGF2, KDR, and PDGFRA) on oncogenic pathways.
CONCLUSION: Benzodiazepine derivatives presented here display anticancer activity. The compounds effect on both breast cancer and endothelial cell lines show their potential as drug templates to inhibit breast cancer and its metastasis.
Huang B, Fu SJ, Fan WZ, et al.PKCε inhibits isolation and stemness of side population cells via the suppression of ABCB1 transporter and PI3K/Akt, MAPK/ERK signaling in renal cell carcinoma cell line 769P.
Cancer Lett. 2016; 376(1):148-54 [PubMed
] Related Publications
Protein kinase C epsilon (PKCε), a member of the novel PKC family, is known to be a transforming oncogene and tumor biomarker for many human solid cancers including renal cell carcinoma (RCC). We isolated side population (SP) cells from the RCC 769P cell line, and proved that those cells possess cancer stem cell (CSC) characteristics. In this study, to identify the function of PKCε in cancer stemness of 769P SP cells, we reduced the expression of PKCε in those cells, following the results demonstrated that PKCε depletion had a negative correlation with the existence of SP cells in 769P cell line. Down-regulation of PKCε also suppresses the CSC potential of sorted 769P SP cells in several ways: proliferation potential, resistance to chemotherapeutics and in vivo tumor formation ability. Our study also reveals that PKCε is associated with ABCB1 and this association probably contributed to the SP cells isolation from 769P cell line. Furthermore, the expression of ABCB1 is directly regulated by PKCε. Additionally, after the depletion of PKCε, the phosphorylation of pAkt, pStat3 and pERK was apparently suppressed in 769P SP cells, whereas PKCε overexpression could promote the phosphorylation of AKT, STAT3 and ERK in 769P Non-SP cells. Overall, PKCε down-regulation suppresses sorting and the cancer stem-like phenotype of RCC 769P SP cells through the regulation of ABCB1 transporter and the PI3K/Akt, Stat3 and MAPK/ERK pathways that are dependent on the phosphorylation effects. Thus, PKCε may work as an important mediator in cancer stem cell pathogenesis of renal cell cancer.
Long non-coding RNAs (lncRNAs) modulate gene expression, and lncRNA misregulation is associated with cancer. However, precise functional roles in biological and disease processes have been described for only a few lncRNAs. Identification of genome-wide lncRNA-mediated transcriptional dysregulations may improve cancer treatments. In the present study, we used a computational framework that combined lncRNA and gene expression profiles with transcription factor (TF)-target relationships to comprehensively identify dysregulatory lncRNA-TF-gene triplets. In glioblastoma (GBM), we found that most lncRNAs affect multiple targets and primarily affect TF activity in trans. Six different classes of lncRNA-mediated transcriptional dysregulations were identified, with most lncRNAs either enhancing or attenuating target gene expression. Functional analysis of lncRNAs via their dysregulated targets implicated lncRNA modulators in some hallmarks of cancer, providing a new way to predict lncRNA function. Finally, we identified several lncRNA-TF-gene triplets (including HOTAIR-MXI1-CD58/PRKCE and HOTAIR-ATF5-NCAM1) that are associated with glioblastoma prognosis. The integration of lncRNA modulators into transcriptional regulatory networks will further enhance our understanding of lncRNA functions in cancer.
Pathak HB, Zhou Y, Sethi G, et al.A Synthetic Lethality Screen Using a Focused siRNA Library to Identify Sensitizers to Dasatinib Therapy for the Treatment of Epithelial Ovarian Cancer.
PLoS One. 2015; 10(12):e0144126 [PubMed
] Free Access to Full Article Related Publications
Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC). The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK) and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1) was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other targeted agents that have similarly shown poor clinical activity.
Liu H, Yin W, Liu B, et al.Screening of candidate genes in fibroblasts derived from patients with Dupuytren's contracture using bioinformatics analysis.
Rheumatol Int. 2015; 35(8):1343-50 [PubMed
] Related Publications
Our study aimed to identify candidate genes associated with Dupuytren's contracture (DC) and elucidate their roles in DC development. The microarray data of GSE21221 were downloaded from Gene Expression Omnibus database, including six samples from carpal tunnel-derived fibroblasts and six samples from DC-derived fibroblasts. The differentially expressed genes (DEGs) in DC samples were screened using limma package. GO annotation and KEGG pathway analyses were performed by DAVID online tool. Protein-protein interaction network and expression correlation network were constructed to identify crucial relationships between DEGs. Finally, candidate DC-associated genes were predicted based on comparative toxicogenomics database. A total of 529 DEGs (138 up- and 391 down-regulated) in DC-derived fibroblasts were screened and compared with carpal tunnel-derived fibroblasts. Only ten DC-associated genes, such as neurotrophin 3 (NTF3) and protein kinase C, epsilon (PRKCE), were further screened. In addition, NTF3 was significantly enriched in MAPK signaling pathway, in which other DEGs, such as nuclear receptor subfamily 4, group A, member 1 (NR4A1), fibroblast growth factor 22 (FGF22) and BDNF, were enriched. Besides, NTF3 could co-express with fibrillin 2 (FBN2), and PRKCE could co-express with zinc finger protein 516 (ZNF516), solute carrier organic anion transporter family, member 2A1 (SLCO2A1), chromosome 10 open reading frame 10 (C10orf10) and Kelch domain containing 7A (KLHDC7A). Our study indicates that these DEGs, including NTF3, FBN2, NR4A1, FGF22, BDNF, PRKCE, ZNF516, SLCO2A1, C10orf10 and KLHDC7A, may play important roles in DC development and serve as candidate molecular targets for treating DC.
RIG-I-like receptors are the key cytosolic sensors for RNA viruses and induce the production of type I interferons (IFN) and pro-inflammatory cytokines through a sole adaptor IFN-β promoter stimulator-1 (IPS-1) (also known as Cardif, MAVS and VISA) in antiviral innate immunity. These sensors also have a pivotal role in anticancer activity through induction of apoptosis. However, the mechanism for their anticancer activity is poorly understood. Here, we show that anticancer vaccine adjuvant, PolyIC (primarily sensed by MDA5) and the oncolytic virus, Newcastle disease virus (NDV) (sensed by RIG-I), induce anticancer activity. The ectopic expression of IPS-1 into type I IFN-responsive and non-responsive cancer cells induces anticancer activity. PolyIC transfection and NDV infection upregulate pro-apoptotic gene TRAIL and downregulate the anti-apoptotic genes BCL2, BIRC3 and PRKCE. Furthermore, stable knockdown of IPS-1, IRF3 or IRF7 in IFN-non-responsive cancer cells show reduced anticancer activity by suppressing apoptosis via TRAIL and anti-apoptotic genes. Collectively, our study shows that IPS-1 induces anticancer activity through upregulation of pro-apoptotic gene TRAIL and downregulation of the anti-apoptotic genes BCL2, BIRC3 and PRKCE via IRF3 and IRF7 in type I IFN-dependent and -independent manners.
MicroRNA-34a (miR-34a) functions to regulate protein expression at the posttranscriptional level by binding the 3' UTR of target genes and regulates functions of vascular endothelial cells. However, the role of miR-34a in regulating blood-tumor barrier (BTB) permeability remains unknown. In this study, we show that miR-34a overexpression leads to significantly increased permeability of BTB, whereas miR-34a silencing reduces the permeability of the BTB. In addition, miR-34a overexpression significantly down-regulates the expression and distribution of tight junction-related proteins in glioma endothelial cells (GECs), paralleled by protein kinase Cε (PKCε) reduction. Moreover, luciferase reporter gene analysis shows that PKCε is the target gene of miR-34a. We also show that cotransfection of miR-34a and PKCε inversely coregulates BTB permeability and protein expression levels of tight junction-related proteins. Pretreatment of ψεRACK, a PKCε-specific activator, decreases BTB permeability in miR-34a-overexpressed GECs and up-regulates expression levels of tight junction proteins. In contrast, pretreatment of εV1-2, a specific PKCε inhibitor, gives opposite results. Collectively, our findings indicate that miR-34a regulates BTB function by targeting PKCε; after phosphorylation, PKCε is activated and contributes to regulation of the expression of tight junction-related proteins, ultimately altering BTB permeability.
The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, although the precise underlying mechanisms remain unclear. Here, we report a protein kinase C-ɛ (PKCɛ)- and ATF2-mediated mechanism that facilitates resistance by transcriptionally repressing the expression of interferon-β1 (IFNβ1) and downstream type-I IFN signaling that is otherwise induced upon exposure to chemotherapy. Treatment of early-stage melanomas expressing low levels of PKCɛ with chemotherapies relieves ATF2-mediated transcriptional repression of IFNβ1, resulting in impaired S-phase progression, a senescence-like phenotype and increased cell death. This response is lost in late-stage metastatic melanomas expressing high levels of PKCɛ. Notably, nuclear ATF2 and low expression of IFNβ1 in melanoma tumor samples correlates with poor patient responsiveness to biochemotherapy or neoadjuvant IFN-α2a. Conversely, cytosolic ATF2 and induction of IFNβ1 coincides with therapeutic responsiveness. Collectively, we identify an IFNβ1-dependent, cell-autonomous mechanism that contributes to the therapeutic resistance of melanoma via the PKCɛ-ATF2 regulatory axis.
Exit from mitosis is controlled by silencing of the spindle assembly checkpoint (SAC). It is important that preceding exit, all sister chromatid pairs are correctly bioriented, and that residual catenation is resolved, permitting complete sister chromatid separation in the ensuing anaphase. Here we determine that the metaphase response to catenation in mammalian cells operates through PKCε. The PKCε-controlled pathway regulates exit from the SAC only when mitotic cells are challenged by retained catenation and this delayed exit is characterized by BubR1-high and Mad2-low kinetochores. In addition, we show that this pathway is necessary to facilitate resolution of retained catenanes in mitosis. When delayed by catenation in mitosis, inhibition of PKCε results in premature entry into anaphase with PICH-positive strands and chromosome bridging. These findings demonstrate the importance of PKCε-mediated regulation in protection from loss of chromosome integrity in cells failing to resolve catenation in G2.
Monoclonal antibodies (mAb) can modulate cancer cell signal transduction and recruit antitumor immune effector mechanisms-including antibody-dependent cellular cytotoxicity (ADCC). Although several clinically effective antibodies can promote ADCC, therapeutic resistance is common. We hypothesized that oncogenic signaling networks within tumor cells affect their sensitivity to ADCC. We developed a screening platform and targeted 60 genes derived from an EGFR gene network using RNAi in an in vitro ADCC model system. Knockdown of GRB7, PRKCE, and ABL1 enhanced ADCC by primary and secondary screens. ABL1 knockdown also reduced cell proliferation, independent of its ADCC enhancement effects. c-Abl overexpression decreased ADCC sensitivity and rescued the effects of ABL1 knockdown. Imatinib inhibition of c-Abl kinase activity also enhanced ADCC-phenocopying ABL1 knockdown-against several EGFR-expressing head-and-neck squamous cell carcinoma cell lines by ex vivo primary natural killer cells. Our findings suggest that combining c-Abl inhibition with ADCC-promoting antibodies, such as cetuximab, could translate into increased therapeutic efficacy of mAbs.
A proinflammatory cytokine IL-32 acts as an intracellular mediator. IL-32α interacts with many intracellular molecules, but there are no reports of interaction with a transcriptional repressor BCL6. In this study, we showed that PMA induces an interaction between IL-32α, PKCε, and BCL6, forming a trimer. To identify the mechanism of the interaction, we treated cells with various inhibitors. In HEK293 and THP-1 cell lines, treatment with a pan-PKC inhibitor, PKCε inhibitor, and PKCδ inhibitor decreased BCL6 and IL-32α protein expression. MAPK inhibitors and classical PKC inhibitor did not decrease PMA-induced BCL6 and IL-32α protein expression. Further, the pan-PKC inhibitor and PKCε inhibitor disrupted PMA-induced interaction between IL-32α and BCL6. These data demonstrate that the intracellular interaction between IL-32α and BCL6 is induced by PMA-activated PKCε. PMA induces post-translational modification of BCL6 by conjugation to SUMO-2, while IL-32α inhibits. PKCε inhibition eliminated PMA-induced SUMOylation of BCL6. Inhibition of BCL6 SUMOylation by IL-32α affected the cellular function and activity of the transcriptional repressor BCL6 in THP-1 cells. Thus, we showed that IL-32α is a negative regulator of the transcriptional repressor BCL6. IL-32α inhibits BCL6 SUMOylation by activating PKCε, resulting in the modulation of BCL6 target genes and cellular functions of BCL6.
Definitive radiotherapy improves locoregional control and survival in inoperable non-small cell lung cancer patients. However, radiation-induced toxicities (pneumonitis/esophagitis) are common dose-limiting inflammatory conditions. We therefore conducted a pathway-based analysis to identify inflammation-related single-nucleotide polymorphisms associated with radiation-induced pneumonitis or esophagitis. A total of 11,930 single-nucleotide polymorphisms were genotyped in 201 stage I-III non-small cell lung cancer patients treated with definitive radiotherapy. Validation was performed in an additional 220 non-small cell lung cancer cases. After validation, 19 single-nucleotide polymorphisms remained significant. A polygenic risk score was generated to summarize the effect from validated single-nucleotide polymorphisms. Significant improvements in discriminative ability were observed when the polygenic risk score was added into the clinical/epidemiological variable-based model. We then used 277 lymphoblastoid cell lines to assess radiation sensitivity and expression quantitative trait loci (eQTL) relationships of the identified single-nucleotide polymorphisms. Three genes (PRKCE, DDX58, and TNFSF7) were associated with radiation sensitivity. We concluded that inflammation-related genetic variants could contribute to the development of radiation-induced toxicities.
Overexpression of PKCϵ, a kinase associated with tumor aggressiveness and widely implicated in malignant transformation and metastasis, is a hallmark of multiple cancers, including mammary, prostate, and lung cancer. To characterize the mechanisms that control PKCϵ expression and its up-regulation in cancer, we cloned an ∼ 1.6-kb promoter segment of the human PKCϵ gene (PRKCE) that displays elevated transcriptional activity in cancer cells. A comprehensive deletional analysis established two regions rich in Sp1 and STAT1 sites located between -777 and -105 bp (region A) and -921 and -796 bp (region B), respectively, as responsible for the high transcriptional activity observed in cancer cells. A more detailed mutagenesis analysis followed by EMSA and ChIP identified Sp1 sites in positions -668/-659 and -269/-247 as well as STAT1 sites in positions -880/-869 and -793/-782 as the elements responsible for elevated promoter activity in breast cancer cells relative to normal mammary epithelial cells. RNAi silencing of Sp1 and STAT1 in breast cancer cells reduced PKCϵ mRNA and protein expression, as well as PRKCE promoter activity. Moreover, a strong correlation was found between PKCϵ and phospho-Ser-727 (active) STAT1 levels in breast cancer cells. Our results may have significant implications for the development of approaches to target PKCϵ and its effectors in cancer therapeutics.
Zhang X, Li D, Li M, et al.MicroRNA-146a targets PRKCE to modulate papillary thyroid tumor development.
Int J Cancer. 2014; 134(2):257-67 [PubMed
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MicroRNAs are single-stranded noncoding RNAs composed of approximately 22 nucleotides that suppress gene expression by selectively binding via base-pairing to the complementary 3'-untranslated region (3'-UTR) of messenger RNA transcripts. Protein kinase C epsilon (PKCε) is an important modulating member of the transducing Ras/Raf-1 signal pathway; a computational search revealed miR-146a putatively binds to the 3'-UTR of the PRKCE gene, and thus decreasing PKCε expression. Moreover, PKCε inhibits mitochondrial apoptosis and is associated with the Bcl family. However, it has been previously reported that miR-146a expression in papillary thyroid carcinoma (PTC) is slightly elevated. Thus, we hypothesized that because miR-146a expression depends on nuclear factor kappaB (NF-κB) activation and NF-κB expression is elevated in PTC, miR-146a is potentially upregulated in PTC via negative feedback of NF-κB, and thus suppressing PKCε expression. In our study, we investigated whether overexpression of miR-146a, a tumor-suppressing-miR, in PTC cells decreases cell survival and induces apoptosis. Luciferase reporter assay analysis confirmed the direct binding of miR-146a and PRKCE 3'-UTR. Specific overexpression of exogenous miR-146a significantly decreased PKCε levels in PTC cell line NPA-187 and increased apoptosis. Additionally, using stably expressing miR-146a thyroid carcinoma cells to establish subcutaneous tumors, the tumor growth exhibited significant inhibition. Our study confirmed the tumor-suppressing role of miR-146a in thyroid carcinoma cells and contributes to the knowledge regarding modulation of Ras/Raf-1 signal transduction and apoptosis via PKCε targeted by miR-146a in PTC; moreover, our findings confirmed that miR-146a is involved in the feedback system of the classical NF-κB signal pathway in PTC.
MicroRNAs post-transcriptionally regulate gene expression and thereby contribute to the modulation of numerous complex and disease-relevant cellular phenotypes, including cell proliferation, cell motility, apoptosis, and stress response. In breast cancer cell systems, miR-31 has been shown to inhibit cell migration, invasion, and metastasis. Here, we link enhanced expression of miR-31 to the inhibition of the oncogenic NF-κB pathway, thus supporting the tumor-suppressive function of this microRNA. We identified protein kinase C epsilon (PKCε encoded by the PRKCE gene) as a novel direct target of miR-31 and show that down-regulation of PKCε results in impaired NF-κB signaling, enhanced apoptosis, and increased sensitivity of MCF10A breast epithelial and MDA-MB-231 triple-negative breast cancer cells toward ionizing radiation as well as treatment with chemotherapeutics. Mechanistically, we attribute this sensitization to anti-cancer treatments to the PRKCE-mediated down-regulation of the anti-apoptotic factor BCL2. In clinical breast cancer samples, high BCL2 expression was associated with poor prognosis. Furthermore, we found an inverse correlation between miR-31 and BCL2 expression, highlighting the functional relevance of the indirect down-regulation of BCL2 via direct targeting of PRKCE by miR-31.
Many types of human tumor cells have overexpressed pyruvate kinase M2 (PKM2). However, the mechanism underlying this increased PKM2 expression remains to be defined. We demonstrate here that EGFR activation induces PLCγ1-dependent PKCε monoubiquitylation at Lys321 mediated by RINCK1 ubiquitin ligase. Monoubiquitylated PKCε interacts with a ubiquitin-binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKCε phosphorylates IKKβ at Ser177 and activates IKKβ. Activated RelA interacts with HIF1α, which is required for RelA to bind the PKM promoter. PKCε- and NF-κB-dependent PKM2 upregulation is required for EGFR-promoted glycolysis and tumorigenesis. In addition, PKM2 expression correlates with EGFR and IKKβ activity in human glioblastoma specimens and with grade of glioma malignancy. These findings highlight the distinct regulation of NF-κB by EGF, in contrast to TNF-α, and the importance of the metabolic cooperation between the EGFR and NF-κB pathways in PKM2 upregulation and tumorigenesis.
BACKGROUND: MicroRNAs can play an important role in tumorigenesis through post-transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma.
DESIGN AND METHODS: MicroRNA profiles of enriched follicular lymphoma tumor cells from 16 patients were generated by assaying 851 human microRNAs. Tandem gene expression profiles were obtained for predicting microRNA targets.
RESULTS: The expression of 133 microRNAs was significantly different (> 2-fold; P<0.05) between follicular lymphoma and follicular hyperplasia. Forty-four microRNAs in three groups generated a unique follicular lymphoma signature. Of these, ten microRNAs were increased (miR-193a-5p, -193b*, -345, -513b, -574-3p, -584, -663, -1287, -1295, and -1471), 11 microRNAs were decreased (miR-17*, -30a, -33a, -106a*, -141, -202, -205, -222, -301b, -431*, and -570), and 23 microRNAs formed a group that was increased in most cases of follicular lymphoma but showed lower expression in a subset of cases (let-7a, let-7f, miR-7-1*, -9, -9*, -20a, -20b, -30b, -96, -98, -194, -195, -221*, -374a, -374b, -451, -454, -502-3p, -532-3p, -664*, -1274a, -1274b, and -1260). Higher expression of this last group was associated with improved response to chemotherapy. Gene expression analysis revealed increased expression of MAPK1, AKT1, PRKCE, IL4R and DROSHA and decreased expression of CDKN1A/p21, SOCS2, CHEK1, RAD51, KLF4, BLIMP1 and IRF4 in follicular lymphoma. Functional studies indicated that CDKN1A/p21 and SOCS2 expression is directly regulated by miR-20a/-20b and miR-194, respectively.
CONCLUSIONS: Follicular lymphoma is characterized by a unique microRNA signature, containing a subset of microRNAs whose expression correlate with response to chemotherapy. miR-20a/b and miR-194 target CDKN1A and SOCS2 in follicular lymphoma, potentially contributing to tumor cell proliferation and survival.
Kinases play key roles in cell signaling and represent major targets for drug development, but the regulation of their activation and their associations with health and disease have not been systematically analyzed. Here, we carried out a bioinformatic analysis of the expression levels of 459 human kinase genes in 5681 samples consisting of 44 healthy and 55 malignant human tissues. Defining the tissues where the kinase genes were transcriptionally active led to a functional genomic taxonomy of the kinome and a classification of human tissues and disease types based on the similarity of their kinome gene expression. The co-expression network around each of the kinase genes was defined in order to determine the functional context, i.e. the biological processes that were active in the cells and tissues where the kinase gene was expressed. Strong associations for individual kinases were found for mitosis (69 genes, including AURKA and BUB1), cell cycle control (73 genes, including PLK1 and AURKB), DNA repair (49 genes, including CHEK1 and ATR), immune response (72 genes, including MATK), neuronal (131 genes, including PRKCE) and muscular (72 genes, including MYLK2) functions. We then analyzed which kinase genes gain or lose transcriptional activity in the development of prostate and lung cancers and elucidated the functional associations of individual cancer associated kinase genes. In summary, we report here a systematic classification of kinases based on the bioinformatic analysis of their expression in human tissues and diseases, as well as grouping of tissues and tumor types according to the similarity of their kinome transcription.
Peng Y, Hu Y, Feng N, et al.L-3-n-butyl-phthalide alleviates hydrogen peroxide-induced apoptosis by PKC pathway in human neuroblastoma SK-N-SH cells.
Naunyn Schmiedebergs Arch Pharmacol. 2011; 383(1):91-9 [PubMed
] Related Publications
Alzheimer's disease (AD) is the most common form of dementia. Oxidative stress is one of the earliest events in the neurological and pathological changes of AD. L-3-n-butyl-phthalide (L-NBP), an anti-cerebral ischemia agent, has been shown a potential in AD treatment. In this study, we investigated the neuroprotective effect of L-NBP on hydrogen peroxide (H₂O₂)-induced apoptosis in human neuroblastoma SK-N-SH cells. H₂O₂ significantly reduced cell viability and increased the number of apoptotic-like cells, indicating that H₂O₂ induced neurotoxicity. In addition, real-time PCR and western blot studies showed that Bcl-2 and Bcl-w expressions were decreased, and Bax expression was increased with H₂O₂ treatment. Moreover, protein kinase C (PKC) α expression was down-regulated after H₂O₂ treatment. All of these phenotypes induced by H₂O₂ were markedly reversed by L-NBP. Pretreatment with L-NBP significantly increased cell viability of H₂O₂-damaged cells, and reduced H₂O₂-induced neuronal apoptosis. L-NBP treatment at dose of 10 μM inhibited H₂O₂-induced down-regulation of Bcl-2, Bcl-w, and PKCα but also attenuated the overexpression of Bax. PKC inhibitor, calphostin C, significantly attenuated the protective effects of L-NBP. Our findings suggest that L-NBP may protect neurons against H₂O₂-induced apoptosis by modulating apoptosis-related genes and activating PKCα pathway.
Gromova P, Ralea S, Lefort A, et al.Kit K641E oncogene up-regulates Sprouty homolog 4 and trophoblast glycoprotein in interstitial cells of Cajal in a murine model of gastrointestinal stromal tumours.
J Cell Mol Med. 2009; 13(8A):1536-48 [PubMed
] Free Access to Full Article Related Publications
Gastrointestinal stromal tumours (GIST) are thought to derive from the interstitial cells of Cajal (ICC) or an ICC precursor. Oncogenic mutations of the receptor tyrosine kinase KIT are present in most GIST. KIT K642E was originally identified in sporadic GIST and later found in the germ line of a familial GIST cohort. A mouse model harbouring a germline Kit K641E mutant was created to model familial GIST. The expression profile was investigated in the gastric antrum of the Kit(K641E) murine GIST model by microarray, quantitative PCR and immunofluorescence. Gja1/Cx43, Gpc6, Gpr133, Pacrg, Pde3a, Prkar2b, Prkcq/Pkce, Rasd2, Spry4 and Tpbg/5T4 were found to be up-regulated. The proteins encoded by Gja1/Cx43, Pde3a, Prkcq/Pkce were localized in Kit-ir ICC in wild-type and Kit(K641E) animals while Spry4 and Tpbg/5T4 were detected in Kit-ir cells only in Kit(K641E), but not in Kit(WT/WT) animals. Most up-regulated genes in this mouse model belong to the gene expression profile of human GIST but also to the profile of normal Kit(+) ICC in the mouse small intestine. Spry4 and Tpbg/5T4 may represent candidates for targeted therapeutic approaches in GIST with oncogenic KIT mutations.
Hakimuddin F, Tiwari K, Paliyath G, Meckling KGrape and wine polyphenols down-regulate the expression of signal transduction genes and inhibit the growth of estrogen receptor-negative MDA-MB231 tumors in nu/nu mouse xenografts.
Nutr Res. 2008; 28(10):702-13 [PubMed
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The antitumor properties of the Merlot grape (and Merlot wine) polyphenols were evaluated in relation to their ability to modulate gene expression in developing tumors using an athymic nude mouse model transplanted with the estrogen receptor-negative MDA-MB231 cells. Groups of mice were fed a modified AIN 93G diet (Research Diets Inc, New Brunswick, NJ) with the experimental groups receiving 100 mg/kg body weight equivalent of polyphenols by gavage 3 times per week. After 1 week of acclimation and another week of polyphenol supplementation, MDA-MB231 cells were transplanted and the growth patterns of the tumors monitored. After 33 days of tumor growth, the animals were euthanized, the tumors isolated, and gene expression profiles analyzed using signal transduction and cell cycle arrays. The development of tumors was almost totally arrested in grape polyphenol-treated mice. Total polyphenols isolated from the wine were more effective in reducing tumor growth as compared with a hydrophobic polyphenol fraction isolated from the wine, showing a 50% and 60% reduction in tumor growth on day 33, respectively. Analysis of gene expression showed that genes such as CDK2, FAS, LEF1, PRKCE, and PTGS2, belonging to the NFkappaB, phospholipase C, and calcium signaling pathways, were down-regulated in tumors that developed in grape polyphenol-treated mice. Several genes related to cell cycle regulation, such as CDK5RAP1, RBBP8, and SERTAD1, were up-regulated in these tumors. Changes in the expression of these genes were less pronounced in tumors of wine polyphenol-treated mice. The study highlights the potential influences of dietary polyphenolic components on gene expression in estrogen receptor-negative tumors and its relation to inhibition of tumor growth.
Rahmatpanah FB, Carstens S, Guo J, et al.Differential DNA methylation patterns of small B-cell lymphoma subclasses with different clinical behavior.
Leukemia. 2006; 20(10):1855-62 [PubMed
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Non-Hodgkin's lymphoma (NHL) is a group of malignancies of the immune system with variable clinical behaviors and diverse molecular features. Despite the progress made in classification of NHLs based on classical methods, molecular classifications are a work in progress. Toward this goal, we used an array-based technique called differential methylation hybridization (DMH) to study small B-cell lymphoma (SBCL) subtypes. A total of 43 genomic DMH experiments were performed. From these results, several statistical methods were used to generate a set of differentially methylated genes for further validation. Methylation of LHX2, POU3F3, HOXC10, NRP2, PRKCE, RAMP, MLLT2, NKX6.1, LRP1B and ARF4 was validated in cell lines and patient samples and demonstrated subtype-related preferential methylation patterns. For LHX2 and LRP1B, bisulfite sequencing, real-time reverse transcriptase-polymerase chain reaction and induction of gene expression following treatment with the demethylating agent, 5'-aza-2'-deoxycytidine, were confirmed. This new epigenetic information is helping to define molecular portraits of distinct subtypes of SBCL that are not recognized by current classification systems and provides valuable potential insights into the biology of these tumors.
Saito M, Hori M, Obara Y, et al.Neurotrophic factor production in human astrocytoma cells by 2,5,6-tribromogramine via activation of epsilon isoform of protein kinase C.
Eur J Pharm Sci. 2006; 28(4):263-71 [PubMed
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It is known that astrocytes secrete several neurotrophic factors to promote the survival of neurons. For the treatment of neuronal disorders, low molecular weight compounds inducing neurotrophic factor synthesis are useful, because neurotrophic factors are polypeptides which cannot cross the blood brain barrier. When rat pheochromocytoma (PC-12) cells were cultivated in the medium of human astrocytoma cells (1321N1) treated with 2,5,6-tribromogramine, they differentiated to neuron-like cells possessing neurites, indicating that 2,5,6-tribromogramine released neurotrophic factors from 1321N1 cells. In fact, 2,5,6-tribromogramine increased nerve growth factor (NGF) protein synthesis and secretion through mRNA expression. 2,5,6-Tribromogramine inhibited carbachol-induced phosphoinositide hydrolysis as well as phorbol 12,13-myristate acetate did. The inhibition was recovered by bisindolylmaleimide I (GF109203X), a specific protein kinase C (PKC) inhibitor, indicating that 2,5,6-tribromogramine may activate PKC. The morphological differentiation of PC-12 cells by the medium treated with 2,5,6-tribromogramine was also reduced by GF109203X. 2,5,6-Tribromogramine translocated PKC-epsilon but not PKC-alpha or PKC-zeta, to membrane fraction from cytosol fraction. These results indicate that 2,5,6-tribromogramine promotes the synthesis and secretion of neurotrophic factors including NGF in 1321N1 cells via an activation of PKC-epsilon.
In this study, we examined the role of protein kinase C (PKC)-epsilon in the apoptosis and survival of glioma cells using tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-stimulated cells and silencing of PKCepsilon expression. Treatment of glioma cells with TRAIL induced activation, caspase-dependent cleavage, and down-regulation of PKCepsilon within 3 to 5 hours of treatment. Overexpression of PKCepsilon inhibited the apoptosis induced by TRAIL, acting downstream of caspase 8 and upstream of Bid cleavage and cytochrome c release from the mitochondria. A caspase-resistant PKCepsilon mutant (D383A) was more protective than PKCepsilon, suggesting that both the cleavage of PKCepsilon and its down-regulation contributed to the apoptotic effect of TRAIL. To further study the role of PKCepsilon in glioma cell apoptosis, we employed short interfering RNAs directed against the mRNA of PKCepsilon and found that silencing of PKCepsilon expression induced apoptosis of various glioma cell lines and primary glioma cultures. To delineate the molecular mechanisms involved in the apoptosis induced by silencing of PKCepsilon, we examined the expression and phosphorylation of various apoptosis-related proteins. We found that knockdown of PKCepsilon did not affect the expression of Bcl2 and Bax or the phosphorylation and expression of Erk1/2, c-Jun-NH2-kinase, p38, or STAT, whereas it selectively reduced the expression of AKT. Similarly, TRAIL reduced the expression of AKT in glioma cells and this decrease was abolished in cells overexpressing PKCepsilon. Our results suggest that the cleavage of PKCepsilon and its down-regulation play important roles in the apoptotic effect of TRAIL. Moreover, PKCepsilon regulates AKT expression and is essential for the survival of glioma cells.
Gillespie S, Zhang XD, Hersey PVariable expression of protein kinase C epsilon in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis.
Mol Cancer Ther. 2005; 4(4):668-76 [PubMed
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Protein kinase C (PKC) activation is believed to protect against apoptosis induced by death receptors. We have found however that the effect of activation of PKC on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma differs between cell lines. Pretreatment with phorbol 12-myristate 13-acetate (PMA) led to inhibition of apoptosis in the majority of the melanoma cell lines, but those with relatively low PKC epsilon expression were sensitized to TRAIL-induced apoptosis. Introduction of PKC epsilon into PKC epsilon-low cell lines reversed sensitization of the cells to TRAIL-induced apoptosis by PMA. In contrast, a dominant-negative form of PKC epsilon caused an increase in sensitivity. The changes in sensitivity to TRAIL-induced apoptosis were reflected in similar changes in conformation of Bax and its relocation from the cytosol to mitochondria. Similarly, there were concordant increases or decreases in mitochondrial release of second mitochondria-derived activator of caspase/DIABLO, activation of caspase-3, and processing of its substrates. Activation of PKC seemed to mediate its effects upstream of mitochondria but downstream of caspase-8 and Bid in that pretreatment with PMA did not cause significant changes in the expression levels of TRAIL death receptors, alterations in the levels of caspase-8 activation, or cleavage of Bid. PKC activated the anti-apoptotic extracellular signal-regulated kinase 1/2 pathway, but inhibitors of this pathway only partially reversed the protective effect of PKC against TRAIL-induced apoptosis. These results provide further insights into the variable responses of melanoma to TRAIL-induced apoptosis and may help define responsive phenotypes to treatment of melanoma with TRAIL.
Gillespie SK, Zhang XD, Hersey PIngenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells.
Mol Cancer Ther. 2004; 3(12):1651-8 [PubMed
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Ingenol 3-angelate (PEP005), one of the active ingredients in an extract from Euphorbia peplus, was shown in preclinical studies to have activity against human melanoma xenografts in nude mice. In the present study, we have tested its ability to induce the apoptosis of melanoma cells in vitro in the absence or presence of tumor necrosis factor-related apoptosis inducing ligand (TRAIL). The results showed that at relatively high concentrations (100 microg/mL), PEP005 killed melanoma cells mainly by induction of necrosis. In 20% of cell lines, evidence of apoptosis was observed. Apoptosis was caspase-dependent and associated with changes in mitochondrial membrane potential that were not inhibitable by overexpression of Bcl-2 or inhibition of caspases but were blocked by inhibition of protein kinase C (PKC). Low concentrations (1 or 10 microg/mL) of PEP005 either increased or decreased TRAIL-induced apoptosis in a cell line-dependent manner. These changes in TRAIL-induced apoptosis seemed to be due to activation of PKC and varying levels of PKC isoenzymes in different melanoma cell lines. PEP005-mediated enhancement of apoptosis seemed to be associated with low expression of the PKCepsilon isoform. These results indicate that PEP005 may enhance or inhibit sensitivity of melanoma to treatments associated with TRAIL-induced apoptosis depending on the PKC isoform content of melanoma cells.