Expression Of C-myc Proto-oncogene Research Articles

Discovery of indole-2-one derivatives as BRD4 (BD1) selective inhibitors

Bromodomain protein 4 (BRD4) is a member of the BET family, and its overexpression is closely associated with the development of many tumors. Inhibition of BRD4 shows great therapeutic potential in anti-tumor, and pan-BRD4 inhibitors show adverse effects of dose limiting toxicity and thrombocytopenia in clinical trials. To improve clinical effects and reduce side effects, more efforts have focused on seeking selective inhibitors of BD1 or BD2. Herein, a series of indole-2-one derivatives were designed and synthesized through docking-guided optimization to find BRD4-BD1 selective inhibitors, and their BRD4 inhibitory and antiproliferation activities were evaluated. Among them, compound 21r had potent BRD4 inhibitory activity (the IC50 values of 41 nM and 313 nM in BD1 and BD2 domain), excellent anti-proliferation (the IC50 values of 4.64 ± 0.30 µM, 0.78 ± 0.03 µM, 5.57 ± 1.03 µM against HL-60, MV-4–11 and HT-29 cells), and displayed low toxicity against normal cell GES-1 cells. Further studies revealed that 21r inhibited proliferation by decreasing the expression of proto-oncogene c-Myc, blocking cell cycle in G0/G1 phase, and inducing apoptosis in MV-4–11 cells in a dose-dependent manner. All the results showed that compound 21r was a potent BRD4 inhibitor with BD1 selectivity, which had potential in treatment of leukemia.

Therapeutic potential of anti-PIK3CG treatment for multiple myeloma via inhibiting c-Myc pathway

Multiple myeloma (MM) is a malignant plasma cell disease. The activity of PIK3CG (PI3K catalytic subunit γ) is regulated directly by G-protein-coupled receptor and has been confirmed to be highly expressed in MM cells. This study aimed to determine the effect of pharmacological inhibition of PIK3CG on MM. We found that different concentrations of the PIK3CG inhibitor AS-605240 could suppress the growth of MM cell lines and the expression of c-Myc. The combination of PIK3CG inhibitor and the chemotherapy Melphalan could effectively inhibit the proliferation and migration of MM cells, promote the cell apoptosis, and decrease the ratio of Bcl-2/Bax and the expression of vimentin. The expression of proto-oncogene c-Myc was decreased and the sensitivity of cells to chemotherapeutic drugs was enhanced. Collectively, PIK3CG regulates growth of MM via c-Myc pathway, thus emerging as a promising molecular targeted therapy.

Estrogens drive the endoplasmic reticulum-associated degradation and promote proto-oncogene c-Myc expression in prostate cancer cellsby androgen receptor/estrogen receptor signaling.

The tumorigenic properties of prostate cancer are regulated by advanced hormonal regulation-mediated complex molecular signals. Therefore, characterizing the regulation of these signal transduction systems is crucial for understanding prostate cancer biology. Recent studies have shown that endoplasmic reticulum (ER)-localized protein quality control mechanisms, including ER-associated degradation (ERAD) andunfolded protein response (UPR) signaling contribute to prostate carcinogenesis and to the development of drug resistance. It has also been determined that these systems are tightly regulated by androgens. However, the role of estrogenic signaling in prostate cancer and its effects on protein quality control mechanisms is not fully understood. Herein, we investigated the regulatory effects of estrogens on ERAD and UPR and their impacts on prostate carcinogenesis. We found that estrogens strongly regulated the ERAD components and IRE1⍺ branch of UPR by Er⍺/β/ARaxis. Besides,estrogenic signaling rigorously regulatedthe tumorigenicity of prostate cancer cells by promoting c-Myc expression and epithelial-mesenchymal transition (EMT). Moreover, estrogenic signal blockage significantly decreased the tumorigenic features of prostate cancer cells. Additionally, simultaneous inhibition of androgenic/estrogenic signals more efficiently inhibited tumorigenicity of prostate cancer cells, including proliferation, migration, invasion and colonial growth. Furthermore, computational-based molecular docking, molecular dynamics simulations and MMPBSA calculations supported the estrogenic stimulation of AR. Present findings suggested that ERAD components and IRE1⍺ signaling are tightlyregulated by estrogen-stimulated AR and Er⍺/β. Our data suggest that treatment approaches targeting the co-inhibition of androgenic/estrogenic signals may pave the way for new treatment approaches to be developed for prostate cancer. The present model of the impact of estrogens on ERAD and UPR signaling in androgen-sensitive prostate cancer cells.

A20 Enhances the Expression of the Proto-Oncogene C-Myc by Downregulating TRAF6 Ubiquitination after ALV-A Infection.

Hens infected with avian leukosis virus subgroup A (ALV-A) experience stunted growth, immunosuppression, and potentially, lymphoma development. According to past research, A20 can both promote and inhibit tumor growth. In this study, DF-1 cells were infected with ALV-A rHB2015012, and Gp85 expression was measured at various time points. A recombinant plasmid encoding the chicken A20 gene and short hairpin RNA targeting chicken A20 (A20-shRNA) was constructed and transfected into DF-1 cells to determine the effect on ALV-A replication. The potential signaling pathways of A20 were explored using bioinformatics prediction, co-immunoprecipitation, and other techniques. The results demonstrate that A20 and ALV-A promoted each other after ALV-A infection of DF-1 cells, upregulated A20, inhibited TRAF6 ubiquitination, and promoted STAT3 phosphorylation. The phosphorylated-STAT3 (p-STAT3) promoted the expression of proto-oncogene c-myc, which may lead to tumorigenesis. This study will help to further understand the tumorigenic process of ALV-A and provide a reference for preventing and controlling ALV.

Expression of proto-oncogene c-Myc in patients with urinary bladder transitional cell carcinoma

Background:c-Myc is a proto-oncogene located on human chromosome 8. It encodes a transcriptional factor which regulates the expression of approximately 10% to 15% of human genes, playing a crucial role in cell growth, differentiation, cellular metabolism, apoptosis, and cell transformation. The aim of this study is to correlate the expression of c-Myc in patients suffering from urinary bladder transitional cell carcinoma with tumor grade, stage, and lymph node metastases.Materials and methods:Formalin-fixed, paraffin-embedded tissue samples were obtained from 54 consecutive patients who underwent transurethral resection of bladder tumor or radical cystectomy (RC) as treatment for urinary bladder transitional cell carcinoma. Immunohistochemistry was performed using c-Myc monoclonal antibody and c-Myc expression was then analyzed for correlation with tumor stage, grade, and lymph node metastases.Results:From a total of 54 patients, 42 (77.8%) had c-Myc positive staining and 12 (22.2%) were c-Myc negative. In the c-Myc positive group, 28 patients (66.7%) had low grade tumors and 33 (78.6%) presented with non-muscle-invasive disease (p < 0.05). In the c-Myc negative group, 10 patients (83.3%) had high-grade disease and 8 (66.7%) presented with muscle-invasive disease (p < 0.05). Lymph node metastases were evaluated in 17 patients who underwent RC. Of these, 5 had lymph node metastases, 4 of whom had c-Myc negative staining (p < 0.05).Conclusions:In our study, c-Myc negative staining was associated with higher grade and higher stage disease. On the contrary, most c-Myc positive tumors were low grade and non-muscle-invasive disease. In patients who underwent RC, c-Myc negative staining was associated with lymph node metastases.

Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells

Cancer cells have an increased need for glucose and, despite aerobic conditions, obtain their energy through aerobic oxidation and lactate fermentation, instead of aerobic oxidation alone. Glutamine is an essential amino acid in the human body. Glutaminolysis and glycolysis are crucial for cancer cell survival. In the therapy of estrogen receptor α (ERα)-positive breast cancer (BC), the focus lies on hormone sensitivity targeting therapy with selective estrogen receptor modulators (SERMs) such as 4-hydroxytamoxifen (4-OHT), although this therapy is partially limited by the development of resistance. Therefore, further targets for therapy improvement of ERα-positive BC with secondary 4-OHT resistance are needed. Hence, increased glucose requirement and upregulated glutaminolysis in BC cells could be used. We have established sublines of ERα-positive MCF7 and T47D BC cells, which were developed to be resistant to 4-OHT. Further, glycolysis inhibitor 2-Deoxy-D-Glucose (2-DG) and glutaminase inhibitor CB-839 were analyzed. Co-treatments using 4-OHT and CB-839, 2-DG and CB-839, or 4-OHT, 2-DG and CB-839, respectively, showed significantly stronger inhibitory effects on viability compared to single treatments. It could be shown that tamoxifen-resistant BC cell lines, compared to the non-resistant cell lines, exhibited a stronger reducing effect on cell viability under co-treatments. In addition, the tamoxifen-resistant BC cell lines showed increased expression of proto-oncogene c-Myc compared to the parental cell lines. This could be reduced depending on the treatment. Suppression of c-Myc expression using specific siRNA completely abolished resistance to 4OH-tamoxifen. In summary, our data suggest that combined treatments affecting the metabolism of BC are suitable depending on the cellularity and resistance status. In addition, the anti-metabolic treatments affected the expression of the proto-oncogene c-Myc, a key player in the regulation of cancer cell metabolism.

Hinge like domain motion facilitates human RBMS1 protein binding to proto-oncogene c-myc promoter.

DNA binding proteins recognize DNA specifically or non-specifically using direct and indirect readout mechanisms like sliding, hopping, and diffusion. However, a common difficulty in explicitly elucidating any particular mechanism of site-specific DNA-protein recognition is the lack of knowledge regarding target sequences and inadequate account of non-specific interactions, in general. Here, we decipher the structural basis of target search performed by the key regulator of expression of c-myc proto-oncogene, the human RBMS1 protein. In this study, we have shown the structural reorganization of this multi-domain protein required for recognizing the specific c-myc promoter sequence. The results suggest that a synergy between structural re-organization and thermodynamics is necessary for the recognition of target sequences. The study presents another perspective of looking at the DNA-protein interactions.

Role of aryl hydrocarbon receptor in central nervous system tumors: Biological and therapeutic implications.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, whose canonical pathway mainly regulates the genes involved in xenobiotic metabolism. However, it can also regulate several responses in a non-canonical manner, such as proliferation, differentiation, cell death and cell adhesion. AhR plays an important role in central nervous system tumors, as it can regulate several cellular responses via different pathways. The polymorphisms of the AHR gene have been associated with the development of gliomas. In addition, the metabolism of tumor cells promotes tumor growth, particularly in tryptophan synthesis, where some metabolites, such as kynurenine, can activate the AhR pathway, triggering cell proliferation in astrocytomas, medulloblastomas and glioblastomas. Furthermore, as part of the changes in neuroblastomas, AHR is able to downregulate the expression of proto-oncogene c-Myc, induce differentiation in tumor cells, and cause cell cycle arrest and apoptosis. Collectively, these data suggested that the modulation of the AhR pathway may downregulate tumor growth, providing a novel strategy for applications for the treatment of certain tumors through the control of the AhR pathway.

The Shuganhuazheng Formula in Triple-Negative Breast Cancer: A Study Based on Network Pharmacology and In Vivo Experiments

Breast cancer is the most common cancer in women. Among breast cancer subtypes, triple-negative breast cancer (TNBC) has the highest degree of malignancy and the worst prognosis. The Shuganhuazheng formula (SGHZF) is a traditional Chinese herbal formula for the treatment of TNBC, but the mechanism of SGHZF in the treatment of TNBC remains unclear. In this study, the therapeutic effect and mechanism of SGHZF against TNBC were preliminarily determined based on in vivo experimental verification and network pharmacology. In terms of therapeutic effects, the antitumour effect was verified by measuring and calculating tumour volume, and the expression of proto-oncogene c-Myc was verified by PCR. In terms of the mechanism, potential therapeutic targets were identified by overlapping the SGHZF-related and TNBC-related targets. After comprehensively analysing the results of the protein-protein interaction (PPI), gene ontology (GO) function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, Akt and HIF-1α were selected for verification by using immunohistochemical and Western blot analyses. The results of the study indicated that SGHZF can inhibit breast tumour growth in mice and that the mechanism may be related to the inhibition of Akt and HIF-1α expression.

Expansion and Activation of Human Natural Killer Cells ex vivo in the Presence of Transgenic Feeder Cells

Preliminary results of clinical trials show that the use of activated and expanded ex vivo natural killer cells is a promising tool for adoptive immunotherapy of acute myeloid leukemia, as well as a number of solid tumors, when used together with targeted monoclonal antibodies. However, the introduction of this approach into clinical practice is limited by the possibility of obtaining a sufficient amount of the NK cell product with required characteristics. To solve this problem, we obtained transgenic feeder cells based on immortalized K562 cells expressing the recombinant membrane-bound variant of human interleukin-21 and 4-1BBL protein. Cocultivation of mononuclear cells obtained from the peripheral blood of ten healthy donors with genetically modified feeder cells resulted in significant expansion of natural killer cells (median expansion fold 21 589 times; minimum, 3150 times; maximum, 304 328 times) with a minimum content of T-cells (median, 0.5%; minimum, 0.06%; maximum, 4.7%) compared with their initial number. NK cells obtained in this way were not contaminated with the BCR–ABL1 oncogene from feeder cells and had a lower expression of c-MYC protooncogene compared to the initial level.

A Positive Feedback Loop Between c-Myc Upregulation, Glycolytic Shift, and Histone Acetylation Enhances Cancer Stem Cell-like Property and Tumorigenicity of Cr(VI)-transformed Cells.

Chronic hexavalent chromium [Cr(VI)] exposure causes lung cancer and other types of cancer; however, the mechanism of Cr(VI) carcinogenesis remains to be clearly defined. Our recent study showed that chronic Cr(VI) exposure upregulates the proto oncogene c-Myc expression, which contributes significantly to Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property and tumorigenesis. c-Myc is a master regulator of cancer cell abnormal metabolism and accumulating evidence suggests that metabolism dysregulation plays an important role in both cancer development and progression. However, little is known about the role of metabolism dysregulation in Cr(VI) carcinogenesis. This study was performed to investigate the potential role and mechanism of metabolism dysregulation in Cr(VI) carcinogenesis. It was found that Cr(VI)-transformed cells display glycolytic shift, which depends on the upregulation of c-Myc. The glycolytic shift in Cr(VI)-transformed cells led to increased production of acetyl coenzyme A (acetyl-CoA) and elevation of histone acetylation. This, in turn, upregulated the expression of an acetyl-CoA producing key enzyme ATP citrate lyase and c-Myc, forming a positive feedback loop between the upregulation of c-Myc expression, glycolytic shift and increased histone acetylation. It was further determined that glucose depletion not only reverses the glycolytic shift in Cr(VI)-transformed cells, but also significantly reduces their growth, CSC-like property and tumorigenicity. These findings indicate that glycolytic shift plays an important role in maintaining malignant phenotypes of Cr(VI)-transformed cells, suggesting that metabolism dysregulation is critically involved in Cr(VI) carcinogenesis.

SUMOylation down-regulates rDNA transcription by repressing expression of upstream-binding factor and proto-oncogene c-Myc

Ribosome biogenesis is critical for proliferating cells and requires the coordinated activities of three eukaryotic RNA polymerases. We recently showed that the small ubiquitin-like modifier (SUMO) system controls the global level of RNA polymerase II (Pol II)-controlled transcription in mammalian cells by regulating cyclin-dependent kinase 9 activity. Here, we present evidence that the SUMO system also plays a critical role in the control of Pol I transcription. Using an siRNA-based knockdown approach, we found that multiple SUMO E3 ligases of the PIAS (protein inhibitor of activated STAT) family are involved in SUMO-mediated repression of ribosomal DNA (rDNA) gene transcription. We demonstrate that endogenous SUMO represses rDNA transcription primarily by repressing upstream-binding factor and proto-oncogene c-Myc expression and that ectopic overexpression of SUMO-associated enzymes additionally represses rDNA transcription via c-Myc SUMOylation and its subsequent degradation. The results of our study reveal a critical role of SUMOylation in the control of rDNA transcription, uncover the underlying mechanisms involved, and indicate that the SUMO system coordinates Pol I- and Pol II-mediated transcription in mammalian cells.

BIOACTIVE COMPOUNDS OF RASAMALA (ALTINGIA EXCELSA NORNHA) LEAVES AS C-MYC PROTO ONCOGENE EXPRESSION SUPPRESSOR OF HUMAN TONGUE CANCER CELL IN VITRO

Background : Tongue cancer is a common neoplasm found in oral cavity. It is characterized by aggressive cell growth, poor prognosis and being the cause of mortality. Objectives : to discover bioactive compounds of Rasamala leaves which possess an activity to inhibit SP-C1 human tongue cancer cell proliferation by reducing the expression of c-Myc proto oncogene. Methods : This is an experimental laboratory study using SP-C1 human tongue cancer cell. Separation of bioactive compounds from Rasamala leaves ethyl acetate extract was using various chromatography techniques guided by antiproliferative assay. Results : Two compounds were produced consisting of kaempferol (1) and quercetin (2). Compound 1 and 2 were tested to assess antiproliferative activity of kaempferol and quercetin upon SP-C1tongue cancer cell. IC 50 values obtained from antiproliferative assay of each compound were 0.72 and 0.70 ug/ml respectively. Data analysis using ANCOVA test attained a significant value of α=0.05 and proceeded for probit analysis. The activity of compound 1 and 2 was tested on c-Myc proto oncogene and it was acquired that compound 1 and 2 can suppress c-myc proto oncogene expression. Conclusion : Rasamala compounds consist of kaempferol (1) and quercetin (2) which possess an activity as tongue cancer cell proliferation inhibitor by reducing c-myc proto oncogene expression.

PO-084 Ascorbic acid selectively targets glucose metabolism of osteosarcoma stem cells

IntroductionThere is increasing evidence that cancer stem cells (CSCs) could mediate resistance to chemo- and radiotherapy, metastasis and recurrence in a wide range of solid tumours. Notch signalling pathway is involved in CSCs maintenance. Notch influences intra- and intercellular communications of various cell types in embryogenesis and adult organs. The oncogenic role of Notch signalling in survival, proliferation, self-renewal, differentiation and migration of cancer cells is demonstrated in most solid tumours and leukaemia. This study aims to explore the effect of Notch1 suppression on CSCs in human lung (A549) and colorectal (HCT116) adenocarcinoma cell lines.Material and methodsKnockdown of Notch1 by shRNA was confirmed by PCR and western-blot analyses. PCR was used for estimation of stemness, epithelia-to-mesenchyma transition (EMT) markers and proto-oncogene c-MYC expression. The proportion of CD133+ cells in different subpopulations was identified by Flow cytometry. Cell migration potential was examined by Boyden chamber assay. The effect of Notch1 inhibition on CSCs was established using classical detection methods of CSCs in heterogeneous cancer cell cultures: tumourisphere formation, tumourigenicity in vivo and quantitative assessment of ABC-transporter activity assays.Results and discussionsNotch1 inhibition resulted in stemness (SOX2, OCT3/4, NES), EMT (TWIST1, HES1, SNAIL1), CSCs (CD133) markers, c-MYC expression decrease and CDH1 (E-cadherin) expression increase suggesting that Notch pathway is involved in EMT. Loss of Notch1 did not influence cell proliferation in vitro but reduced migration potential. It was confirmed that Notch signalling interruption leads to reduction of stemness features: decreased drug resistance (A549 but not HCT116), ability to form tumourispheres and tumourigenic potential in vivo. ABC-transporter activity in HCT116 could be upregulated by TAZ/YAP signalling pathway and not by Notch. Moreover, reduced Notch1 expression increased the minimum inoculum cell dose for xenograft formation. The xenograft vascularisation assay revealed that Notch1 inhibition is not necessary for neovascularizaton but it is essential for angiogenesis but in tumour.ConclusionThe Notch signalling pathway is important for maintaining the CSCs population, stemness and migration so Notch1 could be considered as a potential therapeutic target in lung and colorectal cancer. The study was supported Russian Science Foundation (RSCF), grant No. 14-15-00467.

PO-081 Notch signalling pathway plays a crucial role in maintaining the cancer stem cell population in lung and colorectal cancer

IntroductionThere is increasing evidence that cancer stem cells (CSCs) could mediate resistance to chemo- and radiotherapy, metastasis and recurrence in a wide range of solid tumours. Notch signalling pathway is involved in CSCs maintenance. Notch influences intra- and intercellular communications of various cell types in embryogenesis and adult organs. The oncogenic role of Notch signalling in survival, proliferation, self-renewal, differentiation and migration of cancer cells is demonstrated in most solid tumours and leukaemia. This study aims to explore the effect of Notch1 suppression on CSCs in human lung (A549) and colorectal (HCT116) adenocarcinoma cell lines.Material and methodsKnockdown of Notch1 by shRNA was confirmed by PCR and western-blot analyses. PCR was used for estimation of stemness, epithelia-to-mesenchyma transition (EMT) markers and proto-oncogene c-MYC expression. The proportion of CD133+ cells in different subpopulations was identified by Flow cytometry. Cell migration potential was examined by Boyden chamber assay. The effect of Notch1 inhibition on CSCs was established using classical detection methods of CSCs in heterogeneous cancer cell cultures: tumourisphere formation, tumourigenicity in vivo and quantitative assessment of ABC-transporter activity assays.Results and discussionsNotch1 inhibition resulted in stemness (SOX2, OCT3/4, NES), EMT (TWIST1, HES1, SNAIL1), CSCs (CD133) markers, c-MYC expression decrease and CDH1 (E-cadherin) expression increase suggesting that Notch pathway is involved in EMT. Loss of Notch1 did not influence cell proliferation in vitro but reduced migration potential. It was confirmed that Notch signalling interruption leads to reduction of stemness features: decreased drug resistance (A549 but not HCT116), ability to form tumourispheres and tumourigenic potential in vivo. ABC-transporter activity in HCT116 could be upregulated by TAZ/YAP signalling pathway and not by Notch. Moreover, reduced Notch1 expression increased the minimum inoculum cell dose for xenograft formation. The xenograft vascularisation assay revealed that Notch1 inhibition is not necessary for neovascularizaton but it is essential for angiogenesis but in tumour.ConclusionThe Notch signalling pathway is important for maintaining the CSCs population, stemness and migration so Notch1 could be considered as a potential therapeutic target in lung and colorectal cancer. The study was supported Russian Science Foundation (RSCF), grant No. 14-15-00467.

Abstract 5452: Pimozide suppresses the growth of brain tumor by targeting oncogenic pathways

Abstract Brain tumor is considered as one of the most aggressive and incurable form of cancer. Majority of the brain tumors have a median survival rate of only 12%. Even though advanced treatments such as surgical removal, chemotherapy and radiotherapy are available, brain tumor persists to be lethal. Obstacles associated with the current treatment options are: recurrence, development of resistance and inability to cross blood brain barrier (BBB). BBB restricts majority of drugs to reach the brain thus resulting in an ineffective treatment. Pimozide (PMZ) is an antipsychotic drug used for the treatment of schizophrenia and chronic psychosis. In this study, pimozide has shown significant reduction in the viability of U-87MG, U-251MG, DAOY and T98G cell lines with an IC50 ranging from 11µM to 20µM after 24 h of treatment. Pimozide induced apoptosis in these cell lines as evaluated by FITC/Annexin assay and further validated by the cleavage of caspase 3 as well as PARP by western blot analysis. Pimozide treatment resulted in the concentration dependent decrease in the expression of GLI1, OCT4, SOX2 and NANOG in U87MG, U251MG, DAOY and T98G brain cancer cell lines, depicting a reduction in the stem cell like property of these cell lines. In addition, pimozide treatment inhibited the expression of proto-oncogene c-Myc. Inhibition of Gli1 and c-Myc demonstrates that pimozide might also inhibit the growth of cancer cells by targeting SHH signaling. Our results further demonstrated that oral administration of pimozide (25mg/kg) inhibits the brain tumors in intracranial tumor model with no significant difference in average weight of critical organs. It is important to note that pimozide is an FDA approved drug with no considerable toxicity. Overall, this study depicts that pimizode is a potential candidate to target brain tumors. Citation Format: Itishree Kaushik, Alok Ranjan, Blake Schwettmann, Sanjay Srivastava. Pimozide suppresses the growth of brain tumor by targeting oncogenic pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5452.

PROSTATE AND BREAST CANCER

Background: CK2, a serine/threonine, protein kinase, targets over and above300 substrates including c-Myc. CK2 expression is elevated in human cancers includingbreast cancer and prostate cancer. c-Myc protooncogene expression is also up-regulated inthese cancers. Objectives: To evaluate the co expression and correlation of CK2 and c-Mycin prostate cancer as compared to their correlation in breast cancer. Study Design: Crosssectional analytical study. Setting: Army Medical College and AFIP, Duration: Two years.Methods: A retrospective study of immunohistochemical analysis, approved by Armed ForcesInstitute of Pathology Ethical Committee. Paraffin embedded tissues of diagnosed prostatecancer, 30 in number, 30 cases of Benign Prostatic Hypertrophy (BPH) and 30 cases of breastadenocarcinoma, were included in the study. We stained tissue sections for CK2 and c-Mycand measured staining intensity for each protein expression. Data analysis was done by SPSSversion 20. Pearson correlation coefficient was used for correlating the expression of bothproteins. P-value was calculated. Results: A strong correlation of CK2 with c-Myc was seen inprostate cancer tissue, in comparison to BPH. There was a very significant correlation presentbetween CK2 and c-Myc, especially in invasive cases of breast cancer. Conclusion: CK2 andc-Myc expressions are highly and significantly correlated in prostate cancer and breast cancerespecially in invasive cases. CK2 has influence over c-Myc and both can be used for forecastingthe cancer phenotype and aggression of disease.

A COMPARISON OF CK2 MODULATION OF C-MYC IN PROSTATE AND BREAST CANCER

Background: CK2, a serine/threonine, protein kinase, targets over and above300 substrates including c-Myc. CK2 expression is elevated in human cancers includingbreast cancer and prostate cancer. c-Myc protooncogene expression is also up-regulated inthese cancers. Objectives: To evaluate the co expression and correlation of CK2 and c-Mycin prostate cancer as compared to their correlation in breast cancer. Study Design: Crosssectional analytical study. Setting: Army Medical College and AFIP, Duration: Two years.Methods: A retrospective study of immunohistochemical analysis, approved by Armed ForcesInstitute of Pathology Ethical Committee. Paraffin embedded tissues of diagnosed prostatecancer, 30 in number, 30 cases of Benign Prostatic Hypertrophy (BPH) and 30 cases of breastadenocarcinoma, were included in the study. We stained tissue sections for CK2 and c-Mycand measured staining intensity for each protein expression. Data analysis was done by SPSSversion 20. Pearson correlation coefficient was used for correlating the expression of bothproteins. P-value was calculated. Results: A strong correlation of CK2 with c-Myc was seen inprostate cancer tissue, in comparison to BPH. There was a very significant correlation presentbetween CK2 and c-Myc, especially in invasive cases of breast cancer. Conclusion: CK2 andc-Myc expressions are highly and significantly correlated in prostate cancer and breast cancerespecially in invasive cases. CK2 has influence over c-Myc and both can be used for forecastingthe cancer phenotype and aggression of disease.

Alterations of oncogenes expression in NK cells in patients with cancer.

IntroductionC‐kit/SCF signaling plays a key role in regulating NK cell homeostasis, maturation, proliferation, and cytotoxicity. C‐kit‐deficiency in NK cells results in significant reduction of their number, suggesting an imperative role for c‐kit signaling in NK cell biology. We have recently showed that human NK cells express not only c‐kit‐receptor, but also both membrane‐bound and soluble forms of c‐kit ligand—Stem cell factor. The goal of this study was to characterize the c‐kit/SCF autocrine loop in peripheral blood NK cells obtained from patients with cancer.MethodsUsing Smart Flare and qRT‐PCR, we have characterized expression of c‐kit and two forms of SCF in patients’ NK cells and correlated these results with the expression of c‐myc and STAT3.ResultsOur results demonstrated that the expression of proto‐oncogenes c‐myc and c‐kit was significantly decreased in NK cells from all cancer patients. Expression of membrane‐bound SCF in NK cells correlated with the presence of remote metastases.ConclusionsWe suggest that the abnormal signaling and expression of c‐kit/SCF, c‐myc, and STAT3 in NK cells is responsible for the defect in their cytolytic activity in cancer and these defects at the gene expression level may be the cause rather than the result of tumor progression.

Isolation, characterization, and expression of proto-oncogene cMyc in large yellow croaker Larimichthys crocea.

cMyc is a vital transcription factor that involves in the regulation of cell proliferation, growth, differentiation, and apoptosis. In the present study, cMyc in Larimichthys crocea (Lc-cMyc) was cloned and analyzed for investigating its function. The full-length cDNA of Lc-cMyc was 2089bp encoding a 440-amino-acid protein (Lc-cMyc). Lc-cMyc had the characteristic helix-loop-helix-leucine-zipper (HLH-LZ) DNA-binding domain and highly conservative in evolution. The expression of Lc-cMyc was detected by quantitative real-time PCR (qRT-PCR) and in situ hybridization, respectively. In tissues, the gender differences of Lc-cMyc expression existed only in gonad and Lc-cMyc was extremely significantly expressed in ovary with the highest level in 635-dph ovary, especially in stages II (late) and III (early) oocytes. A certain degree of expression was examined in head kidney of both sexes and testis with high expression in spermatocyte. In embryos, Lc-cMyc was expressed at all embryonic stages. In early embryogenesis (from two-cell stage to mutiple-cell stage), Lc-cMyc was expressed very highly with a peak at two-cell stage. In late embryogenesis (from blastula stage to 1-day-post-hatching stage), the high expression of Lc-cMyc was detected as the following order: 1-day-post-hatching stage>pre-hatching stage>the appearance-of-optic-vesicles stage=mutiple-cell stage>beginning-of-heart-pulsation stage. The distribution of Lc-cMyc concentrated gradually in the back of embryos until in the head. In conclusion, the spatio-temporal expression patterns of Lc-cMyc indicated an essential role in oogenesis and embryogenesis and contributed to insight into the molecular mechanisms of regulating pluripotency in large yellow croaker.