JUNB

Gene Summary

Gene:JUNB; JunB proto-oncogene, AP-1 transcription factor subunit
Aliases: AP-1
Location:19p13.13
Summary:-
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor jun-B
Source:NCBIAccessed: 30 August, 2019

Ontology:

What does this gene/protein do?
Show (40)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Liver Cancer
  • DNA-Binding Proteins
  • Lymphoma, Large-Cell, Anaplastic
  • Immunohistochemistry
  • Proteins
  • Proto-Oncogene Proteins c-jun
  • Oligonucleotide Array Sequence Analysis
  • Down-Regulation
  • Phosphorylation
  • Cancer Gene Expression Regulation
  • Breast Cancer
  • Biomarkers, Tumor
  • Promoter Regions
  • Chronic Myelogenous Leukemia
  • Protein Binding
  • Neoplasm Proteins
  • Gene Expression Profiling
  • Mutation
  • Transcription
  • Messenger RNA
  • DNA Methylation
  • Cell Proliferation
  • Succinate Dehydrogenase
  • Neoplastic Cell Transformation
  • Base Sequence
  • Hepatocellular Carcinoma
  • siRNA
  • Proto-Oncogene Proteins c-fos
  • Chromosome 19
  • Neoplasm Invasiveness
  • p300-CBP Transcription Factors
  • MicroRNAs
  • Transcription Factors
  • Diffuse Large B-Cell Lymphoma
  • Cell Movement
  • NF-kappa B
  • Apoptosis
  • JUNB
  • Receptor Protein-Tyrosine Kinases
  • JUN
  • Gene Expression
  • ALK
  • Cervical Cancer
Tag cloud generated 30 August, 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).

Latest Publications: JUNB (cancer-related)

Freire PP, Fernandez GJ, Cury SS, et al.
The Pathway to Cancer Cachexia: MicroRNA-Regulated Networks in Muscle Wasting Based on Integrative Meta-Analysis.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Cancer cachexia is a multifactorial syndrome that leads to significant weight loss. Cachexia affects 50%-80% of cancer patients, depending on the tumor type, and is associated with 20%-40% of cancer patient deaths. Besides the efforts to identify molecular mechanisms of skeletal muscle atrophy-a key feature in cancer cachexia-no effective therapy for the syndrome is currently available. MicroRNAs are regulators of gene expression, with therapeutic potential in several muscle wasting disorders. We performed a meta-analysis of previously published gene expression data to reveal new potential microRNA-mRNA networks associated with muscle atrophy in cancer cachexia. We retrieved 52 differentially expressed genes in nine studies of muscle tissue from patients and rodent models of cancer cachexia. Next, we predicted microRNAs targeting these differentially expressed genes. We also include global microRNA expression data surveyed in atrophying skeletal muscles from previous studies as background information. We identified deregulated genes involved in the regulation of apoptosis, muscle hypertrophy, catabolism, and acute phase response. We further predicted new microRNA-mRNA interactions, such as miR-27a/

Kang EJ, Baek YM, Hahm E, et al.
Functionalized
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications
Cyclodextrins (CDs) have beneficial characteristics for drug delivery, including hydrophobic interior surfaces. Nanocarriers with

Bhardwaj R, Suzuki A, Leland P, et al.
Identification of a novel role of IL-13Rα2 in human Glioblastoma multiforme: interleukin-13 mediates signal transduction through AP-1 pathway.
J Transl Med. 2018; 16(1):369 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Previously, we have demonstrated that Interleukin 13 receptor alpha 2 (IL-13Rα2) is overexpressed in approximate 78% Glioblastoma multiforme (GBM) samples. We have also demonstrated that IL-13Rα2 can serve as a target for cancer immunotherapy in several pre-clinical and clinical studies. However, the significance of overexpression of IL-13Rα2 in GBM and astrocytoma and signaling through these receptors is not known. IL-13 can signal through IL-13R via JAK/STAT and AP-1 pathways in certain cell lines including some tumor cell lines. Herein, we have investigated a role of IL-13/IL-13Rα2 axis in signaling through AP-1 transcription factors in human glioma samples in situ.
METHODS: We examined the activation of AP-1 family of transcription factors (c-Jun, Fra-1, Jun-D, c-Fos, and Jun-B) after treating U251, A172 (IL-13Rα2 +ve) and T98G (IL-13Rα2 -ve) glioma cell lines with IL-13 by RT-qPCR, and immunocytochemistry (ICC). We also performed colorimetric ELISA based assay to determine AP-1 transcription factor activation in glioma cell lines. Furthermore, we examined the expression of AP-1 transcription factors in situ in GBM and astrocytoma specimens by multiplex-immunohistochemistry (IHC). Student t test and ANOVA were used for statistical analysis of the results.
RESULTS: We have demonstrated up-regulation of two AP-1 transcription factors (c-Jun and Fra-1) at mRNA and protein levels upon treatment with IL-13 in IL-13Rα2 positive but not in IL-13Rα2 negative glioma cell lines. Both transcription factors were also overexpressed in patient derived GBM specimens, however, in contrast to GBM cell lines, c-Fos is also overexpressed in patient derived specimens. Astrocytoma specimens showed lesser extent of immunostaining for IL-13Rα2 and three AP-1 factors compared to GBM specimens. By transcription factor activation assay, we demonstrated that AP-1 transcription factors (C-Jun and Fra-1) were activated upon treatment of IL-13Rα2 + GBM cell lines but not IL-13Rα2 - GBM cell line with IL-13. Our results demonstrate functional activity of AP-1 transcription factor in GBM cell lines in response to IL-13.
CONCLUSIONS: These results indicate that IL-13/IL-13Rα2 axis can mediate signal transduction in situ via AP-1 pathway in GBM and astrocytoma and may serve as a new target for GBM immunotherapy.

Jun BK, Ho B, Yuen T
Intracranial multiple myeloma with intraparenchymal involvement: Case report and literature review.
J Clin Neurosci. 2019; 59:335-337 [PubMed] Related Publications
Intraparenchymal extension of multiple myeloma is a rare manifestation of the disease. Here, we present a case of a patient with multiple myeloma lesions situated adjacent to the meninges and intraparenchymally.

Jun BG, Kim SG, Kim YD, et al.
Combined therapy of transarterial chemoembolization and stereotactic body radiation therapy versus transarterial chemoembolization for ≤5cm hepatocellular carcinoma: Propensity score matching analysis.
PLoS One. 2018; 13(10):e0206381 [PubMed] Free Access to Full Article Related Publications
Patients with liver cirrhosis and hepatocellular carcinoma (HCC) are often ineligible for resection or local ablation therapy due to poor liver function and/or difficult location. The aim of this study is to evaluate therapeutic outcomes of stereotactic body radiotherapy (SBRT) combined with transarterial chemoembolization (TACE) compared with TACE alone for HCC measuring less than 5 cm. From March 2011 to December 2016, 85 patients underwent SBRT with TACE (SBRT-TACE group) and 114 underwent TACE (TACE group) at 4 tertiary hospitals. Local control rate (LCR), progression-free survival (PFS) and overall survival (OS) were compared after propensity-score matching (1:1 ratio). The SBRT-TACE group showed significantly higher 1- and 3-year LCR than the TACE group (91.1% and 89.9%, respectively vs 69.9% and 44.8%, respectively; P < 0.001). The SBRT-TACE group showed better 1- and 3-year PFS than the TACE group (56.5% and 32.3%, respectively vs 42.2% and 21.6%, respectively; P = 0.022). However, 1-, 3- and 5-year OS was not different between the SBRT-TACE and TACE groups (98.8%, 89.1% and 80.7%, respectively vs 99.7%, 83.3% and 71.0%, respectively; P = 0.206). In multivariate analysis, the overall SBRT added to TACE did not contribute to extend PFS. However, in patients with less than 2 tumors, the combined therapy was effective (HR 0.590, 95% CI 0.392-0.889, P = 0.012). SBRT-TACE is superior to TACE in terms of LCR. Particularly, SBRT-TACE may be an effective alternative in patients with HCC number (≤2), which is not indicated for resection or local ablation.

Wang S, Li X, Zhang W, et al.
Genome-Wide Investigation of Genes Regulated by ERα in Breast Cancer Cells.
Molecules. 2018; 23(10) [PubMed] Free Access to Full Article Related Publications
Estrogen receptor alpha (ERα), which has been detected in over 70% of breast cancer cases, is a driving factor for breast cancer growth. For investigating the underlying genes and networks regulated by ERα in breast cancer, RNA-seq was performed between ERα transgenic MDA-MB-231 cells and wild type MDA-MB-231 cells. A total of 267 differentially expressed genes (DEGs) were identified. Then bioinformatics analyses were performed to illustrate the mechanism of ERα. Besides, by comparison of RNA-seq data obtained from MDA-MB-231 cells and microarray dataset obtained from estrogen (E2) stimulated MCF-7 cells, an overlap of 126 DEGs was screened. The expression level of ERα was negatively associated with metastasis and EMT in breast cancer. We further verified that ERα might inhibit metastasis by regulating of VCL and TNFRSF12A, and suppress EMT by the regulating of JUNB and ID3. And the relationship between ERα and these genes were validated by RT-PCR and correlation analysis based on TCGA database. By PPI network analysis, we identified TOP5 hub genes, FOS, SP1, CDKN1A, CALCR and JUNB, which were involved in cell proliferation and invasion. Taken together, the whole-genome insights carried in this work can help fully understanding biological roles of ERα in breast cancer.

Wang P, Magdolen V, Seidl C, et al.
Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer.
Br J Cancer. 2018; 119(7):1-9 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND: Tissue kallikrein-related peptidases 4, 5, 6 and 7 (KLK4-7) strongly increase the malignancy of ovarian cancer cells. Deciphering their downstream effectors, we aimed at finding new potential prognostic biomarkers and treatment targets for ovarian cancer patients. KLK4-7-transfected (OV-KLK4-7) and vector-control OV-MZ-6 (OV-VC) ovarian cancer cells were established to select differentially regulated factors.
METHODS: With three independent approaches, PCR arrays, genome-wide microarray and proteome analyses, we identified 10 candidates (MSN, KRT19, COL5A2, COL1A2, BMP5, F10, KRT7, JUNB, BMP4, MMP1). To determine differential protein expression, we performed western blot analyses, immunofluorescence and immunohistochemistry for four candidates (MSN, KRT19, KRT7, JUNB) in cells, tumour xenograft and patient-derived tissues.
RESULTS: We demonstrated that KLK4-7 clearly regulates expression of MSN, KRT19, KRT7 and JUNB at the mRNA and protein levels in ovarian cancer cells and tissues. Protein expression of the top-upregulated effectors, MSN and KRT19, was investigated by immunohistochemistry in patients afflicted with serous ovarian cancer and related to KLK4-7 immunoexpression. Significant positive associations were found for KRT19/KLK4, KRT19/KLK5 and MSN/KLK7.
CONCLUSION: These findings imply that KLK4-7 exert key modulatory effects on other cancer-related genes and proteins in ovarian cancer. These downstream effectors of KLK4-7, MSN and KRT19 may represent important therapeutic targets in serous ovarian cancer.

Sun Y, Wang J, Pan S, et al.
LINC00657 played oncogenic roles in esophageal squamous cell carcinoma by targeting miR-615-3p and JunB.
Biomed Pharmacother. 2018; 108:316-324 [PubMed] Related Publications
BACKGROUND: The prognosis of esophageal squamous cell carcinoma (ESCC) is relatively poor due to the absence of efficient treatment. In this manuscript, we have investigated the specific roles and molecular mechanisms of LINC00657 to order to identify novel therapeutic targets for ESCC.
METHOD: The LINC00657 expression in ESCC tissues and cell lines were evaluated by quantitative real-time PCR. The expression of LINC00657 in ESCC cells was regulated by lentivirus transfection. Online bioinformatics analysis tools were used to predict the potential targets of LINC00657 and miR-615-3p. TCGA database was used to analyze the prognosis of ESCC patients. Transwell, wound healing assay and MTT were performed to investigate the ESCC cells' biological functions. JunB expression was evaluated by Western blot.
RESULT: LINC00657 was moderately increased in ESCC both in vivo and in vitro and up regulated by irradiation. LINC00657 knockdown could inhibit the migration and proliferation of ESCC cells. And downregulation of LINC00657 significantly enhanced the radio-sensitivity. Moreover, LINC00657 could act as a ceRNA to increase the expression of JunB by binding to miR-615-3p. Meanwhile, overexpression of miR-615-3p resulted in anti-tumor effects and led to the down-regulation of JunB. Survival analysis from TCGA indicated that ESCC patients with higher JunB expression had significant poorer prognosis.
CONCLUSION: LINC00657 might be involved in regulating ESCC's response to radiation; and it functioned as an oncogene in ESCC by targeting miR-615-3p and JunB, providing novel potential therapeutic targets.

Shang HS, Lu HF, Lee CH, et al.
Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells.
Environ Toxicol. 2018; 33(11):1168-1181 [PubMed] Related Publications
Quercetin is one of the natural components from natural plant and it induces cell apoptosis in many human cancer cell lines. However, no available reports show that quercetin induces apoptosis and altered associated gene expressions in human gastric cancer cells, thus, we investigated the effect of quercetin on the apoptotic cell death and associated gene expression in human gastric cancer AGS cells. Results indicated that quercetin induced cell morphological changes and reduced total viability via apoptotic cell death in AGS cells. Furthermore, results from flow cytometric assay indicated that quercetin increased reactive oxygen species (ROS) production, decreased the levels of mitochondrial membrane potential (ΔΨ

Jun BG, Kim YD, Kim SG, et al.
Hepatitis B virus reactivation after radiotherapy for hepatocellular carcinoma and efficacy of antiviral treatment: A multicenter study.
PLoS One. 2018; 13(7):e0201316 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Convincing data that support routine use of preventive therapy against hepatitis B virus (HBV) reactivation in radiotherapy (RT) for hepatocellular carcinoma (HCC) are lacking. The aim of this study was to investigate the incidence, clinical significance, and risk factors of HBV reactivation after RT. Medical records of 133 HBsAg (+) HCC patients who received radiotherapy from March 2009 to February 2016 were reviewed. Patients were divided into two groups: 1) non-antiviral group, those who did not receive antiviral therapy before RT (n = 27); and antiviral group (those who underwent antiviral therapy before RT) (n = 106). Factors related to HBV reactivation in HCC patients were evaluated. 17 (12.7%) of 133 patients developed HBV reactivation after RT. Patients in the antiviral group had significantly lower rates of HBV reactivation than those in the non-antiviral group (7.5% vs. 33.3%, p<0.001). HBV related hepatitis was also lower in the antiviral group (3.8% vs. 14.8%, p = 0.031). In multivariate analysis, absence of antiviral treatment (OR: 8.339, 95% CI: 2.532-27.470, p<0.001) and combined treatment of RT with transarterial chemoembolizatoin (TACE) (OR: 5.313, 95% CI: 1.548-18.232, p = 0.008) were risk factors for HBV reactivation. HBV reactivation can occur after radiotherapy. Combination treatment of RT with TACE and non-antiviral treatment are major risk factors for HBV reactivation during or after RT. Therefore, preventive antiviral therapy should be recommended for patients with HCC who are scheduled to receive RT.

Ishikawa C, Senba M, Mori N
Mitotic kinase PBK/TOPK as a therapeutic target for adult T‑cell leukemia/lymphoma.
Int J Oncol. 2018; 53(2):801-814 [PubMed] Related Publications
Adult T‑cell leukemia/lymphoma (ATLL) is a disorder involving human T-cell leukemia virus type 1 (HTLV‑1)-infected T‑cells characterized by increased clonal neoplastic proliferation. PDZ-binding kinase (PBK) [also known as T‑lymphokine-activated killer cell-originated protein kinase (TOPK)] is a serine/threonine kinase expressed in proliferative cells and is phosphorylated during mitosis. In this study, the expression and phosphorylation of PBK/TOPK were examined by western blot analysis and RT‑PCR. We found that PBK/TOPK was upregulated and phosphorylated in HTLV‑1-transformed T‑cell lines and ATLL‑derived T‑cell lines. Notably, CDK1/cyclin B1, which phosphorylates PBK/TOPK, was overexpressed in these cells. HTLV‑1 infection upregulated PBK/TOPK expression in peripheral blood mononuclear cells (PBMCs) in co-culture assays. The potent PBK/TOPK inhibitors, HI‑TOPK‑032, and fucoidan from brown algae, decreased the proliferation and viability of these cell lines in a dose‑dependent manner. By contrast, the effect of HI‑TOPK‑032 on PBMCs was less pronounced. Treatment with HI‑TOPK‑032 resulted in G1 cell cycle arrest, and decreased CDK6 expression and pRb phosphorylation, which are critical determinants of progression through the G1 phase. In addition, HI‑TOPK‑032 induced apoptosis, as evidenced by morphological changes, the cleavage of poly(ADP-ribose) polymerase with the activation of caspase‑3, -8 and -9, and an increase in the sub‑G1 cell population and APO2.7-positive cells. Moreover, HI‑TOPK‑032 inhibited the expression of cellular inhibitor of apoptosis 2 (c-IAP2), X-linked inhibitor of apoptosis protein (XIAP), survivin and myeloid cell leukemia‑1 (Mcl‑1), and induced the expression of Bak and interferon-induced protein with tetratricopeptide repeats (IFIT)1, 2 and 3. It is noteworthy that the use of this inhibitor led to the inhibition of the phosphorylation of IκB kinase (IKK)α, IKKβ, IκBα, phosphatase and tensin homolog (PTEN) and Akt, and to the decreased protein expression of JunB and JunD, suggesting that PBK/TOPK affects the nuclear factor-κB, Akt and activator protein‑1 signaling pathways. In vivo, the administration of HI‑TOPK‑032 suppressed tumor growth in an ATLL xenograft model. Thus, on the whole, this study on the identification and functional analysis of PBK/TOPK suggests that this kinase is a promising molecular target for ATLL treatment.

Gong C, Shen J, Fang Z, et al.
Abnormally expressed JunB transactivated by IL-6/STAT3 signaling promotes uveal melanoma aggressiveness via epithelial-mesenchymal transition.
Biosci Rep. 2018; 38(4) [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and it carries a high risk of metastasis and mortality. Various proinflammatory cytokines have been found to be significantly increased in the aqueous humor or vitreous fluid of UM patients; however, the role of these cytokines in UM metastasis remains elusive. In the present study, we found that long-term interleukin (IL)-6 exposure promoted the migration and invasion of UM cells, diminished cell-cell adhesion, and enhanced focal adhesion. Moreover, IL-6 treatment decreased the membranous epithelial marker TJP1 and increased the cytoplasmic mesenchymal marker Vimentin. Further investigation demonstrated that JunB played a critical role in IL-6-induced UM epithelial-mesenchymal transition (EMT). In UM cells, the expression of JunB was significantly up-regulated during the IL-6-driven EMT process. Additionally, JunB induction occurred at the transcriptional level in a manner dependent on phosphorylated STAT3, during which activated STAT3 directly bound to the JunB promoter. Importantly, the knockdown of STAT3 prevented the IL-6-induced EMT phenotype as well as cell migration and invasion, whereas JunB overexpression recovered the attenuated aggressiveness of UM cells. Similarly, with IL-6 stimulation, the stable overexpression of JunB strengthened the migratory and invasive capabilities of UM cells and induced the EMT-promoting factors (Snail, Twist1, matrix metalloproteinase (MMP)-2, MMP-14, and MMP-19). Analysis of The Cancer Genome Atlas (TCGA) database indicated that JunB was positively correlated with IL-6 and STAT3 in UM tissues. The present study proposes an IL-6/STAT3/JunB axis leading to UM aggressiveness by EMT, which illustrates the negative side of inflammatory response in UM metastasis.

Kadin ME, Morgan J, Xu H, et al.
IL-13 is produced by tumor cells in breast implant-associated anaplastic large cell lymphoma: implications for pathogenesis.
Hum Pathol. 2018; 78:54-62 [PubMed] Related Publications
More than 500 women worldwide have developed a CD30+ T-cell lymphoma around breast implants, strongly suggesting a cause-and-effect relationship, and designated as breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The mechanism of lymphomagenesis is unknown. Recently, a bacterial biofilm containing gram-negative bacilli was discovered on the surface of breast implants associated with ALCL. We and others have described overexpression of the proto-oncogene JUNB and mutations of JAK1/2, TP53 and STAT3 in BIA-ALCL. Here we report that BIA-ALCL cell lines and anaplastic lymphoma cells in clinical specimens produce IL-13, the signature cytokine of allergic inflammation. Supporting the link of BIA-ALCL to allergic inflammation, lymphoma cells were often surrounded by eosinophils and mast cells, features typically absent in systemic ALCL. Because of the link of IL-13 to allergy, we looked for IgE and found it decorating the surface of mast cells and antigen-presenting follicular dendritic cells in capsules and lymph nodes infiltrated by anaplastic lymphoma cells, but not uninvolved capsules. Plasma cells within capsules and regional lymph nodes were identified as a possible source of IgE. Together, these findings suggest the hypothesis that an amplified immune response with features of a chronic allergic reaction in a susceptible patient underlies the pathogenesis of BIA-ALCL.

Wu W, Zaal EA, Berkers CR, et al.
CTGF/VEGFA-activated Fibroblasts Promote Tumor Migration Through Micro-environmental Modulation.
Mol Cell Proteomics. 2018; 17(8):1502-1514 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Fibroblast activation is associated with tumor progression and implicated in metastasis, but the initial triggering signals required to kick-start this process remain largely unknown. Because small cancerous lesions share limited physical contact with neighboring fibroblasts, we reasoned the first tumor-derived signal for fibroblast activation should be secreted and diffusible. By pulsed metabolic labeling and click-chemistry based affinity enrichment, we sieved through the ductal carcinoma secretome for potential fibroblast activators. Using immuno-depletion/supplementation assays on various secreted factors, we pinpointed that tumor-secreted CTGF/VEGFA alone is sufficient to activate paired mammary fibroblasts from the same patient via ROCK1 and JunB signaling. Fibroblasts activated in this manner are distinct in morphology, growth, and adopt a highly tumor-like secretion profile, which in turn promotes tumor migration by counteracting oxidative and lactate stress. These findings reveal a profound division-of-labor between normal and cancer cells under the directive of the latter, and allude to potential metastatic prevention through inhibiting local fibroblast activation.

Kokosar M, Benrick A, Perfilyev A, et al.
A Single Bout of Electroacupuncture Remodels Epigenetic and Transcriptional Changes in Adipose Tissue in Polycystic Ovary Syndrome.
Sci Rep. 2018; 8(1):1878 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
A single bout of electroacupuncture results in muscle contractions and increased whole body glucose uptake in women with polycystic ovary syndrome (PCOS). Women with PCOS have transcriptional and epigenetic alterations in the adipose tissue and we hypothesized that electroacupuncture induces epigenetic and transcriptional changes to restore metabolic alterations. Twenty-one women with PCOS received a single bout of electroacupuncture, which increased the whole body glucose uptake. In subcutaneous adipose tissue biopsies, we identified treatment-induced expression changes of 2369 genes (Q < 0.05) and DNA methylation changes of 7055 individual genes (Q = 0.11). The largest increase in expression was observed for FOSB (2405%), and the largest decrease for LOC100128899 (54%). The most enriched pathways included Acute phase response signaling and LXR/RXR activation. The DNA methylation changes ranged from 1-16%, and 407 methylation sites correlated with gene expression. Among genes known to be differentially expressed in PCOS, electroacupuncture reversed the expression of 80 genes, including PPARγ and ADIPOR2. Changes in the expression of Nr4a2 and Junb are reversed by adrenergic blockers in rats demonstrating that changes in gene expression, in part, is due to activation of the sympathetic nervous system. In conclusion, low-frequency electroacupuncture with muscle contractions remodels epigenetic and transcriptional changes that elicit metabolic improvement.

Xu M, Yin L, Cai Y, et al.
Epigenetic regulation of integrin β6 transcription induced by TGF-β1 in human oral squamous cell carcinoma cells.
J Cell Biochem. 2018; 119(5):4193-4204 [PubMed] Related Publications
Overexpression of integrin αvβ6 is believed to play an important role in the invasion and metastasis of oral squamous cell carcinoma (OSCC). However, little is known about the molecular mechanisms leading to αvβ6 upregulation in OSCC. As the integrin β6 (ITGB6) is the only partner with αv, the expression of αvβ6 is dependent on ITGB6, it is, therefore, pivotal to investigate the mechanisms underlying ITGB6 overexpression in OSCC. We previously reported the cloning and characterization of human ITGB6 gene. In the current study, we further investigated the molecular mechanisms of ITGB6 expression and the upregulation by carcinogenesis related cytokine-transforming growth factor-β1 (TGF-β1) in OSCC cells. We first demonstrated that TGF-β1 can induce ITGB6 mRNA and protein express in a time and concentration dependent manner, and the induced-ITGB6 mRNA was not due to increase the mRNA stability, but regulated at transcriptional level. By using a luciferase reporter assay, site-mutation, RNA interference, and chromatin immunoprecipitation assay, we revealed for the first time that JunB, a member of the activator protein-1 (AP-1) family, is involved in the positive regulation to the ITGB6 transcription induced by TGF-β1 in OSCC cells. Furthermore, our data also demonstrated that histone acetyltransferase (HAT) CBP mediated histone H3 and H4 hyperacetylation, and RNA Polymerase II recruitment to ITGB6 promoter, facilitated the binding of transcription factor JunB to ITGB6 promoter after TGF-β1 stimulation. Collectively, these findings demonstrate that JunB and CBP-mediated histone hyperacetylation are responsible for TGF-β1 induced ITGB6 transcription in OSCC cells, suggesting that epigenetic mechanisms are responsible for the active transcription expression of ITGB6 induced by TGF-β1 in OSCC cells.

Kang H, Jeong S, Jo A, et al.
Ultrasensitive NIR-SERRS Probes with Multiplexed Ratiometric Quantification for In Vivo Antibody Leads Validation.
Adv Healthc Mater. 2018; 7(4) [PubMed] Related Publications
Immunotargeting ability of antibodies may show significant difference between in vitro and in vivo. To select antibody leads with high affinity and specificity, it is necessary to perform in vivo validation of antibody candidates following in vitro antibody screening. Herein, a robust in vivo validation of anti-tetraspanin-8 antibody candidates against human colon cancer using ratiometric quantification method is reported. The validation is performed on a single mouse and analyzed by multiplexed surface-enhanced Raman scattering using ultrasensitive and near infrared (NIR)-active surface-enhanced resonance Raman scattering nanoprobes (NIR-SERRS dots). The NIR-SERRS dots are composed of NIR-active labels and Au/Ag hollow-shell assembled silica nanospheres. A 93% of NIR-SERRS dots is detectable at a single-particle level and signal intensity is 100-fold stronger than that from nonresonant molecule-labeled spherical Au NPs (80 nm). The result of SERRS-based antibody validation is comparable to that of the conventional method using single-photon-emission computed tomography. The NIR-SERRS-based strategy is an alternate validation method which provides cost-effective and accurate multiplexing measurements for antibody-based drug development.

Sundqvist A, Morikawa M, Ren J, et al.
JUNB governs a feed-forward network of TGFβ signaling that aggravates breast cancer invasion.
Nucleic Acids Res. 2018; 46(3):1180-1195 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
It is well established that transforming growth factor-β (TGFβ) switches its function from being a tumor suppressor to a tumor promoter during the course of tumorigenesis, which involves both cell-intrinsic and environment-mediated mechanisms. We are interested in breast cancer cells, in which SMAD mutations are rare and interactions between SMAD and other transcription factors define pro-oncogenic events. Here, we have performed chromatin immunoprecipitation (ChIP)-sequencing analyses which indicate that the genome-wide landscape of SMAD2/3 binding is altered after prolonged TGFβ stimulation. De novo motif analyses of the SMAD2/3 binding regions predict enrichment of binding motifs for activator protein (AP)1 in addition to SMAD motifs. TGFβ-induced expression of the AP1 component JUNB was required for expression of many late invasion-mediating genes, creating a feed-forward regulatory network. Moreover, we found that several components in the WNT pathway were enriched among the late TGFβ-target genes, including the invasion-inducing WNT7 proteins. Consistently, overexpression of WNT7A or WNT7B enhanced and potentiated TGFβ-induced breast cancer cell invasion, while inhibition of the WNT pathway reduced this process. Our study thereby helps to explain how accumulation of pro-oncogenic stimuli switches and stabilizes TGFβ-induced cellular phenotypes of epithelial cells.

Wan S, Meyer AS, Weiler SME, et al.
Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness.
Hepatology. 2018; 67(5):1842-1856 [PubMed] Related Publications
The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the basolateral cell polarity complex protein scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison with HCC cells stably expressing wild-type Scrib (Scrib
CONCLUSION: Perturbation of hepatocellular polarity due to overexpression and cytoplasmic enrichment of Scrib supports tumor initiation and HCC cell dissemination through specific molecular mechanisms. Biomarker signatures identified in this study can be used for the identification of HCC patients with higher risk for the development of metastasis. (Hepatology 2018;67:1842-1856).

Khan FM, Sadeghi M, Gupta SK, Wolkenhauer O
A Network-Based Integrative Workflow to Unravel Mechanisms Underlying Disease Progression.
Methods Mol Biol. 2018; 1702:247-276 [PubMed] Related Publications
Unraveling mechanisms underlying diseases has motivated the development of systems biology approaches. The key challenges for the development of mathematical models and computational tool are (1) the size of molecular networks, (2) the nonlinear nature of spatio-temporal interactions, and (3) feedback loops in the structure of interaction networks. We here propose an integrative workflow that combines structural analyses of networks, high-throughput data, and mechanistic modeling. As an illustration of the workflow, we use prostate cancer as a case study with the aim of identifying key functional components associated with primary to metastasis transitions. Analysis carried out by the workflow revealed that HOXD10, BCL2, and PGR are the most important factors affected in primary prostate samples, whereas, in the metastatic state, STAT3, JUN, and JUNB are playing a central role. The identified key elements of each network are validated using patient survival analysis. The workflow presented here allows experimentalists to use heterogeneous data sources for the identification of diagnostic and prognostic signatures.

Ishikawa C, Mori N
In vitro and in vivo anti-primary effusion lymphoma activities of fucoidan extracted from Cladosiphon okamuranus Tokida.
Oncol Rep. 2017; 38(5):3197-3204 [PubMed] Related Publications
Primary effusion lymphoma (PEL) caused by Kaposi's sarcoma-associated herpesvirus (KSHV) is characterized by lymphomatous effusion in body cavities and poor prognosis. There is still no effective treatment for PEL. Fucoidan, a major sulfated polysaccharide isolated from brown seaweeds, has an attractive array of bioactivities such as cancer inhibition. However, the effects of fucoidan on PEL cells remain unclear. We investigated the anti-PEL effects of fucoidan obtained from Cladosiphon okamuranus Tokida cultivated in Okinawa. Fucoidan dose-dependently inhibited the proliferation of KSHV-infected PEL cell lines, and provoked G1 cell cycle arrest, which was accompanied by CDK4 and CDK6 downregulation. Fucoidan also induced apoptosis of PEL cells through caspase-3, -8 and -9 activation; this occurred partly through the downregulation of anti-apoptotic Bcl-xL, Mcl-1 and XIAP proteins. Fucoidan also suppressed nuclear factor-κB, activator protein-1 (AP-1), and T-lymphokine-activated killer cell-originated protein kinase (TOPK) signaling pathways through inhibition of phosphorylation of IκBα and TOPK, and the expression of AP-1 family proteins, JunB and JunD. Oral administration of fucoidan effectively inhibited the development of PEL cells and ascites in a xenograft SCID mouse model, with minimal serious adverse effects. Notably, native fucoidan exhibited a more efficient anti-PEL effect than nanoparticle fucoidan. These preclinical findings highlight the anti-PEL actions of fucoidan, suggesting it could be potentially useful for the prevention and treatment of PEL.

Kong X, Kuilman T, Shahrabi A, et al.
Cancer drug addiction is relayed by an ERK2-dependent phenotype switch.
Nature. 2017; 550(7675):270-274 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Observations from cultured cells, animal models and patients raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR-Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/threonine-protein kinase BRAF, in order to functionally mine their genome for 'addiction genes'. Here we describe a signalling pathway comprising ERK2 kinase and JUNB and FRA1 transcription factors, disruption of which allowed addicted tumour cells to survive on treatment discontinuation. This occurred in both cultured cells and mice and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of the epithelial-mesenchymal transition. In melanoma cells, this reprogramming caused the shutdown of microphthalmia-associated transcription factor (MITF), a lineage survival oncoprotein; restoring this protein reversed phenotype switching and prevented the lethality associated with drug addiction. In patients with melanoma that had progressed during treatment with a BRAF inhibitor, treatment cessation was followed by increased expression of the receptor tyrosine kinase AXL, which is associated with the phenotype switch. Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells. Our results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.

Hong A, Moriceau G, Sun L, et al.
Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma.
Cancer Discov. 2018; 8(1):74-93 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Melanoma resistant to MAPK inhibitors (MAPKi) displays loss of fitness upon experimental MAPKi withdrawal and, clinically, may be resensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi addiction in MAPKi-resistant

Lin DPL, Carnagarin R, Dharmarajan A, Dass CR
Transdifferentiation of myoblasts into osteoblasts - possible use for bone therapy.
J Pharm Pharmacol. 2017; 69(12):1661-1671 [PubMed] Related Publications
OBJECTIVES: Transdifferentiation is defined as the conversion of one cell type to another and is an ever-expanding field with a growing number of cells found to be capable of such a process. To date, the fact remains that there are limited treatment options for fracture healing, osteoporosis and bone repair post-destruction by bone tumours. Hence, this review focuses on the transdifferentiation of myoblast to osteoblast as a means to further understand the transdifferentiation process and to investigate a potential therapeutic option if successful.
KEY FINDINGS: The potent osteoinductive effects of the bone morphogenetic protein-2 are largely implicated in the transdifferentiation of myoblast to osteoblast. Bone morphogenetic protein-2-induced activation of the Smad1 protein ultimately results in JunB synthesis, the first transcriptional step in myoblast dedifferentiation. The upregulation of the activating protein-1 binding activity triggers the transcription of the runt-related transcription factor 2 gene, a transcription factor that plays a major role in osteoblast differentiation.
SUMMARY: This potential transdifferentiation treatment may be utilised for dental implants, fracture healing, osteoporosis and bone repair post-destruction by bone tumours.

Lollies A, Hartmann S, Schneider M, et al.
An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma.
Leukemia. 2018; 32(1):92-101 [PubMed] Related Publications
Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30

Ishikawa C, Senba M, Mori N
Butein inhibits NF-κB, AP-1 and Akt activation in adult T-cell leukemia/lymphoma.
Int J Oncol. 2017; 51(2):633-643 [PubMed] Related Publications
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) but there is no effective treatment for HTLV-1-associated diseases. Herein, we determined the effect of butein, a bioactive plant polyphenol, on cell growth, apoptosis and signaling pathways in HTLV-1-infected T-cell lines and on tumor growth in SCID mice. Treatment with butein caused a decrease in viability of HTLV-1-infected T-cell lines. T cells cultured with butein showed obvious apoptosis morphology, and cleavage of poly(ADP-ribose) polymerase with activation of caspase-3, -8 and -9. Pretreatment of cells with caspase inhibitor partially blocked butein-induced inhibition of cell viability. Butein also resulted in cell cycle arrest at G1 phase. Butein markedly downregulated the protein expression levels of CDK4, CDK6, cyclin D1, cyclin D2, cyclin E, survivin, XIAP, c-IAP2 and phospho-pRb. Butein also inhibited i) total and phospho-protein levels of IκB kinase (IKK)α and IKKβ, ii) degradation and phosphorylation of IκBα, iii) JunB and JunD, iv) total and phospho-protein levels of Akt, v) phosphorylation of RelA, vi) heat shock protein 90, and vii) DNA-binding activity of NF-κB and AP-1. In mice harboring ATLL xenograft tumors, butein caused a significant inhibition of tumor growth and reduced serum levels of soluble interleukin-2 receptor α chain and soluble cluster of differentiation 30. Considered together, the results indicated that butein has antiproliferative and proapoptotic properties through the suppression of NF-κB, AP-1 and Akt signaling in HTLV-1-infected T cells, both in vitro and in vivo, suggesting its therapeutic potential against HTLV-1-associated diseases including ATLL.

Ahn HJ, Lee SJ, Park JK, et al.
Catheter probe endoscopic ultrasonography by using cold lubricating jelly-filled method for esophageal subepithelial tumors.
Dis Esophagus. 2017; 30(8):1-6 [PubMed] Related Publications
Catheter probe endoscopic ultrasonography (C-EUS) by ultrasonographic jelly-filled method has been used to evaluate esophageal subepithelial tumors (SETs). Ultrasonographic jelly is safe on the skin, but its internal safety has not been demonstrated. The jelly stored at room temperature is easily injected into the esophagus through the instrument channel of the endoscope. However, using jelly stored at room temperature remains problematic because the jelly is drained rapidly. We used cold lubricating jelly and an intravenous extension tube to resolve these problems. In this study, we evaluated the safety and efficacy of cold lubricating jelly-filled method. The medical records of patients who underwent C-EUS by using water or cold lubricating jelly-filled method for esophageal SETs from March 2013 to September 2016 in Gangneung Asan hospital were reviewed. Clinical characteristics and EUS findings were evaluated retrospectively. Image quality and procedure time between water and cold lubricating jelly-filled method were compared retrospectively. This study included 138 patients (74 males, 64 females) with esophageal SET with a mean age of 57.1 ± 11.1 years. Thirty-four patients had lesions in the upper esophagus, 58 patients had lesions in the middle esophagus, and 46 patients had lesions in the lower esophagus. The EUS diagnoses were leiomyoma (82.6%), hemangioma (4.3%), extrinsic compressive lesion (3.6%), granulosa cell tumor (2.9%), ectopic calcification (1.4%), cyst (1.4%), lipoma (0.7%), varix (0.7%), and inconclusive lesion (2.2%). The mean image score in the cold lubricating jelly filled-method group was higher than that in the water-filled method group (3.2 ± 0.7 vs. 2.8 ± 0.7, P = 0.002). The procedure time in the cold lubricating jelly filled-method group was shorter than that in the water-filled method group (10 minutes 27 seconds ± 4 minutes 22 seconds versus 13 minutes 20 seconds ± 6 minutes 20 seconds, P = 0.045). No procedure-related complication was observed. C-EUS using the cold lubricating jelly-filled method seems to provide better image quality and shorter procedure time compared with C-EUS using the water-filled method.

Lim CH, Lee IS, Jun BY, et al.
Incidence and clinical characteristics of gastroenteropancreatic neuroendocrine tumor in Korea: a single-center experience.
Korean J Intern Med. 2017; 32(3):452-458 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
BACKGROUND/AIMS: Neuroendocrine tumors (NETs) may originate from heterogeneous neuroendocrine cells. The incidence is increasing worldwide, and World Health Organization (WHO) updated its classification in 2010. We investigated clinical characteristics of gastroenteropancreatic NETs in a single center.
METHODS: Clinicopathologic characteristics of patients with pathologically confirmed gastroenteropancreatic NET in Seoul St. Mary Hospital from March 2009 to August 2011 were retrospectively analyzed. The grade and stage were determined according to WHO 2010 classification and TNM Staging System for Neuroendocrine Tumors (7th ed., 2010) of American Joint Committee on Cancer.
RESULTS: One hundred and twenty-five patients (median age, 50; male, 61.3%) were analyzed. Among 100,000 patients who visited the hospital, incidence was 24.1. Only two patients (1.6%) had a functional NET. The rectum (n = 99, 79.8%) was most common primary site and found in early stage. The prevalence by stages was 84.7% stage I, 8.9% stage IV, 4.8% stage II, and 1.6% stage III. The pathology grading was 74.5% grade 1, 12.7% grade 2, and 12.7% grade 3. Tumor stage correlated positively with pathologic grade (Spearman's rank correlation coefficient, 0.644).
CONCLUSIONS: Wide range of clinicopathological features of Korean gastroenteropancreatic NETs were demonstrated using WHO 2010 classification. Rectal NET was most frequent and found in early stage.

Wang S, He Z, Li D, et al.
Aberrant methylation of RUNX3 is present in Aflatoxin B
Toxicology. 2017; 385:1-9 [PubMed] Related Publications
Chronic exposure to aflatoxin B

Kim YI, Jeong S, Jung KO, et al.
Simultaneous Detection of EGFR and VEGF in Colorectal Cancer using Fluorescence-Raman Endoscopy.
Sci Rep. 2017; 7(1):1035 [PubMed] Article available free on PMC after 02/10/2019 Related Publications
Fluorescence endomicroscopy provides quick access to molecular targets, while Raman spectroscopy allows the detection of multiple molecular targets. Using a simultaneous fluorescence-Raman endoscopic system (FRES), we herein demonstrate its potential in cancer diagnosis in an orthotopically induced colorectal cancer (CRC) xenograft model. In the model, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) were targeted with antibody-conjugated fluorescence and surface-enhanced Raman scattering (F-SERS) dots. FRES demonstrated fast signal detection and multiplex targeting ability using fluorescence and Raman signals to detect the F-SERS dots. In addition, FRES showed a multiplex targeting ability even on a subcentimeter-sized CRC after spraying with a dose of 50 µg F-SERS dots. In conclusion, molecular characteristics of tumor cells (EGFR in cancer cell membranes) and tumor microenvironments (VEGF in the extracellular matrix) could be simultaneously investigated when performing a colonoscopy.

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