Gene Summary

Gene:CEBPB; CCAAT enhancer binding protein beta
Aliases: TCF5, IL6DBP, NF-IL6, C/EBP-beta
Summary:This intronless gene encodes a transcription factor that contains a basic leucine zipper (bZIP) domain. The encoded protein functions as a homodimer but can also form heterodimers with CCAAT/enhancer-binding proteins alpha, delta, and gamma. Activity of this protein is important in the regulation of genes involved in immune and inflammatory responses, among other processes. The use of alternative in-frame AUG start codons results in multiple protein isoforms, each with distinct biological functions. [provided by RefSeq, Oct 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:CCAAT/enhancer-binding protein beta
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
Show (31)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 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.

Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: CEBPB (cancer-related)

Huang E, Huang H, Guan T, et al.
Involvement of C/EBPβ-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis.
Toxicol Lett. 2019; 312:11-21 [PubMed] Related Publications
Methamphetamine (METH) is a widely abused illicit psychoactive drug. Our previous study has shown that CCAAT-enhancer binding protein β (C/EBPβ) is an important regulator in METH-induced neuronal autophagy and apoptosis. However, the detailed molecular mechanisms underlying this process remain poorly understood. Previous studies have demonstrated that DNA damage-inducible transcript 4 (DDIT4), Trib3 (tribbles pseudo kinase 3), alpha-synuclein (α-syn) are involved in METH-induced dopaminergic neurotoxicity. We hypothesized that C/EBPβ is involved in METH-induced DDIT4-mediated neuronal autophagy and Trib3-mediated neuronal apoptosis. We tested our hypothesis by examining the effects of silencing C/EBPβ, DDIT4, Trib3 or α-syn with small interfering ribonucleic acid (siRNA) on METH-induced autophagy and apoptosis in the human neuroblastoma SH-SY5Y cells. We also measured the levels of phosphorylated tuberous sclerosis complex 2 (TSC2) protein and Parkin protein level in SH-SY5Y cells. Furthermore, we demonstrated the effect of silencing C/EBPβ on METH-caused neurotoxicity in the striatum of rats by injecting LV-shC/EBPβ lentivirus using a stereotaxic positioning system. The results showed that METH exposure increased C/EBPβ, DDIT4 protein expression. Elevated DDIT4 expression raised up p-TSC2/TSC2 protein expression ratio, inhibited mTOR signaling pathway, activating cell autophagy. We also found that METH exposure increased the expression of Trib3, α-syn, decreased the Parkin protein expression. Lowering levels of Parkin raised up α-syn expression, which initiated mitochondrial apoptosis by down-regulating anti-apoptotic Bcl-2, followed by up-regulation of pro-apoptotic Bax, resulting in translocation of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria to cytoplasm and activation of caspase-dependent pathways. These findings were supported by data showing METH-induced autophagy and apoptosis was significantly inhibited by silencing C/EBPβ, DDIT4, Trib3 or α-syn, or by Parkin over-expression. Based on the present data, a novel of mechanism on METH-induced cell toxicity is proposed, METH exposure increased C/EBPβ protein expression, triggered DDIT4/TSC2/mTOR signaling pathway, and evoked Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Collectively, these results suggest that C/EBPβ plays an important role in METH-triggered autophagy and apoptosis and it may be a potential target for therapeutics in METH-caused neurotoxicity.

Li H, Yang F, Chai L, et al.
CCAAT/Enhancer Binding Protein β-Mediated MMP3 Upregulation Promotes Esophageal Squamous Cell Cancer Invasion
Genet Test Mol Biomarkers. 2019; 23(5):304-309 [PubMed] Related Publications

Liu X, Chen H, Hou Y, et al.
Adaptive EGF expression sensitizes pancreatic cancer cells to ionizing radiation through activation of the cyclin D1/P53/PARP pathway.
Int J Oncol. 2019; 54(4):1466-1480 [PubMed] Related Publications
It is well-known that the activation status of the P53, signal transducer and activator of transcription (Stat)3 and nuclear factor (NF)‑κB signaling pathways determines the radiosensitivity of cancer cells. However, the function of these pathways in radiosensitive vs radioresistant cancer cells remains elusive. The present study demonstrated that adaptive expression of epidermal growth factor (EGF) following exposure to ionizing radiation (IR) may induce radiosensitization of pancreatic cancer (PC) cells through induction of the cyclin D1/P53/poly(ADP‑ribose) polymerase pathway. By contrast, adaptively expressed interleukin (IL)‑6 and insulin‑like growth factor (IGF)‑1 may promote radioresistance of PC cells, likely through activation of the Stat3 and NF‑κB pathways. In addition, cyclin D1 and survivin, which are specifically expressed in the G1/S and G2/M phase of the cell cycle, respectively, are mutually exclusive in radiosensitive and radioresistant PC cells, while Bcl‑2 and Bcl‑xL expression does not differ between radiosensitive and radioresistant PC cells. Therefore, adaptively expressed EGF and IL‑6/IGF‑1 may alter these pathways to promote the radiosensitivity of PC cancers. The findings of the present study highlight potential makers for the evaluation of radiosensitivity and enable the development of effective regimens for cancer radiotherapy.

Yang Y, Liu L, Fang M, et al.
The chromatin remodeling protein BRM regulates the transcription of tight junction proteins: Implication in breast cancer metastasis.
Biochim Biophys Acta Gene Regul Mech. 2019; 1862(5):547-556 [PubMed] Related Publications
Claudins are a group of cell tight junction proteins that play versatile roles in cancer biology. Recent studies have correlated down-regulation of Claudins with augmented breast cancer malignancy and poor prognosis. The mechanism underlying repression of Claudin transcription in breast cancer cells is not well understood. Here we report that expression levels of Brahma (BRM) were down-regulated in triple negative breast cancer cells (MDA-231) compared to the less malignant MCF-7 cells and in high-grade human breast cancer specimens compared to low-grade ones. TGF-β treatment in MCF-7 cells repressed BRM transcription likely through targeting C/EBPβ. BRM over-expression suppressed whereas BRM knockdown promoted TGF-β induced migration and invasion of MCF-7 cells. BRM down-regulation was accompanied by the loss of a panel of Claudins in breast cancer cells. BRM directly bound to the promoter region of Claudin genes via interacting with Sp1 and activated transcription by modulating histone modifications. Together, our data have identified a novel epigenetic pathway that links Claudin transcription to breast cancer metastasis.

Du Q, Tan Z, Shi F, et al.
PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation.
Cancer Sci. 2019; 110(6):2050-2062 [PubMed] Free Access to Full Article Related Publications
The PPAR coactivator-1α (PGC1α) is an important transcriptional co-activator in control of fatty acid metabolism. Mitochondrial fatty acid oxidation (FAO) is the primary pathway for the degradation of fatty acids and promotes NADPH and ATP production. Our previous study demonstrated that upregulation of carnitine palmitoyl transferase 1 A (CPT1A), the key regulator of FAO, promotes radiation resistance of nasopharyngeal carcinoma (NPC). In this study, we found that high expression of PGC1α is associated with poor overall survival in NPC patients after radiation treatment. Targeting PGC1α could sensitize NPC cells to radiotherapy. Mechanically, PGC1α binds to CCAAT/enhancer binding protein β (CEBPB), a member of the transcription factor family of CEBP, to promote CPT1A transcription, resulting in activation of FAO. Our results revealed that the PGC1α/CEBPB/CPT1A/FAO signaling axis promotes radiation resistance of NPC. These findings indicate that the expression of PGC1α could be a prognostic indicator of NPC, and targeting FAO in NPC with high expression of PGC1α might improve the therapeutic efficacy of radiotherapy.

Li T, Li M, Xu C, et al.
miR‑146a regulates the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6.
Oncol Rep. 2019; 41(5):2897-2908 [PubMed] Related Publications
The aim of the present study was to investigate whether miRNA‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. miR‑146a expression was increased in human cervical cancer. Both overall survival (OS) and disease‑free survival (DFS) of low miR‑146a expression were higher than those of high miR‑146a expression. Additionally, IL‑17a expression was lower in patients with high miR‑146a expression compared to that of patients with lower miR‑146a expression. In a co‑culture of cervical cancer and CD4+ T cells, downregulation of miR‑146a inhibited cell growth and induced apoptosis of cervical cancer cells, while overexpression of miR‑146a promoted cell growth and reduced apoptosis of cervical cancer cells. Downregulation of miR‑146a induced TRAF6 and NF‑κB protein expression, increased IL‑6, IL‑17A and IL‑21 levels, and enhanced p‑STAT3 protein expression. The inhibition of TRAF6 attenuated the effects of anti‑miR‑146a on the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. Collectively, miR‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6. miR‑146a may function as an oncogene in cervical cancer via Th17 cell differentiation by targeting TRAF6.

Xiao L, Luo Y, Tai R, Zhang N
Estrogen receptor β suppresses inflammation and the progression of prostate cancer.
Mol Med Rep. 2019; 19(5):3555-3563 [PubMed] Free Access to Full Article Related Publications
Previous studies demonstrated that estrogen receptor β (ERβ) signaling alleviates systemic inflammation in animal models, and suggested that ERβ‑selective agonists may deactivate microglia and suppress T cell activity via downregulation of nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB). In the present study, the role of ERβ in lipopolysaccharide (LPS)‑induced inflammation and association with NF‑κB activity were investigated in PC‑3 and DU145 prostate cancer cell lines. Cells were treated with LPS to induce inflammation, and ELISA was performed to determine the expression levels of inflammatory cytokines, including tumor necrosis factor‑α (TNF‑α), monocyte chemoattractant protein 1 (MCP‑1), interleukin (IL)‑1β and IL‑6. MTT and Transwell assays, and Annexin V/propidium iodide staining were conducted to measure cell viability, apoptosis and migration, respectively. Protein expression was determined via western blot analysis. LPS‑induced inflammation resulted in elevated expression levels of TNF‑α, IL‑1β, MCP‑1 and IL‑6 compared with controls. ERβ overexpression significantly inhibited the LPS‑induced production of TNF‑α, IL‑1β, MCP‑1 and IL‑6. In addition, the results indicated that ERβ suppressed viability and migration, and induced apoptosis in prostate cancer cells, which was further demonstrated by altered expression of proliferating cell nuclear antigen, B‑cell lymphoma 2‑associated X protein, caspase‑3, E‑cadherin and matrix metalloproteinase‑2. These effects were reversed by treatment with the ERβ antagonist PHTPP or ERβ‑specific short interfering RNA. ERβ overexpression reduced the expression levels of p65 and phosphorylated NF‑κB inhibitor α (IκBα), but not total IκBα expression in LPS‑treated cells. In conclusion, ERβ suppressed the viability and migration of the PC‑3 and DU145 prostate cancer cell lines and induced apoptosis. Furthermore, it reduced inflammation and suppressed the activation of the NF‑κB pathway, suggesting that ERβ may serve roles as an anti‑inflammatory and anticancer agent in prostate cancer.

Xiong L, Wu F, Wu Q, et al.
Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming.
Nat Commun. 2019; 10(1):335 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear. Here, our affinity- and bisulfite-based whole-genome sequencing analyses reveal global enhancer hypomethylation in human HCCs. Integrative epigenomic characterization further pinpoints a recurrent hypomethylated enhancer of CCAAT/enhancer-binding protein-beta (C/EBPβ) which correlates with C/EBPβ over-expression and poorer prognosis of patients. Demethylation of C/EBPβ enhancer reactivates a self-reinforcing enhancer-target loop via direct transcriptional up-regulation of enhancer RNA. Conversely, deletion of this enhancer via CRISPR/Cas9 reduces C/EBPβ expression and its genome-wide co-occupancy with BRD4 at H3K27ac-marked enhancers and super-enhancers, leading to drastic suppression of driver oncogenes and HCC tumorigenicity. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebpβ enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBPβ over-expression, thereby contributing to hepatocarcinogenesis through global transcriptional reprogramming.

Rahman MR, Islam T, Gov E, et al.
Identification of Prognostic Biomarker Signatures and Candidate Drugs in Colorectal Cancer: Insights from Systems Biology Analysis.
Medicina (Kaunas). 2019; 55(1) [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report aimed to identify molecular biomarker signatures in CRC. We analyzed two microarray datasets (GSE35279 and GSE21815) from the Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein⁻protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity Map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. A total of 727 upregulated and 99 downregulated DEGs were detected. The PI3K/Akt signaling, Wnt signaling, extracellular matrix (ECM) interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and two microRNAs (miRNAs) (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan⁻Meier curves indicated remarkable performance of reporter molecules in the estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting the development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC.

Zhao X, Reebye V, Hitchen P, et al.
Mechanisms involved in the activation of C/EBPα by small activating RNA in hepatocellular carcinoma.
Oncogene. 2019; 38(18):3446-3457 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is generally accompanied by high mortality and low cure rate. CCAAT enhancer-binding proteins (CEBPs) are transcriptional regulators that play a key role in maintaining liver function. Altered expression of C/EBPα and C/EBPβ occurs in many tumours including HCC. saRNAs are small double-stranded RNAs that enhance target gene expression at the transcriptional level. In this report, we activate CEPBA with saRNAs and suppress CEBPB with siRNAs in cells that represent three different degrees of HCC. We performed functional assays to investigate the effects of enhancing C/EBPα and its downstream targets, p21 and albumin across these lines. We also used Mass-spectrometry (MS) subsequent to a ChIP pull-down assay to characterise the components of the protein complex involved in regulating saRNA function. Putative saRNA interacting protein candidates that were identified by MS were knocked-down with siRNAs to investigate its impact on saRNA activity. We confirmed CEBPA-saRNA decreased proliferation and migration in the differentiated lines (HepG3/Hep3B). The undifferentiated line (PLCPRF5) showed saRNA-induced increase in CEBPA but with no loss in proliferation. This effect was reversed when CEBPB was suppressed with CEBPB-siRNA. When interrogating saRNA mode of action; three saRNA interacting proteins, CTR9, HnRNPA2/B1 and DDX5 were identified by MS. Targeted knock-down of these two proteins (by siRNA) abrogated saRNA activity. This study provides insight into how different HCC lines are affected by CEBPA-saRNAs and that endogenous abundance of CEBPB and saRNA accessory proteins may dictate efficacy of CEBPA-saRNA when used in a therapeutic context.

Khodabandehlou N, Mostafaei S, Etemadi A, et al.
Human papilloma virus and breast cancer: the role of inflammation and viral expressed proteins.
BMC Cancer. 2019; 19(1):61 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer is currently the most common neoplasm diagnosed in women globally. There is a growing body of evidence to suggest that human papillomavirus (HPV) infection may play a key role in invasiveness of breast cancer. The aim of this study was to determine the presence of HPV in patients with breast cancer and its possible association with cancer progression.
METHODS: Breast specimens were collected from 72 patients with breast cancer and 31 healthy controls. The presence of HPV was investigated by polymerase chain reaction (PCR) and genotyping was performed for positive cases. We also evaluated the viral factors such as E6, E2, and E7 in HPV positive cases. Enzyme-linked immunosorbent assay (ELISA (and Real-time PCR techniques were used to measure the expression level of anti-carcinogenic genes, such as p53, retinoblastoma (RB), breast and ovarian cancer susceptibility gene (BRCA1, BRCA2) and inflammatory cytokines, including tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), nuclear factor-kB (NF-kB), and different interleukins [ILs] (IL-1,IL6, and IL-17).
RESULTS: The HPV DNA was detected in 48.6% of breast cancer samples, whereas only 16.1% of controls were positive for HPV. We observed statistically significant differences between breast cancer patients and HPV presence (P = 0.003). HPV type 18 was the most prevalent virus genotype in patients. The expression of P53, RB, BRCA1, and BRCA2 were decreased in patients with HPV-positive breast cancer as compared to HPV-negative breast cancer and healthy controls. (All P-values were less than 0.05). The presence of the HPV was associated with increased inflammatory cytokines (IL-1, IL-6, IL-17, TGF-β, TNF-α, and NF-kB) and tumor progression.
CONCLUSION: The present study demonstrated that HPV infection may implicate in the development of some types of breast cancer.

Buondonno I, Gazzano E, Tavanti E, et al.
Endoplasmic reticulum-targeting doxorubicin: a new tool effective against doxorubicin-resistant osteosarcoma.
Cell Mol Life Sci. 2019; 76(3):609-625 [PubMed] Related Publications
Doxorubicin is one of the most effective drugs for the first-line treatment of high-grade osteosarcoma. Several studies have demonstrated that the major cause for doxorubicin resistance in osteosarcoma is the increased expression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). We recently identified a library of H

Jin B, Gong Y, Li H, et al.
C/EBPβ promotes the viability of human bladder cancer cell by contributing to the transcription of bladder cancer specific lncRNA UCA1.
Biochem Biophys Res Commun. 2018; 506(3):674-679 [PubMed] Related Publications
Urothelial Carcinoma Antigen 1 (UCA1) is a cell and tissue specific long non-coding RNA (lncRNA) associated with the tumorigenesis and invasion of bladder cancer. However, the mechanism driving the over-transcription of UCA1 in bladder cancer cells remains unclear. It has been reported that C/EBPβ has a significant role of regulation in tumorigenesis. Here we report that the expression of UCA1 was dramatically inhibited in 5637 cells with C/EBPβ down-regulation. Additionally, the function tests indicated that C/EBPβ could promote 5637 cells growth and colony formation by inducing the expression level of UCA1. These data suggest that C/EBPβ was involved in transcriptional regulation of UCA1 and contributed substantially to its high expression and proliferation promoting in bladder cancer cells.

Yu CW, Cheng KC, Chen LC, et al.
Pro-inflammatory cytokines IL-6 and CCL2 suppress expression of circadian gene Period2 in mammary epithelial cells.
Biochim Biophys Acta Gene Regul Mech. 2018; 1861(11):1007-1017 [PubMed] Related Publications
Chronic inflammation is known to contribute to tumor initiation and cancer progression. In breast tissue, the core circadian gene Period (PER)2 plays a critical role in mammary gland development and possesses tumor suppressor function. Interleukin (IL)-6 and C-C motif chemokine ligand (CCL) 2 are among the most abundant cytokines in the inflammatory microenvironment. We found that acute stimulation by IL-6/CCL2 reduced PER2 expression in non-tumorigenic breast epithelial cells. Longer term exposure to IL-6/CCL2 suppressed PER2 to an even lower level. IL-6 activated STAT3/NFκB p50 signaling to recruit HDAC1 to the PER2 promoter. CCL2 activated the PI3K/AKT pathway to promote ELK-1 cytoplasm-to-nucleus translocation, recruit HDAC1 to the proximal PER2 promoter and facilitate DNMT3-EZH2-PER2 promoter association. Ectopic expression of PER2 inhibited IL-6 or CCL2 induced mammosphere forming ability and reduced sphere size indicating that PER2 repression in breast epithelial cells can be crucial to activate tumorigenesis in an inflammatory microenvironment. The diminished expression of PER2 can be observed over a time scale of hours to weeks following IL-6/CCL2 stimulation suggesting that PER2 suppression occurs in the early stage of the interaction between an inflammatory microenvironment and normal breast epithelial cells. These data show new mechanisms by which mammary cells interact with a cancerous microenvironment and provide additional evidence that PER2 expression contributes to breast tumorigenesis.

Jinesh GG, Flores ER, Brohl AS
Chromosome 19 miRNA cluster and CEBPB expression specifically mark and potentially drive triple negative breast cancers.
PLoS One. 2018; 13(10):e0206008 [PubMed] Free Access to Full Article Related Publications
Triple negative breast cancers (TNBCs) are known to express low PGR, ESR1, and ERBB2, and high KRT5, KRT14, and KRT17. However, the reasons behind the increased expressions of KRT5, KRT14, KRT17 and decreased expressions of PGR, ESR1, and ERBB2 in TNBCs are not fully understood. Here we show that, expression of chromosome 19 miRNA cluster (C19MC) specifically marks human TNBCs. Low REST and high CEBPB correlate with expression of C19MC, KRT5, KRT14, and KRT17 and enhancers of these genes/cluster are regulated by CEBPB and REST binding sites. The C19MC miRNAs in turn can potentially target REST to offer a positive feedback loop, and might target PGR, ESR1, ERBB2, GATA3, SCUBE2, TFF3 mRNAs to contribute towards TNBC phenotype. Thus our study demonstrates that C19MC miRNA expression marks TNBCs and that C19MC miRNAs and CEBPB might together determine the TNBC marker expression pattern.

Yu SH, Zhu KY, Chen J, et al.
JMJD3 facilitates C/EBPβ-centered transcriptional program to exert oncorepressor activity in AML.
Nat Commun. 2018; 9(1):3369 [PubMed] Free Access to Full Article Related Publications
JMJD3, a stress-inducible H3K27 demethylase, plays a critical regulatory role in the initiation and progression of malignant hematopoiesis. However, how this histone modifier affects in a cell type-dependent manner remains unclear. Here, we show that in contrast to its oncogenic effect in preleukemia state and lymphoid malignancies, JMJD3 relieves the differentiation-arrest of certain subtypes (such as M2 and M3) of acute myeloid leukemia (AML) cells. RNA sequencing and ChIP-PCR analyses revealed that JMJD3 exerts anti-AML effect by directly modulating H3K4 and H3K27 methylation levels to activate the expression of a number of key myelopoietic regulatory genes. Mechanistic exploration identified a physical and functional association of JMJD3 with C/EBPβ that presides the regulatory network of JMJD3. Thus, the leukemia regulatory role of JMJD3 varies in a disease phase- and lineage-dependent manner, and acts as a potential oncorepressor in certain subsets of AML largely by coupling to C/EBPβ-centered myelopoietic program.

Qian K, Wang S, Fu M, et al.
Transcriptional regulation of
J Biol Chem. 2018; 293(36):13989-14000 [PubMed] Article available free on PMC after 07/09/2019 Related Publications
Many intracellular proteins are reversibly modified by

Xia Y, Cheng X, Li Y, et al.
Hepatitis B Virus Deregulates the Cell Cycle To Promote Viral Replication and a Premalignant Phenotype.
J Virol. 2018; 92(19) [PubMed] Article available free on PMC after 07/09/2019 Related Publications
Hepatitis B virus (HBV) infection is a major health problem worldwide, and chronically infected individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms whereby HBV causes HCC are largely unknown. Using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expression and signaling pathways of infected hepatocytes and whether these effects are relevant to productive HBV infection and HBV-associated HCC. Using a human growth factor antibody array, we first showed that HBV infection induced a distinct profile of growth factor production by PHHs, marked particularly by significantly lower levels of the transforming growth factor β (TGF-β) family of proteins in the supernatant. Transcriptome profiling next revealed multiple changes in cell proliferation and cell cycle control pathways in response to HBV infection. A human cell cycle PCR array validated deregulation of more than 20 genes associated with the cell cycle in HBV-infected PHHs. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G

Yousefi H, Momeny M, Ghaffari SH, et al.
IL-6/IL-6R pathway is a therapeutic target in chemoresistant ovarian cancer.
Tumori. 2019; 105(1):84-91 [PubMed] Related Publications
INTRODUCTION:: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide and despite an initial response to therapeutic agents, the majority of patients have chemoresistant disease. There is no treatment strategy with proven efficacy against chemoresistant EOC and in this setting, overcoming therapy resistance is the key to successful treatment.
METHODS:: This study aimed to investigate expression of interleukin-6 (IL-6) (IL-6) and IL-6 receptor (IL-6R) in a panel of the EOC cell lines. To achieve this, the expression of IL-6 and its receptor were compared in the EOC cells using quantitative reverse transcription polymerase chain reaction. MTT assay was performed to obtain chemosensitivity of the EOC cells.
RESULTS:: In this report, we show that expressions of IL6 and IL6R are higher in therapy-resistant EOC cells compared to sensitive ones. Higher expression of IL6 and its receptor correlated with resistance to certain chemotherapeutic agents. Moreover, our findings showed that combination of tocilizumab (Actemra; Roche), an anti-IL-6R monoclonal antibody, with carboplatin synergistically inhibited growth and proliferation of the EOC cells and the most direct axis for IL-6 gene expression was NF-κB pathway.
CONCLUSION:: Collectively, our findings suggest that blockade of the IL-6 signaling pathway with anti-IL-6 receptor antibody tocilizumab might resensitize the chemoresistant cells to the current chemotherapeutics.

Marchwicka A, Marcinkowska E
Regulation of Expression of CEBP Genes by Variably Expressed Vitamin D Receptor and Retinoic Acid Receptor α in Human Acute Myeloid Leukemia Cell Lines.
Int J Mol Sci. 2018; 19(7) [PubMed] Article available free on PMC after 07/09/2019 Related Publications
All-trans-retinoic acid (ATRA) and 1α,25-dihydroxyvitamin D (1,25D) are potent inducers of differentiation of myeloid leukemia cells. During myeloid differentiation specific transcription factors are expressed at crucial developmental stages. However, precise mechanism controlling the diversification of myeloid progenitors is largely unknown, CCAAT/enhancer-binding protein (C/EBP) transcription factors have been characterized as key regulators of the development and function of the myeloid system. Past data point at functional redundancy among C/EBP family members during myeloid differentiation. In this study, we show that in acute myeloid leukemia (AML) cells, high expression of vitamin D receptor gene (

Davis M, Tripathi S, Hughley R, et al.
AR negative triple negative or "quadruple negative" breast cancers in African American women have an enriched basal and immune signature.
PLoS One. 2018; 13(6):e0196909 [PubMed] Article available free on PMC after 07/09/2019 Related Publications
There is increasing evidence that Androgen Receptor (AR) expression has prognostic usefulness in Triple negative breast cancer (TNBC), where tumors that lack AR expression are considered "Quadruple negative" Breast Cancers ("QNBC"). However, a comprehensive analysis of AR expression within all breast cancer subtypes or stratified by race has not been reported. We assessed AR mRNA expression in 925 tumors from The Cancer Genome Atlas (TCGA), and 136 tumors in 2 confirmation sets. AR protein expression was determined by immunohistochemistry in 197 tumors from a multi-institutional cohort, for a total of 1258 patients analyzed. Cox hazard ratios were used to determine correlations to PAM50 breast cancer subtypes, and TNBC subtypes. Overall, AR-negative patients are diagnosed at a younger age compared to AR-positive patients, with the average age of AA AR-negative patients being, 49. AA breast tumors express AR at lower rates compared to Whites, independent of ER and PR expression (p<0.0001). AR-negative patients have a (66.60; 95% CI, 32-146) odds ratio of being basal-like compared to other PAM50 subtypes, and this is associated with an increased time to progression and decreased overall survival. AA "QNBC" patients predominately demonstrated BL1, BL2 and IM subtypes, with differential expression of E2F1, NFKBIL2, CCL2, TGFB3, CEBPB, PDK1, IL12RB2, IL2RA, and SOS1 genes compared to white patients. Immune checkpoint inhibitors PD-1, PD-L1, and CTLA-4 were significantly upregulated in both overall "QNBC" and AA "QNBC" patients as well. Thus, AR could be used as a prognostic marker for breast cancer, particularly in AA "QNBC" patients.

Harada K, Ferdous T, Mizukami Y, Mishima K
Elemental diet inhibits pro‑inflammatory cytokine production in keratinocytes through the suppression of NF‑κB activation.
Oncol Rep. 2018; 40(1):361-368 [PubMed] Related Publications
An elemental diet (ED) has been reported to reduce oral mucositis and dermatitis induced by chemotherapy. However, its molecular mechanism of action as an anti‑inflammatory agent is still unknown. The aim of the present study was to clarify whether ED confers its anti‑inflammatory action via reduction of pro‑inflammatory cytokine production in keratinocytes in vivo and in vitro. We evaluated the efficacy of ED in the treatment of 5‑fluorouracil (5‑FU)‑induced dermatitis of nude mice, and examined the expression of pro‑inflammatory cytokines such as tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β and IL‑6 using immunohistochemistry. Moreover, we assessed the expression and production of these pro‑inflammatory cytokines by western blotting and ELISA assays, respectively, in immortalized human keratinocyte cell line, HaCaT. Furthermore, we investigated the effect of ED on a major inflammation‑related factor, nuclear transcription factor‑κB (NF‑κB), since it controls many genes involved in the inflammation pathway. Our results indicated that ED reduced the expression of TNF‑α, IL‑1β and IL‑6. It also inhibited the nuclear transition of p65 NF‑κB, which is known to regulate inflammatory cytokine expression in keratinocytes suffering from 5‑FU‑induced dermatitis. In addition, ED reduced the production of TNF‑α, IL‑1β and IL‑6 in HaCaT cells. Moreover, ED attenuated 5‑FU‑induced transcriptional activation of NF‑κB. These findings revealed that ED suppresses the expression of pro‑inflammatory cytokines by suppressing NF‑κB in keratinocytes, suggesting the potential usefulness of ED in the treatment of various inflammatory diseases of the dermal region.

Khosravi N, Caetano MS, Cumpian AM, et al.
IL22 Promotes
Cancer Immunol Res. 2018; 6(7):788-797 [PubMed] Article available free on PMC after 07/09/2019 Related Publications

Castellano-Castillo D, Morcillo S, Clemente-Postigo M, et al.
Adipose tissue inflammation and
Clin Epigenetics. 2018; 10:60 [PubMed] Article available free on PMC after 07/09/2019 Related Publications
Background: Lack of vitamin D (VD) has been associated with colorectal cancer (CRC). VD has anti-inflammatory effects and regulates several cellular pathways by means of its receptor, including epigenetic modifications. Adipose tissue dysfunction has been related to low-grade inflammation, which is related to diseases like cancer. The aim of this study was to explore the relationship between serum 25-hydroxyvitamin D (25(OH)D), adipose tissue gene expression of VD receptor (VDR), pro-inflammatory markers, and the epigenetic factor DNA methyltransferase 3a (DNMT3A) as well as VDR promoter methylation in CRC.
Methods: Blood and visceral adipose tissue from 57 CRC and 50 healthy control subjects were collected. CRC subjects had lower serum 25(OH)D levels and higher VDR gene expression, and these were negatively correlated in the CRC group.
Results: Adipose tissue
Conclusion: Our results suggest that adipose tissue may be a key factor in CRC development. The low 25(OH)D levels and high adipose tissue

Liu D, Zhang XX, Li MC, et al.
C/EBPβ enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation.
Nat Commun. 2018; 9(1):1739 [PubMed] Article available free on PMC after 07/09/2019 Related Publications
Chemoresistance is a major unmet clinical obstacle in ovarian cancer treatment. Epigenetics plays a pivotal role in regulating the malignant phenotype, and has the potential in developing therapeutically valuable targets that improve the dismal outcome of this disease. Here we show that a series of transcription factors, including C/EBPβ, GCM1, and GATA1, could act as potential modulators of histone methylation in tumor cells. Of note, C/EBPβ, an independent prognostic factor for patients with ovarian cancer, mediates an important mechanism through which epigenetic enzyme modifies groups of functionally related genes in a context-dependent manner. By recruiting the methyltransferase DOT1L, C/EBPβ can maintain an open chromatin state by H3K79 methylation of multiple drug-resistance genes, thereby augmenting the chemoresistance of tumor cells. Therefore, we propose a new path against cancer epigenetics in which identifying and targeting the key regulators of epigenetics such as C/EBPβ may provide more precise therapeutic options in ovarian cancer.

Guo HM, Sun L, Yang L, et al.
Microvesicles shed from bortezomib-treated or lenalidomide-treated human myeloma cells inhibit angiogenesis in vitro.
Oncol Rep. 2018; 39(6):2873-2880 [PubMed] Related Publications
Angiogenesis plays a significant role in the pathogenesis of multiple myeloma (MM). Microvesicles (MVs), a type of extracellular vesicles, are known as important players in cell-to-cell communication. MM-derived MVs have exhibited the activity of promoting angiogenesis. Bortezomib and lenalidomide are important drugs for treating myeloma. Therefore, the aim of the present study was to investigate whether and how MVs secreted from human myeloma cells exposed to bortezomib and lenalidomide affect angiogenesis. RPMI-8226 human myeloma cells and human umbilical vein endothelial cells (HUVECs) were used. MVs were isolated from the drug-treated RPMI-8226 cells. The number of the MVs were analyzed with flow cytometry. The expression of pro-angiogenic factors was analyzed with PCR and ELISA. The angiogenic potential of HUVECs was examined. NF-κB activation was analyzed using PCR, immunofluorescent staining and western blotting assays. We showed that bortezomib treatment induced an increase in the number of MVs shed from myeloma cells, but the number of MVs was not significantly altered by lenalidomide. The expression levels of vascular endothelial growth factor (VEGF), interleukin 6 (IL-6) and basic fibroblast growth factor (bFGF) were reduced in the MVs from the RPMI-8226 cells exposed to bortezomib and lenalidomide. Consequently, these MVs exhibited reduced angiogenic potential, as evaluated by wound healing tests, Boyden chamber assays and tube formation assays. Co-culturing HUVECs with drug-treated MVs inhibited NF-κB activation in the HUVECs and reduced the secretion of pro-angiogenic factors. In conclusion, bortezomib and lenalidomide treatment of cultured myeloma cells can block MV-induced angiogenesis and hence provides another mechanism for anti-angiogenic therapy.

Song Z, Ren D, Xu X, Wang Y
Molecular cross-talk of IL-6 in tumors and new progress in combined therapy.
Thorac Cancer. 2018; 9(6):669-675 [PubMed] Article available free on PMC after 07/09/2019 Related Publications
IL-6, a cytokine activated by type I interferons (IFNs), is encoded by the IL-6 gene, and secreted by T cells and macrophages. It serves many purposes in the human body and is significant to pathological and physiological activities, such as acute inflammatory responses, autoimmune diseases, and tumor formation. The wide range of IL-6 actions on tumors rely on more than one specific pathway. Advances in modern research have determined that to fulfill its complex physiological functions, IL-6 must be involved in cross-talk with a number of other molecular pathways. Therefore, it is important to clarify the comprehensive pathway network associated with IL-6 activity and to explore the mechanisms to inhibit its pathological activity in order to develop corresponding treatment plans. This study is a simple review of the pathological and physiological actions of IL-6 on the human body. It explains in detail the molecular pathways involved in cross-talk between IL-6 and tumors, summarizing and discussing the latest progress made in IL-6-related internal medicine treatments in recent years, including chemotherapies, targeted therapies, and immunotherapies. Our results provide new insight into the treatment of tumors.

Basu SK, Gonit M, Salotti J, et al.
A RAS-CaMKKβ-AMPKα2 pathway promotes senescence by licensing post-translational activation of C/EBPβ through a novel 3'UTR mechanism.
Oncogene. 2018; 37(26):3528-3548 [PubMed] Article available free on PMC after 07/09/2019 Related Publications
Oncogene-induced senescence (OIS) is an intrinsic tumor suppression mechanism that requires the p53 and RB pathways and post-translational activation of C/EBPβ through the RAS-ERK cascade. We previously reported that in transformed/proliferating cells, C/EBPβ activation is inhibited by G/U-rich elements (GREs) in its 3'UTR. This mechanism, termed "3'UTR regulation of protein activity" (UPA), maintains C/EBPβ in a low-activity state in tumor cells and thus facilitates senescence bypass. Here we show that C/EBPβ UPA is overridden by AMPK signaling. AMPK activators decrease cytoplasmic levels of the GRE binding protein HuR, which is a key UPA component. Reduced cytoplasmic HuR disrupts 3'UTR-mediated trafficking of Cebpb transcripts to the peripheral cytoplasm-a fundamental feature of UPA-thereby stimulating C/EBPβ activation and growth arrest. In primary cells, oncogenic RAS triggers a Ca

Wakabayashi H, Hamaguchi T, Nagao N, et al.
Interleukin-6 receptor inhibitor suppresses bone metastases in a breast cancer cell line.
Breast Cancer. 2018; 25(5):566-574 [PubMed] Related Publications
BACKGROUND: Interleukin-6 (IL-6) is a potent inflammatory cytokine that appears to play a key role in cancer growth and metastasis. In the present study, the effects of IL-6 receptor (IL-6R) on breast cancer aggressiveness and bone metastases were investigated.
METHODS: MDA-MB-231 (MDA-231) cells were treated in the presence or absence of anti-human IL-6 receptor (IL-6R) monoclonal antibody and examined with respect to cell survival. The expressions of signal transducer and activator of transcription 3 (Stat3), vascular endothelial growth factor (VEGF), and receptor activator of NF-κB (RANK) were analyzed by SDS-PAGE and immunoblotting. MDA-231 cells were injected into the left ventricle of mice, and then anti-human IL-6R monoclonal antibody or saline was administered intraperitoneally for 28 days. After 28 days, the incidence of bone metastases was evaluated in the hind limbs by radiography and histology.
RESULTS: Anti-human IL-6R monoclonal antibody reduced bone metastases in an animal model injected with MDA-231 cells on radiological and histomorphometric analyses. The mechanism of bone metastasis inhibition involved inhibited cell proliferation and decreased expressions of phospho-Stat3, VEGF, and RANK in MDA-231 cells.
CONCLUSIONS: The results of the present study suggest that inhibition of IL-6 signaling may become a preventive therapeutic option for breast cancer and bone metastases.

Xu S, Yang Z, Jin P, et al.
Metformin Suppresses Tumor Progression by Inactivating Stromal Fibroblasts in Ovarian Cancer.
Mol Cancer Ther. 2018; 17(6):1291-1302 [PubMed] Related Publications
Ovarian cancer is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in ovarian cancer. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the ovarian cancer tumor cells. First, we found a significant stromal overexpression of IL6 in patient samples that received cisplatin-based treatment, which was further validated in purified fibroblasts challenged with cisplatin. Stromal fibroblast-derived IL6 was proven to mediate ovarian cancer tumor cell chemoresistance. For the first time, we found that the tumor stroma of patients with routine metformin administration exhibited lower IL6 expression. Thus, we presumed that metformin was a potent alleviator of stromal inflammation in ovarian cancer. We found that metformin partly reversed cisplatin-stimulated IL6 secretion in the stromal fibroblasts and attenuated fibroblast-facilitated tumor growth in 3D organotypic cocultures and murine xenograft models. Mechanistically, we found that metformin inhibited IL6 secretion via suppressing NFκB signaling, an upstream controller of stromal inflammation. Collectively, our findings introduced a novel mechanism of metformin in suppressing ovarian cancer progression through diminishing chemotherapy-induced stromal activation. Therefore, we provide an alternative therapeutic option in targeting stromal inflammation and a potential scheme of combination therapy to improve the chemosensitivity in ovarian cancer.

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