Gene Summary

Gene:BAG3; BCL2 associated athanogene 3
Aliases: BIS, MFM6, BAG-3, CAIR-1
Summary:BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:BAG family molecular chaperone regulator 3
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (10)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 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.

  • Down-Regulation
  • Immunohistochemistry
  • Thyroid Cancer
  • DNA-Binding Proteins
  • Biomarkers, Tumor
  • Signal Transduction
  • Transfection
  • Drug Resistance
  • Signal Transducing Adaptor Proteins
  • Gene Knockdown Techniques
  • Apoptosis
  • Ovarian Cancer
  • Chromosome 10
  • Heat Shock Transcription Factors
  • Transcription
  • Neoplasm Invasiveness
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Cell Proliferation
  • MicroRNAs
  • Autophagy
  • HSP70 Heat-Shock Proteins
  • Antineoplastic Agents
  • Ubiquitination
  • Promoter Regions
  • Cell Movement
  • Cell Survival
  • bcl-X Protein
  • Prostate Cancer
  • Transcription Factors
  • Gene Expression
  • siRNA
  • Lung Cancer
  • Western Blotting
  • MMP2
  • Glioblastoma
  • Gene Expression Profiling
  • Epithelial-Mesenchymal Transition
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Apoptosis Regulatory Proteins
  • BCL2 protein
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BAG3 (cancer-related)

Dusek J, Skoda J, Holas O, et al.
Stilbene compound trans-3,4,5,4´-tetramethoxystilbene, a potential anticancer drug, regulates constitutive androstane receptor (Car) target genes, but does not possess proliferative activity in mouse liver.
Toxicol Lett. 2019; 313:1-10 [PubMed] Related Publications
The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.

Benites J, Valderrama JA, Ramos M, et al.
Half-Wave Potentials and In Vitro Cytotoxic Evaluation of 3-Acylated 2,5-
Molecules. 2019; 24(9) [PubMed] Free Access to Full Article Related Publications
A broad range of 3-acyl-2,5-

Mohankumar K, Li X, Sridharan S, et al.
Nuclear receptor 4A1 (NR4A1) antagonists induce ROS-dependent inhibition of mTOR signaling in endometrial cancer.
Gynecol Oncol. 2019; 154(1):218-227 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
OBJECTIVES: NR4A1 is overexpressed in many solid tumors, and the objectives of this study were to investigate the expression and functional role of this receptor in endometrial cancer cells and demonstrate that NR4A1 antagonist inhibit mTOR.
METHODS: Ishikawa and Hec-1B endometrial cells were used as models to investigate the parallel effects of NR4A1 knockdown by RNA interference (siNR4A1) and treatment with bis-indole-derived NR4A1 ligands (antagonists) on cell growth and survival by determining cell numbers and effects on Annexin V staining. Western blot analysis of whole cell lysates was used to determine effects of these treatments on expression of growth promoting, survival and apoptotic genes and mTOR signaling. Effects of NR4A1 antagonists on tumor growth were determined in athymic nude mice bearing Hec-1B cells as xenografts.
RESULTS: siNR4A1 or treatment with bis-indole-derived NR4A1 antagonists inhibited growth of endometrial cancer cells in vitro and endometrial tumors in vivo and this was accompanied by decreased expression of growth promoting and survival genes and mTOR inhibition.
CONCLUSIONS: NR4A1 exhibited pro-oncogenic activity in endometrial cells due, in part, to regulation of cell growth, survival and mTOR signaling, and all of these pathways and their associated gene products were inhibited after treatment with bis-indole-derived NR4A1 antagonists. Moreover, these compounds also blocked endometrial tumor growth in vivo demonstrating that NR4A1 is a potential novel drug target for treatment of endometrial cancer.

Saeinasab M, Bahrami AR, González J, et al.
SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF.
J Exp Clin Cancer Res. 2019; 38(1):172 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Thousands of long noncoding RNAs (lncRNAs) are aberrantly expressed in various types of cancers, however our understanding of their role in the disease is still very limited.
METHODS: We applied RNAseq analysis from patient-derived data with validation in independent cohort of patients. We followed these studies with gene regulation analysis as well as experimental dissection of the role of the identified lncRNA by multiple in vitro and in vivo methods.
RESULTS: We analyzed RNA-seq data from tumors of 456 CRC patients compared to normal samples, and identified SNHG15 as a potentially oncogenic lncRNA that encodes a snoRNA in one of its introns. The processed SNHG15 is overexpressed in CRC tumors and its expression is highly correlated with poor survival of patients. Interestingly, SNHG15 is more highly expressed in tumors with high levels of MYC expression, while MYC protein binds to two E-box motifs on SNHG15 sequence, indicating that SNHG15 transcription is directly regulated by the oncogene MYC. The depletion of SNHG15 by siRNA or CRISPR-Cas9 inhibits cell proliferation and invasion, decreases colony formation as well as the tumorigenic capacity of CRC cells, whereas its overexpression leads to opposite effects. Gene expression analysis performed upon SNHG15 inhibition showed changes in multiple relevant genes implicated in cancer progression, including MYC, NRAS, BAG3 or ERBB3. Several of these genes are functionally related to AIF, a protein that we found to specifically interact with SNHG15, suggesting that the SNHG15 acts, at least in part, by regulating the activity of AIF. Interestingly, ROS levels, which are directly regulated by AIF, show a significant reduction in SNHG15-depleted cells. Moreover, knockdown of SNHG15 increases the sensitiveness of the cells to 5-FU, while its overexpression renders them more resistant to the chemotherapeutic drug.
CONCLUSION: Altogether, these results describe an important role of SNHG15 in promoting colon cancer and mediating drug resistance, suggesting its potential as prognostic marker and target for RNA-based therapies.

Gergely PA, Murnyák B, Bencze J, et al.
Tyrosine Kinase Inhibitor Imatinib Mesylate Alters DMBA-Induced Early Onco/Suppressor Gene Expression with Tissue-Specificity in Mice.
Biomed Res Int. 2019; 2019:8670398 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Tyrosine kinases play crucial roles in cellular development and tumorigenesis. Tyrosine kinase inhibitors (TKIs) are effective and widely used drug molecules in targeted cancer therapies. Altered expressions of protooncogenes and tumor suppressor genes after DMBA (7,12-dimethylbenz[a]anthracene) treatment have been described as early markers of tumor induction; however their tissue-specific effects remain still unclear. Our study was aimed at examining the short-term possible antineoplastic and chemopreventive effects of a TKI compound (imatinib mesylate) on a DMBA-induced mouse tumor model. In addition, we also investigated the tissue-specific expressions of

Gurung SK, Dana S, Mandal K, et al.
Downregulation of c-Myc and p21 expression and induction of S phase arrest by naphthalene diimide derivative in gastric adenocarcinoma cells.
Chem Biol Interact. 2019; 304:106-123 [PubMed] Related Publications
Naphthalene diimide (NDI) derivatives have been shown to exhibit promising antineoplastic properties. In the current study, we assessed the anticancer and anti-bacterial properties of di-substituted NDI derivative. The naphthalene-bis-hydrazimide, 1, negatively affected the cell viability of three cancer cell lines (AGS, HeLa and PC3) and induced S phase cell cycle arrest along with SubG0/G1 accumulation. Amongst three cell lines, gastric cancer cell line, AGS, showed the highest sensitivity towards the NDI derivative 1. Compound 1 induced extensive DNA double strand breaks causing p53 activation leading to transcription of p53 target gene p21 in AGS cells. Reduction in protein levels of p21 and BRCA1 suggested that 1 treated AGS cells underwent cell death due to accumulation of DNA damage as a result of impaired DNA damage repair. β-catenin downregulation and consequently decrease in levels of c-Myc may have led to 1 induced AGS cell proliferation inhibition.1 induced AGS cell S phase arrest was mediated through CylinA/CDK2 downregulation. The possible mechanisms involved in anticancer activity of 1 includes ROS upregulation, induction of DNA damage, disruption of mitochondrial membrane potential causing ATP depletion, inhibition of cell proliferation and downregulation of antiapoptotic factors ultimately leading to mitochondria mediated apoptosis. Further compound 1 also inhibited H. pylori proliferation as well as H. pylori induced morphological changes in AGS cells. These findings suggest that NDI derivative 1 exhibits two-pronged anticancer activity, one by directly inhibiting cancer cell growth and inducing apoptosis and the other by inhibiting H. pylori.

Chou FJ, Chen Y, Chen D, et al.
Preclinical study using androgen receptor (AR) degradation enhancer to increase radiotherapy efficacy via targeting radiation-increased AR to better suppress prostate cancer progression.
EBioMedicine. 2019; 40:504-516 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: While androgen deprivation therapy (ADT) and radiotherapy (RT) are currently used together to treat locally advanced prostate cancer (PCa), RT might have the adverse effect of increasing the PCa androgen receptor (AR) protein expression, which might then increase the resistance to continued RT.
METHODS: We used multiple assays for RT sensitivity, protein and RNA expression of AR and related DDR genes, ROS level, DNA damage/repair level, cell cycle and apoptosis. All statistical comparisons were analyzed with t-test or one-way ANOVA.
FINDINGS: We demonstrated that RT induced AR expression in C4-2 and CWR22Rv-1 cells. We found that combining RT and ASC-J9
INTERPRETATION: Targeting ionizing radiation (IR)-increased AR with the AR degradation enhancer, ASC-J9

Turini S, Bergandi L, Gazzano E, et al.
Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-β as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event.
Int J Mol Sci. 2019; 20(1) [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Asbestos exposure increases the risk of asbestosis and malignant mesothelioma (MM). Both fibrosis and cancer have been correlated with the Epithelial to Mesenchymal Transition (EMT)-an event involved in fibrotic development and cancer progression. During EMT, epithelial cells acquire a mesenchymal phenotype by modulating some proteins. Different factors can induce EMT, but Transforming Growth Factor β (TGF-β) plays a crucial role in promoting EMT. In this work, we verified if EMT could be associated with MM development. We explored EMT in human mesothelial cells (MeT-5A) exposed to chrysotile asbestos: we demonstrated that asbestos induces EMT in MeT-5A cells by downregulating epithelial markers E-cadherin, β-catenin, and occludin, and contemporarily, by upregulating mesenchymal markers fibronectin, α-SMA, and vimentin, thus promoting EMT. In these cells, this mechanism is mediated by increased TGF-β secretion, which in turn downregulates E-cadherin and increases fibronectin. These events are reverted in the presence of TGF-β antibody, via a Small Mother Against Decapentaplegic (SMAD)-dependent pathway and its downstream effectors, such as Zinc finger protein SNAI1 (SNAIL-1), Twist-related protein (Twist), and Zinc Finger E-Box Binding Homeobox 1 (ZEB-1), which downregulate the

Hasni MS, Yakimchuk K
Expression and Effects of Ligand-activated Estrogen Receptors in Chronic Lymphocytic Leukemia.
Anticancer Res. 2019; 39(1):167-172 [PubMed] Related Publications
BACKGROUND/AIM: Recent epidemiological data indicate that lymphoid tumors may be influenced by estrogens. The effects of estrogens are mediated via nuclear estrogen receptors α (ERα) and β (ERβ). This study investigated the potential functions of ligand-activated ERs in chronic lymphocytic leukemia (CLL).
MATERIALS AND METHODS: The ER mRNA expression in B lymphocytes isolated from patients with CLL was analyzed by quantitative real-time polymerase chain reaction. To evaluate the effects of ERβ signaling, primary CLL cells and CLL-derived MEC1 cells were treated with selective ERβ agonists.
RESULTS: The mRNA expression of ERα, ERβ1 and its splice variant ERβ2 was detected in CLL cells. Selective ERβ agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile induced apoptosis in primary CLL cells and suppressed the growth of CLL-derived MEC1 cells.
CONCLUSION: A suppressive effect of ERβ agonists on the growth of ERβ-expressing CLL cells was found, indicating that ERβ may be considered as a potential therapeutic target in CLL.

Moayedi Y, Greenberg SA, Jenkins BA, et al.
Camphor white oil induces tumor regression through cytotoxic T cell-dependent mechanisms.
Mol Carcinog. 2019; 58(5):722-734 [PubMed] Related Publications
Bioactive derivatives from the camphor laurel tree, Cinnamomum camphora, are posited to exhibit chemopreventive properties but the efficacy and mechanism of these natural products are not fully understood. We tested an essential-oil derivative, camphor white oil (CWO), for anti-tumor activity in a mouse model of keratinocyte-derived skin cancer. Daily topical treatment with CWO induced dramatic regression of pre-malignant skin tumors and a two-fold reduction in cutaneous squamous cell carcinomas. We next investigated underlying cellular and molecular mechanisms. In cultured keratinocytes, CWO stimulated calcium signaling, resulting in calcineurin-dependent activation of nuclear factor of activated T cells (NFAT). In vivo, CWO induced transcriptional changes in immune-related genes identified by RNA-sequencing, resulting in cytotoxic T cell-dependent tumor regression. Finally, we identified chemical constituents of CWO that recapitulated effects of the admixture. Together, these studies identify T cell-mediated tumor regression as a mechanism through which a plant-derived essential oil diminishes established tumor burden.

Petrera M, Paleari L, Clavarezza M, et al.
The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients.
BMC Cancer. 2018; 18(1):1210 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials.
METHODS/DESIGN: This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year.
DISCUSSION: A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC.
TRIAL REGISTRATION: EudraCT Number: 2015-004824-77; Identifier: NCT03047837 . Registered on February 1, 2017.

Lee JC, Koh SA, Lee KH, Kim JR
BAG3 contributes to HGF-mediated cell proliferation, migration, and invasion via the Egr1 pathway in gastric cancer.
Tumori. 2019; 105(1):63-75 [PubMed] Related Publications
INTRODUCTION:: Bcl2-associated athanogene 3 (BAG3) is elevated in several types of cancers. However, the role of BAG3 in progression of gastric cancer is unknown. Therefore, the present study aims to find out the role of BAG3 in hepatocyte growth factor (HGF)-mediated tumor progression and the molecular mechanisms by which HGF regulates BAG3 expression.
METHODS:: BAG3 mRNA and protein were measured using reverse transcription polymerase chain reaction and Western blot in the 2 human gastric cancer cell lines, NUGC3 and MKN28, treated with or without HGF. The effects of BAG3 knockdown on cell proliferation, cell invasion, and apoptosis were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the in vitro 2-chamber invasion assay, and flow cytometry in BAG3 short hairpin RNA (shRNA)-transfected cells and control cells. The signaling pathways involved in BAG3 that are regulated by HGF were analyzed. The chromatin immunoprecipitation assay was used to determine binding of Egr1 to the BAG3 promoter.
RESULTS:: BAG3 mRNA and protein levels were increased following treatment with HGF. HGF-mediated BAG3 upregulation increased cell proliferation and cell invasion; however, it decreased apoptosis. HGF-mediated BAG3 upregulation is regulated by an ERK and Egr1-dependent pathway. BAG3 may have an important role in HGF-mediated cell proliferation and metastasis in gastric cancer through an ERK and Egr1-dependent pathway.
CONCLUSION:: This pathway may provide novel therapeutic targets and provide information for further identification of other targets of therapeutic significance in gastric cancer.

Lu Y, Jiang W, Wu X, et al.
Peptide T7-modified polypeptide with disulfide bonds for targeted delivery of plasmid DNA for gene therapy of prostate cancer.
Int J Nanomedicine. 2018; 13:6913-6927 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Background: Vectors are essential for successful gene delivery. In the present study, a tumor-targeting cationic gene vector, known as the disulfide cross-linked arginine-aspartic acid peptide modified by HAIYPRH (T7) peptide (CRD-PEG-T7), was designed for targeted delivery of plasmid DNA (pDNA) for gene therapy of prostate cancer (PCa).
Methods: The structure of CRD-PEG-T7 was determined and the cellular uptake efficacy, gene transfection efficacy, cytotoxicity, and the targeting effect of the CRD-PEG-T7-plasmid DNA complex were examined.
Results: The results demonstrated that the CRD-PEG-T7-plasmid DNA complex was nanosized and had a positively charged surface, good cellular uptake efficacy, minimal cytotoxicity, and a dual-targeting effect as compared with the CRD-PEG-plasmid DNA complex. The peptide T7-modifed new delivery system was able to target the highly expressed transferrin receptor (TfR) on tumor cells with an efficiency four-fold higher than that of the non-modified system.
Conclusion: The results above indicatd that the CRD-PEG-T7-plasmid DNA complex may prove to be a promising gene delivery system targeting bone-metastatic tumor.

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

Jahangiri A, Dadmanesh M, Ghorban K
Suppression of STAT3 by S31-201 to reduce the production of immunoinhibitory cytokines in a HIF1-α-dependent manner: a study on the MCF-7 cell line.
In Vitro Cell Dev Biol Anim. 2018; 54(10):743-748 [PubMed] Related Publications
Signal transducer and activator of transcription 3 (STAT3) interacts with many gene promoters and transcription factors such as hypoxia-induced factor 1α (HIF-1α). Recent evidences proposed that STAT3 and HIF-1α together are responsible for angiogenesis and immune response suppression. The main aim of this study was to inhibit STAT3 and HIF-1α and assess their effects on the expression of immunosuppressive cytokines. S31-201 and PX-478 were used to inhibit STAT3 and HIF-1α, respectively. In both hypoxic and normoxic conditions, intracellular levels of HIF-1α were evaluated by western blotting and flow cytometry. Supernatant levels were also measured for VEGF, IL-10, and TGF-β concentration. S31-201 suppressed proliferation of MCF-7 cells and led to reduced HIF-1α expression in both hypoxic and normoxic conditions. It also decreased production of the immunosuppressive cytokines. STAT3 inhibition suppressed tumor cell growth and cytokine production in a HIF-1α-dependent manner, and can be used as a promising target in cancer therapies.

Rahman FU, Bhatti MZ, Ali A, et al.
Dimetallic Ru(II) arene complexes appended on bis-salicylaldimine induce cancer cell death and suppress invasion via p53-dependent signaling.
Eur J Med Chem. 2018; 157:1480-1490 [PubMed] Related Publications
A series of bis-salicylaldimine ligands bearing two ON-donor functions were reacted with dichloro(p-cymene)ruthenium(II) dimer in the presence of base (NaOAc) and a series of four dimetallic Ru(II) arene complexes (Ru(p-cymene))

Rosenthal EA, Shirts BH, Amendola LM, et al.
Rare loss of function variants in candidate genes and risk of colorectal cancer.
Hum Genet. 2018; 137(10):795-806 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.

Yang F, Qiu W, Li R, et al.
Genome-wide identification of the interactions between key genes and pathways provide new insights into the toxicity of bisphenol F and S during early development in zebrafish.
Chemosphere. 2018; 213:559-567 [PubMed] Related Publications
Bisphenol F (BPF) and bisphenol S (BPS) have been widely used as alternatives to bisphenol A (BPA). With their increasing use, BPF and BPS have also been released into the environment; thus, their potential risks to aquatic organisms and humans are drawing attention. The objective of this study was to identify the interactions between key pathways and hub genes in zebrafish following BPF and BPS exposure, and to evaluate the potential risks to human health. We identified three key pathways using KEGG over-representation test and Gene Set Enrichment Analysis (GSEA): 'Necroptosis,' 'Adipocytokine signaling pathway,' and 'C-type lectin receptor signaling pathway.' Moreover, three hub genes (mst1ra, prkcdb, and pik3cb) and detailed interactions among the pathways were examined by the analyses of PPI network, subcellular location, and shortest-pathway. Surprisingly, all three pathways were strongly associated with a potential risk of cancer, as reported previously. In addition, the results of KOBAS shown in 'Pathways in Cancer' and 'Cancers' belong to the top 10 terms in pathway enrichment analyses using genes related to BPF or BPS in human, as was found using GenCLiP. Moreover, the Kaplan-Meier survival analysis was performed using homologenes (MST1R, PIK3CB and PRKCD) of hub genes in human to evaluate whether exposure to bisphenols may adversely affect breast cancer. Taken together, these studies demonstrate the potential carcinogenicity of BPF and BPS. To our knowledge, this is the first study on three overlapping key pathways and three hub genes to investigate BPF and BPS exposure-related mechanisms and subsequent interactions in zebrafish.

Amr AEE, Abo-Ghalia MH, Moustafa GO, et al.
Design, Synthesis and Docking Studies of Novel Macrocyclic Pentapeptides as Anticancer Multi-Targeted Kinase Inhibitors.
Molecules. 2018; 23(10) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
A series of macrocyclic pyrido-pentapeptide candidates

Lee J, Yun HH, Kim S, et al.
Implication of BIS in the Migration and Invasion of A549 Non-small Cell Lung Cancer Cells.
Anticancer Res. 2018; 38(9):5057-5065 [PubMed] Related Publications
BACKGROUND/AIM: High expression of the Bcl-2-interacting cell death suppressor (BIS), an anti-apoptotic protein, in various human cancers is linked to a poor outcome. The purpose of this study was to clarify whether BIS is associated with the migration and invasive characteristics of A549 cells.
MATERIALS AND METHODS: BIS-knockout (KO) cells were prepared by the CRISPR/Cas9 method. The aggressive behaviors of A549 cells were analyzed by wound healing and a transwell invasion assay as well as 3D spheroid culture.
RESULTS: BIS depletion resulted in significant inhibition of the migration and invasive potential of A549 cells which was accompanied by an increased ratio of E-cadherin/N-cadherin and a decrease in the mRNA levels of Zeb1, Snail, Slug and MMP-2. NF-ĸB activity was suppressed in BIS-KO A549 cells due to the decrease in p65 protein levels, but not in mRNA levels.
CONCLUSION: BIS regulates cell invasion and the induction of the epithelial-mesenchymal transition (EMT) phenotype in A549 cells probably via the NF-ĸB signaling pathway.

da Cruz RS, Carney EJ, Clarke J, et al.
Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring.
Breast Cancer Res. 2018; 20(1):99 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: While many studies have shown that maternal factors in pregnancy affect the cancer risk for offspring, few studies have investigated the impact of paternal exposures on their progeny's risk of this disease. Population studies generally show a U-shaped association between birthweight and breast cancer risk, with both high and low birthweight increasing the risk compared with average birthweight. Here, we investigated whether paternal malnutrition would modulate the birthweight and later breast cancer risk of daughters.
METHODS: Male mice were fed AIN93G-based diets containing either 17.7% (control) or 8.9% (low-protein (LP)) energy from protein from 3 to 10 weeks of age. Males on either group were mated to females raised on a control diet. Female offspring from control and LP fathers were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary carcinogenesis. Mature sperm from fathers and mammary tissue and tumors from female offspring were used for epigenetic and other molecular analyses.
RESULTS: We found that paternal malnutrition reduces the birthweight of daughters and leads to epigenetic and metabolic reprogramming of their mammary tissue and tumors. Daughters of LP fathers have higher rates of mammary cancer, with tumors arising earlier and growing faster than in controls. The energy sensor, the AMP-activated protein kinase (AMPK) pathway, is suppressed in both mammary glands and tumors of LP daughters, with consequent activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, LP mammary tumors show altered amino-acid metabolism with increased glutamine utilization. These changes are linked to alterations in noncoding RNAs regulating those pathways in mammary glands and tumors. Importantly, we detect alterations in some of the same microRNAs/target genes found in our animal model in breast tumors of women from populations where low birthweight is prevalent.
CONCLUSIONS: Our study suggests that ancestral paternal malnutrition plays a role in programming offspring cancer risk and phenotype by likely providing a metabolic advantage to cancer cells.

Murray-Stewart T, Dunworth M, Lui Y, et al.
Curcumin mediates polyamine metabolism and sensitizes gastrointestinal cancer cells to antitumor polyamine-targeted therapies.
PLoS One. 2018; 13(8):e0202677 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Curcumin, a natural polyphenol that contributes to the flavor and yellow pigment of the spice turmeric, is known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. Previous studies demonstrated that curcumin can inhibit ornithine decarboxylase (ODC) activity in human leukemia and breast cancer cells, and pretreatment with dietary curcumin blocks carcinogen-induced ODC activity in rodent models of skin, colon, and renal cancer. The current study investigated the regulation of polyamine metabolism in human gastric and colon carcinoma cell lines in response to curcumin. Curcumin treatment significantly induced spermine oxidase (SMOX) mRNA and activity, which results in the generation of hydrogen peroxide, a source of ROS. Simultaneously, curcumin down regulated spermidine/spermine N1-acetyltransferase (SSAT) activity and the biosynthetic enzymes ODC and S-adenosylmethionine decarboxylase (SAMDC), thereby diminishing intracellular polyamine pools. Combination treatments using curcumin with the ODC inhibitor 2-difluoromethylornithine (DFMO), an agent currently in clinical chemoprevention trials, significantly enhanced inhibition of ODC activity and decreased growth of GI cancer cell lines beyond that observed with either agent alone. Similarly, combining curcumin with the polyamine analogue bis(ethyl)norspermine enhanced growth inhibition that was accompanied by enhanced accumulation of the analogue and decreased intracellular polyamine levels beyond those observed with either agent alone. Importantly, cotreatment with curcumin permitted the lowering of the effective dose of ODC inhibitor or polyamine analogue. These studies provide insight into the polyamine-related mechanisms involved in the cancer cell response to curcumin and its potential as a chemopreventive or chemotherapeutic agent in the GI tract.

Nassan MA, Soliman MM, Ismail SA, El-Shazly S
Effect of
Biosci Rep. 2018; 38(6) [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Breast cancer is one of the most prevalent types of cancer and a leading cause of death in women.
MATERIALS AND METHODS: An experimental model of breast cancer was induced in female albino rats using single intragastric dose of 7, 12 dimethylbenz (α) anthracene (DMBA) in sesame oil (50 mg/kg b.wt). Four months after DMBA administration, incidence of breast cancer was confirmed by measuring cancer antigen 15-3 (CA15-3) serum levels.
RESULTS: Level of CA15-3 was normalized in DMBA group administered TOE for 4 weeks. Administration of DMBA increased expression of

Furusawa Y, Yunoki T, Hirano T, et al.
Identification of genes and genetic networks associated with BAG3‑dependent cell proliferation and cell survival in human cervical cancer HeLa cells.
Mol Med Rep. 2018; 18(4):4138-4146 [PubMed] Related Publications
Bcl‑2‑associated athanogene (BAG) 3, is a member of the BAG protein family and a known co‑chaperone of heat shock protein (HSP) 70. BAG3 serves a role in regulating a variety of cellular functions, including cell growth, proliferation and cell death including apoptosis. BAG3 is a stress‑inducible protein, however the constitutive expression level of BAG3 is increased in cancer cells compared with healthy cells. Recent proteomics technology combined with bioinformatics has revealed that BAG3 participates in an interactome with a number of proteins other than its typical partner HSP70. The functional types represented in the interactome included nucleic acid binding proteins and transcription factors, as well as chaperones, which indicated that overexpression of BAG3 may contribute to proliferation and cell survival through the alteration of gene transcription. While an increasing number of studies have addressed the function of BAG3 as a co‑chaperone protein, BAG3‑dependent alteration of gene transcription has not been studied extensively. The present study established two BAG3 knockout human cervical cancer HeLa cell clones and addressed the role of BAG3 in cell proliferation and survival through gene transcription, using DNA microarray‑based transcriptome analysis and bioinformatics. The present study also identified two genetic networks associated with 'cellular growth and proliferation' and 'cell death and survival', which are dysregulated in the absence of BAG3, and may therefore be linked to BAG3 overexpression in cancer. These findings provide a molecular basis for understanding of BAG3‑dependent cell proliferation and survival from the aspect of alteration of gene expression.

Li N, Chen M, Cao Y, et al.
Bcl-2-associated athanogene 3(BAG3) is associated with tumor cell proliferation, migration, invasion and chemoresistance in colorectal cancer.
BMC Cancer. 2018; 18(1):793 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: CRC is one of the most common malignancies worldwide, and its molecular mechanisms remain unclear. Elevated levels of BAG3 have been reported in various tumors. The present study aimed to explore the expression and function of BAG3 in CRC.
METHODS: BAG3 protein expression was evaluated in 90 CRC specimens using immunohistochemistry in tissue microarrays, and the correlation between BAG3 expression and the clinicopathological features were assessed. In HCT116 cells BAG3 overexpression cell models were constructed, and CRISPR/Cas9 was used for BAG3 knockout. Western blotting and quantitative real-time PCR were used to determine BAG3 expression in HCT-116 Cells. Cell proliferation, migration and invasion were analyzed by cell counting, colony formation assay, EdU cell proliferation assay, RTCA growth curve assays, wound-healing migration assay and transwell invasion assay. The influence of BAG3 expression level on chemoresistance in HCT-116 cells was examined. Gene expression microarray and IPA analyses were employed to explore signaling pathways associated with the control of BAG3.
RESULTS: Using immunohistochemistry, this study found that BAG3 was markedly upregulated in colorectal cancer tissues and that BAG3 levels were significantly associated with tumor size and gender. BAG3 overexpression promoted HCT-116 cell growth, migration and invasion in vitro. In contrast, BAG3 knockout inhibited HCT-116 cell growth, migration and invasion. HCT-116 cells with high expression of BAG3 had higher cell viability and lower apoptosis rate than control cells after treatment with 5-FU, while the BAG3 knockout group demonstrated the opposite effects. So BAG3 expression level was associated with chemoresistance to 5-FU in HCT-116 cells. Gene expression microarrays and bioinformatics analyses of HCT-116 cells with BAG3 knockout demonstrated the involvement of BAG3 in signaling pathways associated with the control of cell proliferation, migration, invasion and chemoresistance in CRC.
CONCLUSIONS: In conclusion, this study provided evidence that BAG3 has a relevant role in CRC biology, and defined potential molecular pathways and networks. So BAG3 may be considered as a potential therapeutic target for anti-tumor therapy in colorectal cancer.

Kandhavelu J, Subramanian K, Khan A, et al.
Computational Analysis of miRNA and their Gene Targets Significantly Involved in Colorectal Cancer Progression.
Microrna. 2019; 8(1):68-75 [PubMed] Related Publications
BACKGROUND: Globally, colorectal cancer (CRC) is the third most common cancer in women and the fourth most common cancer in men. Dysregulation of small non-coding miRNAs have been correlated with colon cancer progression. Since there are increasing reports of candidate miRNAs as potential biomarkers for CRC, this makes it important to explore common miRNA biomarkers for colon cancer. As computational prediction of miRNA targets is a critical initial step in identifying miRNA: mRNA target interactions for validation, we aim here to construct a potential miRNA network and its gene targets for colon cancer from previously reported candidate miRNAs, inclusive of 10 up- and 9 down-regulated miRNAs from tissues; and 10 circulatory miRNAs.
METHODS: The gene targets were predicted using DIANA-microT-CDS and TarBaseV7.0 databases. Each miRNA and its targets were analyzed further for colon cancer hotspot genes, whereupon DAVID analysis and mirPath were used for KEGG pathway analysis.
RESULTS: We have predicted 874 and 157 gene targets for tissue and serum specific miRNA candidates, respectively. The enrichment of miRNA revealed that particularly hsa-miR-424-5p, hsa-miR-96-5p, hsa-miR-1290, hsa-miR-224, hsa-miR-133a and has-miR-363-3p present possible targets for colon cancer hallmark genes, including BRAF, KRAS, EGFR, APC, amongst others. DAVID analysis of miRNA and associated gene targets revealed the KEGG pathways most related to cancer and colon cancer. Similar results were observed in mirPath analysis. A new insight gained in the colon cancer network pathway was the association of hsa-mir-133a and hsa-mir-96-5p with the PI3K-AKT signaling pathway. In the present study, target prediction shows that while hsa-mir-424-5p has an association with mostly 10 colon cancer hallmark genes, only their associations with MAP2 and CCND1 have been experimentally validated.
CONCLUSION: These miRNAs and their targets require further evaluation for a better understanding of their associations, ultimately with the potential to develop novel therapeutic targets.

Hedrick E, Mohankumar K, Safe S
TGFβ-Induced Lung Cancer Cell Migration Is NR4A1-Dependent.
Mol Cancer Res. 2018; 16(12):1991-2002 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
TGFβ induces migration of lung cancer cells (A549, H460, and H1299), dependent on activation of c-Jun N-terminal kinase (JNK1), and is inhibited by the JNK1 inhibitor SP600125. Moreover, TGFβ-induced migration of the cells is also blocked by the nuclear export inhibitor leptomycin B (LMB) and the orphan nuclear receptor 4A1 (NR4A1) ligand 1,1-bis(3'-indolyl)-1-(

Lou B, Jin R, Cheng J, et al.
A hierarchical assembly strategy to engineer dextran-enveloped polyurethane nanopolyplexes for robust ovarian cancer gene therapy.
Acta Biomater. 2018; 78:260-273 [PubMed] Related Publications
A hierarchical assembly strategy is herein investigated to generate bio-responsive, dextran-enveloped, bioreducible polyurethane nanopolyplexes for nonviral gene therapy against ovarian tumor. Initially, a group of poly(urethane amine)s were designed and characterized for in vitro gene transfection. The polyurethane containing 1,4-bis(3-aminopropyl)piperazine residue (PUBAP) could induce the best in vitro transfection efficacy against SKOV-3 or A2780 ovarian cancer cells. Next, dextran-enveloped PUBAP polyplexes (e-polyplexes) were constructed by a hierarchical assembly procedure involving gene neutralization with PUBAP and subsequent gene condensation with a cationic dextran (SSDP800). Such dextran comprised dextran (15 kDa) as the main chain and multiple disulfide-linked branched polyethylenimine (BPEI) oligomers as the side grafts. Additionally, folate-dextran-enveloped PUBAP polyplexes (FA-e-polyplexes) were fabricated by folate-modified SSDP800. These nanoscale-enveloped polyplexes elicited an improved colloidal stability against salt ions and negatively charged heparin, efficient endosomal escaping, and bioreduction-triggered intracellular gene release. In vitro transfection against SKOV-3 cells illustrated that FA-e-polyplexes exerted higher transfection efficiency in the serum than e-polyplexes and 25 kDa BPEI-polyplexes. In vivo, FA-e-polyplexes yielded higher transgene expression level than e-polyplexes in an SKOV-3 tumor-bearing nude mouse model. In the tumor gene therapy with a small hairpin RNA silencing vascular endothelial growth factor, FA-e-polyplexes afforded higher tumor growth inhibition than polyplexes of folate-PEGylated PUBAP and 25 kDa linear polyethylenimine as positive controls. Importantly, such gene therapy had minor toxic effects on the health of the mouse. This work highlights a practical hierarchical assembly method to construct innovative enveloped polyurethane nanopolyplexes enabling robust ovarian cancer gene therapy.
STATEMENT OF SIGNIFICANCE: It is indispensable to rationally update binary cationic polyplexes into ternary polyplexes for vigorous tumor gene therapy. In this work, we have confirmed that a hierarchical assembly strategy, by using initial gene neutralization and subsequent gene condensation, is facile and effective to promote cationic polyurethane polyplexes into ternary folate-dextran-enveloped polyurethane polyplexes with a relatively high gene-loading capacity. The enveloped polyplex system enables more efficient gene transfection than the PEGylated polyplex counterpart in ovarian cancer in vitro and in vivo, thereby affording robust ovarian cancer gene therapy. The development of innovative enveloped polyplexes may be a new direction for a non-viral gene delivery system.

Li Y, Gu Y, Tang N, et al.
miR-22-Notch Signaling Pathway Is Involved in the Regulation of the Apoptosis and Autophagy in Human Ovarian Cancer Cells.
Biol Pharm Bull. 2018; 41(8):1237-1242 [PubMed] Related Publications
microRNA-22 (miR-22) is a brain-enriched regulatory gene which has been reported to be involved in the development of cancers. The Notch signaling pathway exerts important functions in cell growth. This study is designed to investigate the mechanisms of miR-22-Notch signaling pathway in apoptosis and autophagy of human ovarian cancer cells. After over-expressing miR-22 in human ovarian cancer cell lines OVCAR-3 and SKOV3, cell viability is determined by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) method, cell apoptosis is observed by Flow cytometry (FCM), mRNA expression of miR-22 is measured by RNA preparation and RT-PCR, protein expression of Notch1, Hes1, Beclin1 and LC3B-II is analyzed by Western blot. It is suggested that miR-22 expression is heavily decreased in human ovarian cancer cell lines OVCAR-3 and SKOV3. Over-expression of miR-22 potently suppresses cell viability and authophagy while promotes the percentage of apoptotic cancer cells. In addition, the decreased expression level of Notch1 and its targeted gene is detected in miR-22-over-expressed cells. Moreover, followed by the block of the Notch signaling pathway using Notch1 small interference RNA (siRNA), the effects of miR-22 on the apoptosis and autophagy of human ovarian cancer cell lines OVCAR-3 and SKOV3 are obviously blocked. Together, miR-22 inhibits apoptosis and promotes autophagy of human ovarian cancer cells through the suppression of the Notch signaling pathway, indicating a potential use of miR-22 in the ovarian cancer treatment.

Togashi K, Okada M, Yamamoto M, et al.
A Small-molecule Kinase Inhibitor, CEP-1347, Inhibits Survivin Expression and Sensitizes Ovarian Cancer Stem Cells to Paclitaxel.
Anticancer Res. 2018; 38(8):4535-4542 [PubMed] Related Publications
BACKGROUND: Chemoresistance of cancer stem cells (CSCs) is considered a major cause of post-treatment recurrence that negatively impacts the prognosis of patients with ovarian cancer.
MATERIALS AND METHODS: Using CSCs derived from two different ovarian cancer cell lines, we searched for molecules implicated in the chemoresistance of ovarian CSCs and also drugs with which to target those molecules.
RESULTS: Knockdown of survivin overexpressed in ovarian CSCs resulted in increased sensitivity to paclitaxel. Treatment at clinically relevant concentrations with CEP-1347, a mixed lineage kinase inhibitor with a known safety profile in humans, reduced survivin expression in ovarian CSCs and sensitized them to paclitaxel.
CONCLUSION: Survivin overexpression plays a key role in the chemoresistance of ovarian CSCs. Introduction of CEP-1347, which targets survivin expression in ovarian CSCs, as a chemosensitizer for conventional ovarian cancer chemotherapy may serve as a rational and feasible approach for better management of ovarian cancer.

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