Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-kappaB and Nrf2 Signaling Pathways.
Female; Animals; Anti-Inflammatory Agents/*pharmacology; Rats; Gene Expression Regulation; Signal Transduction; Apoptosis/drug effects; anti-inflammatory effects; Anticarcinogenic Agents/pharmacology; breast tumor; COX-2; Cyclooxygenase 2/genetics/metabolism; DMBA; HSP90; HSP90 Heat-Shock Proteins/genetics/metabolism; I-kappa B Kinase/genetics/metabolism; NF-E2-Related Factor 2/genetics/*metabolism; NF-kappa B/genetics/*metabolism; NF-kappaB; Nrf2; Plant Preparations/*pharmacology; Punica granatum; Punicaceae/*chemistry; Pomegranate; Chemoprevention; Dose-Response Relationship; Drug; Neoplastic; Mammary Neoplasms; 10-Dimethyl-1; 9; Neoplastic/drug effects; Cell Transformation; 2-benzanthracene/toxicity; Experimental/*prevention & control; Animal Studies; Breast Neoplasms; Inflammation Mediators; Physical Education and Training; Neoplasms – Prevention and Control
Pomegranate (Punica granatum L.), a nutrient-rich unique fruit, has been used for centuries for the prevention and treatment of various inflammation-driven diseases. Based on our previous study, a characterized pomegranate emulsion (PE) exhibited a striking inhibition of dimethylbenz(a)anthracene (DMBA)-initiated rat mammary tumorigenesis via antiproliferative and apoptosis-inducing mechanisms. The objective of the present work is to investigate the anti-inflammatory mechanism of action of PE during DMBA rat mammary carcinogenesis by evaluating the expression of cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-kappaB (NF-kappaB) and nuclear factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2). Mammary tumor samples were harvested from our previous chemopreventive study in which PE (0.2-5.0 g/kg) was found to reduce mammary tumorigenesis in a dose-dependent manner. The expressions of COX-2, HSP90, NF-kappaB, inhibitory kappaBalpha (IkappaBalpha) and Nrf2 were detected by immunohistochemical techniques. PE decreased the expression of COX-2 and HSP90, prevented the degradation of IkappaBalpha, hindered the translocation of
Mandal Animesh; Bhatia Deepak; Bishayee Anupam
Nutrients
2017
2017-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3390/nu9050436" target="_blank" rel="noreferrer noopener">10.3390/nu9050436</a>
Six stroma-based RNA markers diagnostic for prostate cancer in European-Americans validated at the RNA and protein levels in patients in China.
diagnosis; Adult; Humans; prostate cancer; Male; Middle Aged; Aged; Young Adult; Gene Expression Profiling; Gene Expression Regulation; Tumor Microenvironment; Biomarkers; China; European Continental Ancestry Group/genetics; microenvironment; Prostate/pathology; Prostatic Neoplasms/*diagnosis/*genetics; race; stroma; 80 and over; Neoplastic; Tumor/*genetics
We previously analyzed human prostate tissue containing stroma near to tumor and from cancer-negative tissues of volunteers. Over 100 candidate gene expression differences were identified and used to develop a classifier that could detect nearby tumor with an accuracy of 97% (sensitivity = 98% and specificity = 88%) based on 364 independent test cases from primarily European American cases. These stroma-based gene signatures have the potential to identify cancer patients among those with negative biopsies. In this study, we used prostate tissues from Chinese cases to validate six of these markers (CAV1, COL4A2, HSPB1, ITGB3, MAP1A and MCAM). In validation by real-time PCR, four genes (COL4A2, HSPB1, ITGB3, and MAP1A) demonstrated significantly lower expression in tumor-adjacent stroma compared to normal stroma (p value
Zhu Jian-Guo; Pan Cong; Jiang Jun; Deng Mingsen; Gao Hengjun; Men Bozhao; McClelland Michael; Mercola Dan; Zhong Wei-D; Jia Zhenyu
Oncotarget
2015
2015-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.18632/oncotarget.4430" target="_blank" rel="noreferrer noopener">10.18632/oncotarget.4430</a>
A class of genes in the HER2 regulon that is poised for transcription in breast cancer cell lines and expressed in human breast tumors.
Humans; Cell Line; *Gene Expression Regulation; Reverse Transcriptase Polymerase Chain Reaction; *Gene Expression Profiling; Breast Neoplasms/genetics/pathology; Gene Regulatory Networks; Homeodomain Proteins/genetics/metabolism; MCF-7 Cells; Nanog Homeobox Protein; Neoplastic Stem Cells/metabolism; Octamer Transcription Factor-3/genetics/metabolism; Regulon/*genetics; RNA Polymerase II/metabolism; SOXB1 Transcription Factors/genetics/metabolism; Tumor Microenvironment/genetics; Receptor; Blotting; Western; Tumor; Neoplastic; ErbB-2/*genetics/metabolism
HER2-positive breast cancer accounts for 25% of all cases and has a poor prognosis. Although progress has been made in understanding signal transduction, little is known of how HER2 achieves gene regulation. We performed whole genome expression analysis on a HER2(+) and HER2(-) breast cancer cell lines and compared these results to expression in 812 primary tumors stratified by their HER2 expression level. Chip-on-chip with anti-RNA polymerase II was compared among breast cancer cell lines to identify genes that are potentially activated by HER2. The expression levels of these HER2-dependent POL II binding genes were determined for the 812 HER2+/- breast cancer tissues. Genes differentially expressed between HER2+/- cell lines were generally regulated in the same direction as in breast cancer tissues. We identified genes that had POLII binding in HER2(+) cell lines, but without significant gene expression. Of 737 such genes "poised" for expression in cell lines, 113 genes were significantly differentially expressed in breast tumors in a HER2-dependent manner. Pathway analysis of these 113 genes revealed that a large group of genes were associated with stem cell and progenitor cell control as indicated by networks centered on NANOG, SOX2, OCT3/4. HER2 directs POL II binding to a large number of genes in breast cancer cells. A "poised" class of genes in HER2(+) cell lines with POLII binding and low RNA expression but is differentially expressed in primary tumors, strongly suggests a role of the microenvironment and further suggests a role for stem cells proliferation in HER2-regulated breast cancer tissue.
Rahmatpanah Farah B; Jia Zhenyu; Chen Xin; Char Jessica E; Men Bozhao; Franke Anna-Clara; Jones Frank E; McClelland Michael; Mercola Dan
Oncotarget
2015
2015-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.18632/oncotarget.2676" target="_blank" rel="noreferrer noopener">10.18632/oncotarget.2676</a>
MiR-21 enhances melanoma invasiveness via inhibition of tissue inhibitor of metalloproteinases 3 expression: in vivo effects of MiR-21 inhibitor.
Humans; Gene Expression Regulation; Cell Line; MicroRNAs/*genetics/metabolism; Cell Movement/genetics; Cell Proliferation/genetics; Melanoma/*genetics/metabolism/pathology; Neoplasm Invasiveness/*genetics/pathology; Skin Neoplasms/*genetics/metabolism/pathology; Tissue Inhibitor of Metalloproteinase-3/*genetics/metabolism; RNA; Tumor; Neoplastic; Small Interfering
Metastatic melanoma is the most aggressive form of this cancer. It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement treatments for melanoma. Increased cell invasion through the extracellular matrix is required for metastasis and is enhanced by matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits MMP activity. It was previously shown by our group that miR-21, a potential regulator of TIMP3, is over-expressed in cutaneous melanoma. It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21. Immunoblot analysis of miR-21-overexpressing cell lines revealed reduced expression of TIMP3 as compared to controls. This in turn led to a significant increase in the invasiveness of the radial growth phase cell line WM1552c and the vertical growth phase cell line WM793b (p \textless 0.05), but not in the metastatic cell lines A375 or MEL 39. The proliferation and migration of miR-21 over-expressing cell lines was not affected. Reduced expression of TIMP3 was achieved by siRNA knockdown and significantly enhanced invasion of melanoma cell lines, mimicking the effects of miR-21 over-expression. Treatment of tumor cells with a linked nucleic acid antagomir to miR-21 inhibited tumor growth and increased tumor expression of TIMP3 in vivo in 01B74 Athymic NCr-nu/nu mice. Intra-tumoral injections of anti-miR-21 produced similar effects. This data shows that increased expression of miR-21 enhanced the invasive potential of melanoma cell lines through TIMP3 inhibition. Therefore, inhibition of miR-21 in melanoma may reduce melanoma invasiveness.
Martin del Campo Sara E; Latchana Nicholas; Levine Kala M; Grignol Valerie P; Fairchild Ene T; Jaime-Ramirez Alena Cristina; Dao Thao-Vi; Karpa Volodymyr I; Carson Mary; Ganju Akaansha; Chan Anthony N; Carson William E 3rd
PloS one
2015
2015
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1371/journal.pone.0115919" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0115919</a>
Establishing reliable miRNA-cancer association network based on text-mining method.
Algorithms; Area Under Curve; Computational Biology/*methods; Data Mining/*methods; False Positive Reactions; Gene Expression Profiling/methods; Gene Expression Regulation; Gene Regulatory Networks; Humans; MicroRNAs/*genetics/*metabolism; Neoplasms/*genetics/metabolism; Neoplastic; Probability; Reproducibility of Results
Associating microRNAs (miRNAs) with cancers is an important step of understanding the mechanisms of cancer pathogenesis and finding novel biomarkers for cancer therapies. In this study, we constructed a miRNA-cancer association network (miCancerna) based on more than 1,000 miRNA-cancer associations detected from millions of abstracts with the text-mining method, including 226 miRNA families and 20 common cancers. We further prioritized cancer-related miRNAs at the network level with the random-walk algorithm, achieving a relatively higher performance than previous miRNA disease networks. Finally, we examined the top 5 candidate miRNAs for each kind of cancer and found that 71% of them are confirmed experimentally. miCancerna would be an alternative resource for the cancer-related miRNA identification.
Li Lun; Hu Xingchi; Yang Zhaowan; Jia Zhenyu; Fang Ming; Zhang Libin; Zhou Yanhong
Computational and mathematical methods in medicine
2014
1905-7
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1155/2014/746979" target="_blank" rel="noreferrer noopener">10.1155/2014/746979</a>
MicroRNA dysregulation in melanoma.
*Gene Expression Regulation; *Melanoma; *MicroRNA; Disease Progression; Humans; Melanoma/*genetics/*pathology; MicroRNAs/*genetics; Neoplastic; Prognosis
Melanoma is the deadliest form of skin cancer. Current challenges facing the management of melanoma include accurate prediction of individuals who will respond to adjuvant therapies as well as early detection of recurrences. These and other challenges have prompted investigation into biomarkers that could be used as diagnostic, prognostic and therapeutic aids. MicroRNAs (miRs) are small
Latchana Nicholas; Ganju Akaansha; Howard J Harrison; Carson William E 3rd
Surgical oncology
2016
2016-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.suronc.2016.05.017" target="_blank" rel="noreferrer noopener">10.1016/j.suronc.2016.05.017</a>
Lipopolysaccharide supports maintaining the stemness of CD133(+) hepatoma cells through activation of the NF-kappaB/HIF-1alpha pathway.
*Cancer stem cells; *Lipopolysaccharide; *Plasticity; *Stemness maintenance; *Tumor microenvironment; AC133 Antigen/genetics/*metabolism; alpha Subunit/genetics/*metabolism; Animals; Antineoplastic Agents – Pharmacodynamics; Antineoplastic Agents/pharmacology; Body Weights and Measures; Carcinoma; Cell Line; Cell Movement – Drug Effects; Cell Movement/drug effects; Cell Physiology; Cell Physiology – Drug Effects; Cell Proliferation/drug effects; Drug Resistance; Gene Expression Regulation; Genes; Genetic Techniques; Hepatocellular; Hepatocellular – Drug Therapy; Hepatocellular – Metabolism; Hepatocellular – Pathology; Hepatocellular/drug therapy/genetics/*metabolism/pathology; Humans; Hypoxia-Inducible Factor 1; Inbred BALB C; Lipopolysaccharides – Pharmacodynamics; Lipopolysaccharides/*pharmacology; Liver Neoplasms; Liver Neoplasms – Drug Therapy; Liver Neoplasms – Metabolism; Liver Neoplasms – Pathology; Liver Neoplasms/drug therapy/genetics/*metabolism/pathology; Male; Mice; Neoplasm; Neoplasm Invasiveness; Neoplastic; Neoplastic Stem Cells/*drug effects/metabolism/pathology; NF-kappa B – Metabolism; NF-kappa B/*metabolism; Nude; Phenotype; Proteins; Proteins – Metabolism; RNA Interference; Signal Transduction – Drug Effects; Signal Transduction/drug effects; Stem Cells – Drug Effects; Stem Cells – Metabolism; Stem Cells – Pathology; Time Factors; Transfection; Tumor Burden; Tumor Microenvironment
Due to the existence of cancer stem cells (CSCs), persistence and relapse of human hepatocellular carcinoma (HCC) are common after treatment with existing anti-cancer therapies. Emerging evidence indicates that lipopolysaccharide (LPS) plays a crucial role in aggravating HCC, but information about the effect of LPS on CSCs of HCC remains scant. Here, we report that the stemness of CD133(+) CSCs sorted from the human HCC cell line Huh7 was maintained well when cells were cultured with LPS. The reduction of CD133 expression was much lesser in cultured CSCs in the presence of LPS. In response to LPS stimulation, CSCs showed an increase in their activity of clonogenesis and tumorigenesis. LPS also supported maintaining CSC abilities of migration, invasion, and chemo-resistance. Treatment with HIF-1alpha-specific siRNA significantly reduced CD133 expression by CSCs at both mRNA and protein levels. Further, the expression of HIF-1alpha and CD133 was reduced in LPS-stimulated CSCs when the NF-kappaB inhibitor was added to the cell culture. HIF-1alpha-specific siRNA also effectively counteracted the effect of LPS on maintaining CSC abilities of migration and invasion. These data indicate that LPS, an important mediator in the liver tumor microenvironment, supports the maintenance of CSC stemness through signaling of the NF-kappaB/HIF-1alpha pathway. Our current study highlights LPS as a potential target for developing new therapeutic approaches to eliminate CSCs during the treatment of HCC.
Lai Fo-Bao; Liu Wen-Ting; Jing Ying-Ying; Yu Guo-Feng; Han Zhi-Peng; Yang Xue; Zeng Jian-Xing; Zhang Hang-Jie; Shi Rong-Yu; Li Xiao-Yong; Pan Xiao-Rong; Li Rong; Zhao Qiu-Dong; Wu Meng-Chao; Zhang Ping; Liu Jing-Feng; Wei Li-Xin
Cancer letters
2016
2016-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.canlet.2016.05.014" target="_blank" rel="noreferrer noopener">10.1016/j.canlet.2016.05.014</a>
Osteoactivin regulates head and neck squamous cell carcinoma invasion by modulating matrix metalloproteases.
*Cell Movement; Carcinoma; Cell Line; cell lines; Enzymologic; extracellular matrix; Gene Expression Regulation; Head and Neck Neoplasms/*enzymology/genetics/pathology; human; Humans; matrix metalloproteinases; Matrix Metalloproteinases; Membrane Glycoproteins/genetics/*metabolism; Messenger/genetics/metabolism; neoplasm invasion; Neoplasm Invasiveness; Neoplastic; RNA; RNA Interference; Secreted/genetics/*metabolism; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Squamous Cell/*enzymology/genetics/pathology; Transfection; Tumor
Nearly 60% of patients with head and neck squamous cell carcinoma (HNSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell migration and invasion, which are in part dependent on extracellular matrix degradation by matrix metalloproteinases. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies, and has been shown to upregulate matrix metalloproteinase (MMP) expression and activity. To determine how OA modulates MMP expression and activity in HNSCC, and to investigate OA effects on cell invasion, we assessed effects of OA treatment on MMP mRNA and protein expression, as well as gelatinase and caseinolytic activity in HNSCC cell lines. We assessed the effects of OA gene silencing on MMP expression, gelatinase and caseinolytic activity, and cell invasion. OA treatment had differential effects on MMP mRNA expression. OA treatment upregulated MMP-10 expression in UMSCC14a (p = 0.0431) and SCC15 (p \textless 0.0001) cells, but decreased MMP-9 expression in UMSCC14a cells (p = 0.0002). OA gene silencing decreased MMP-10 expression in UMSCC12 cells (p = 0.0001), and MMP-3 (p = 0.0005) and -9 (p = 0.0036) expression in SCC25 cells. In SCC15 and SCC25 cells, OA treatment increased MMP-2 (p = 0.0408) and MMP-9 gelatinase activity (p \textless 0.0001), respectively. OA depletion decreased MMP-2 (p = 0.0023) and -9 (p \textless 0.0001) activity in SCC25 cells. OA treatment increased 70 kDa caseinolytic activity in UMSCC12 cells consistent with tissue type plasminogen activator (p = 0.0078). OA depletion decreased invasive capacity of UMSCC12 cells (p \textless 0.0001). OA's effects on MMP expression in HNSCC are variable, and may promote cancer cell invasion.
Arosarena Oneida A; Barr Eric W; Thorpe Ryan; Yankey Hilary; Tarr Joseph T; Safadi Fayez F
Journal of cellular physiology
2018
2018-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jcp.25900" target="_blank" rel="noreferrer noopener">10.1002/jcp.25900</a>
Osteoactivin Promotes Migration of Oral Squamous Cell Carcinomas.
*Cell Movement; Carcinoma; Cell Adhesion; Cell Line; Cell Proliferation; Cell Survival; Enzyme Activation; Gene Expression Regulation; Head and Neck Neoplasms/genetics/*metabolism/pathology; Humans; Integrin beta1/metabolism; Membrane Glycoproteins/genetics/*metabolism; Messenger/metabolism; Mitogen-Activated Protein Kinases/metabolism; Mouth Neoplasms/genetics/*metabolism/pathology; Neoplasm Invasiveness; Neoplastic; Protein Binding; RNA; RNA Interference; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Squamous Cell/genetics/*metabolism/pathology; Time Factors; Transfection; Tumor
Nearly 50% of patients with oral squamous cell carcinoma (OSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell adhesion, migration, and invasion. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies. The aims were to determine how integrin interactions modulate OA-induced OSCC cell migration; and to investigate OA effects on cell survival and proliferation. We confirmed OA mRNA and protein overexpression in OSCC cell lines. We assessed OA's interactions with integrins using adhesion inhibition assays, fluorescent immunocytochemistry and co-immunoprecipitation. We investigated OA-mediated activation of mitogen-activated protein kinases (MAPKs) and cell survival. Integrin inhibition effects on OA-mediated cell migration were determined. We assessed effects of OA knock-down on cell migration and proliferation. OA is overexpressed in OSCC cell lines, and serves as a migration-promoting adhesion molecule. OA co-localized with integrin subunits, and co-immunoprecipitated with the subunits. Integrin blocking antibodies, especially those directed against the beta1 subunit, inhibited cell adhesion (P = 0.03 for SCC15 cells). Adhesion to OA activated MAPKs in UMSCC14a cells and OA treatment promoted survival of SCC15 cells. Integrin-neutralizing antibodies enhanced cell migration with OA in the extracellular matrix. OA knock-down resulted in decreased proliferation of SCC15 and SCC25 cells, but did not inhibit cell migration. OA in the extracellular matrix promotes OSCC cell adhesion and migration, and may be a novel target in the prevention of HNSCC spread. J. Cell. Physiol. 231: 1761-1770, 2016. (c) 2015 Wiley Periodicals, Inc.
Arosarena Oneida A; Dela Cadena Raul A; Denny Michael F; Bryant Evan; Barr Eric W; Thorpe Ryan; Safadi Fayez F
Journal of cellular physiology
2016
2016-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jcp.25279" target="_blank" rel="noreferrer noopener">10.1002/jcp.25279</a>