Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
J Cell Mol Med ; 24(22): 13523-13535, 2020 11.
Article in English | MEDLINE | ID: mdl-33074587

ABSTRACT

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated epithelial malignancy. The high expression of BART-miRNAs (miR-BARTs) during latent EBV infection in NPC strongly supports their pathological importance in cancer progression. Recently, we found that several BART-miRNAs work co-operatively to modulate the DNA damage response (DDR) by reducing Ataxia-telangiectasia-mutated (ATM) activity. In this study, we further investigated the role of miR-BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down-regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2-3p, BART12, BART17-5p and BART19-3p in BRCA1 expression. The ectopic expression of these four miR-BARTs suppressed endogenous BRCA1 expression in EBV-negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR-BARTs activities in C666-1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR-BART17-5p and miR-BART19-3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA-damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR-BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies.


Subject(s)
BRCA1 Protein/genetics , Drug Resistance, Neoplasm/genetics , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/genetics , MicroRNAs , Nasopharyngeal Carcinoma/etiology , RNA, Viral , Animals , BRCA1 Protein/metabolism , Cell Cycle/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Genes, Reporter , Host-Pathogen Interactions/genetics , Humans , Immunohistochemistry , Mice , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/etiology , Nasopharyngeal Neoplasms/pathology , RNA Interference
2.
J Pathol ; 246(2): 180-190, 2018 10.
Article in English | MEDLINE | ID: mdl-29968360

ABSTRACT

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. The EBV-encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element-binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, small interfering RNA (siRNA) knockdown of LMP1 in EBV-infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mammalian target of rapamycin (mTOR) pathway, through the use of either mTOR inhibitors or siRNAs, significantly reduced LMP1-mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1-mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN expression was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells, effects that were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1-mediated lipogenesis promotes tumor cell growth and is involved in EBV-driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Subject(s)
Cell Proliferation , Herpesvirus 4, Human/metabolism , Lipogenesis , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Neoplasms/metabolism , Sterol Regulatory Element Binding Protein 1/metabolism , Viral Matrix Proteins/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Progression , Fatty Acid Synthase, Type I/genetics , Fatty Acid Synthase, Type I/metabolism , Female , Herpesvirus 4, Human/genetics , Humans , Lipid Droplets/metabolism , Lipogenesis/drug effects , Luteolin/pharmacology , Male , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Naphthyridines/pharmacology , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/virology , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/virology , Pyridines/pharmacology , Signal Transduction , Sterol Regulatory Element Binding Protein 1/genetics , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Thiazoles/pharmacology , Viral Matrix Proteins/genetics , Xenograft Model Antitumor Assays
3.
Acta Neuropathol ; 123(4): 553-71, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22249617

ABSTRACT

Overexpression of high mobility group AT-hook 1 (HMGA1) is common in human cancers. Little is known about the mechanisms underlying its deregulation and downstream targets, and information about its clinical and biological significance in medulloblastoma (MB) is lacking. Here, we demonstrated frequent genomic gain at 6p21.33-6p21.31 with copy number increase leading to overexpression of HMGA1 in MB. The overexpression correlated with a high proliferation index and poor prognosis. Moreover, we found that hsa-miR-124a targeted 3'UTR of HMGA1 and negatively modulated the expression in MB cells, indicating that loss/downregulation of hsa-miR-124a reported in our previous study could contribute to the overexpression. Regarding the biological significance of HMGA1, siRNA knockdown and ectopic expression studies revealed the crucial roles of HMGA1 in controlling MB cell growth and migration/invasion through modulation of apoptosis and formation of filopodia and stress fibers, respectively. Furthermore, we identified cdc25A as a target of HMGA1 and showed that physical interaction between HMGA1 and the cdc25A promoter is required for transcriptional upregulation. In clinical samples, HMGA1 and cdc25A were concordantly overexpressed. Functionally, cdc25A is involved in the HMGA1-mediated control of MB cell growth. Finally, netropsin, which competes with HMGA1 in DNA binding, reduced the expression of cdc25A by suppression of its promoter activity and inhibited in vitro and in vivo intracranial MB cell growth. In conclusion, our results delineate the mechanisms underlying the deregulation and reveal the functional significance of HMGA1 in controlling MB cell growth and migration/invasion. Importantly, the results highlight the therapeutic potential of targeting HMGA1 in MB patients.


Subject(s)
Cell Movement/genetics , Cell Proliferation , Cerebellar Neoplasms/metabolism , Gene Expression Regulation, Neoplastic/genetics , HMGA1a Protein/metabolism , Medulloblastoma/metabolism , cdc25 Phosphatases/metabolism , Actin Cytoskeleton/metabolism , Animals , Antiviral Agents/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/mortality , Cerebellar Neoplasms/pathology , Chromatin Immunoprecipitation , Chromosome Aberrations , Chromosomes, Human, Pair 17 , Chromosomes, Human, Pair 6 , Dose-Response Relationship, Drug , Electrophoretic Mobility Shift Assay , Female , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockout Techniques , HMGA1a Protein/genetics , Humans , Male , Medulloblastoma/genetics , Medulloblastoma/mortality , Medulloblastoma/pathology , Mice , Mice, Nude , Neoplasm Invasiveness/pathology , Netropsin/pharmacology , Oligonucleotide Array Sequence Analysis , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Survival Analysis , Time Factors , Xenograft Model Antitumor Assays , cdc25 Phosphatases/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...