Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
1.
J Dermatol Sci ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33642112

RESUMO

BACKGROUND: Excessive inflammation and cell death induced by ultraviolet (UV) cause skin photodamage. Metformin possesses anti-inflammatory and cytoprotective effects. However, whether metformin inhibits inflammation and cell death in UVB-induced acute skin damage is unclear. OBJECTIVE: To evaluate the anti-inflammatory and cytoprotective effects of metformin in vitro and in vivo. Furthermore, its potential mechanism has been explored. METHODS: Transcriptome sequencing and multiplex cytokines analysis were used to evaluate the validity of in vitro UVB-induced acute damage keratinocyte model and anti-inflammatory effects of metformin. We also determined the expression and nuclear translocation of CCAAT/enhancer-binding protein beta (C/EBPß), an important transcriptional factor of Interleukin-1beta (IL-1ß). Cell viability and cell death of keratinocytes were evaluated upon UVB irradiation in the presence or absence of metformin. 0.6% metformin cream was applied on UVB-irradiated mice to explore its pharmacological effects in vivo. RESULTS: Transcriptional landscape of 50 mJ/cm2 UVB-irradiated HaCaT cells is typical of UVB-induced acute damage keratinocyte model in vitro. Metformin alleviated transcription and secretion of IL-1ß, Tumor Necrosis Factor-alpha, and Fibroblast Growth Factor 2, expression and nuclear translocation of C/EBPß in this model. Metformin also protected keratinocytes from cell death caused by UVB-induced cellular secretions, which contributed to its cytoprotective effects. Topical administration of 0.6% metformin cream alleviated UVB-induced skin damage in mice. CONCLUSION: We proved the protective roles of metformin in UVB-challenged keratinocytes and UVB-irradiated mice, which indicated the potential value of metformin in topical therapy against skin photodamage.

4.
Biomark Res ; 8: 41, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32944244

RESUMO

Long non-coding RNAs (lncRNAs) represent an important class of RNAs comprising more than 200 nucleotides, which are produced by RNA polymerase II. Although lacking an open reading framework and protein-encoding activity, lncRNAs can mediate endogenous gene expression by serving as chromatin remodeler, transcriptional or post-transcriptional modulator, and splicing regulator during gene modification. In recent years, increasing evidence shows the significance of lncRNAs in many malignancies, with vital roles in tumorigenesis and cancer progression. Moreover, lncRNAs were also considered potential diagnostic and prognostic markers in cancer. The lncRNA small nuclear RNA host gene 16 (SNHG16), found on chromosome 17q25.1, represents a novel tumor-associated lncRNA. SNHG16 was recently found to exhibit dysregulated expression in a variety of malignancies. There are growing evidence of SNHG16's involvement in characteristics of cancer, including proliferation, apoptosis, together with its involvement in chemoresistance. In addition, SNHG16 has been described as a promising diagnostic and prognostic biomarker in cancer patients. The current review briefly summarizes recently reported findings about SNHG16 and discuss its expression, roles, mechanisms, and diagnostic and prognostic values in human cancers.

5.
Int J Oncol ; 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32901832

RESUMO

EphA2 (EPH receptor A2) (erythropoietin­producing hepatocellular receptor tyrosine kinase subtype A2) plays a crucial role in human cancers, and is a promising target for the development of new anticancer drugs. In this study, we showed that the interaction of Annexin A1 (ANXA1) and EphA2 increased EphA2 stability by inhibiting its proteasome degradation in gastric cancer (GC) and colon cancer (CC) cells, and the amino acid residues 20­30 and 28­30 of ANXA1 N terminal were responsible for binding and stabilizing EphA2. Based on the amino acid residues of ANXA1 responsible for binding EphA2, we developed ANXA1­derived 3 amino acid­long (SKG) and 11 amino acid­long peptides (EYVQTVKSSKG) in fusion to cell­penetrating peptide, named as A1(28­30) and A1(20­30) respectively, and found that A1(28­30) and A1(20­30) blocked the binding of ANXA1 with EphA2, targeted EphA2 degradation, and suppressed the growth of GC and CC cells in vitro and in mice. Our data demonstrated that ANXA1 was able to bind and stabilize EphA2 in GC and CC cells, and disruption of ANXA1­EphA2 interaction by the two ANXA1­derived peptides inhibited the growth of GC and CC cells by targeting EphA2 degradation, presenting a potential strategy for treating GC and CC with these peptides.

6.
J Hematol Oncol ; 13(1): 114, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811512

RESUMO

Eph receptors and the corresponding Eph receptor-interacting (ephrin) ligands jointly constitute a critical cell signaling network that has multiple functions. The tyrosine kinase EphA2, which belongs to the family of Eph receptors, is highly produced in tumor tissues, while found at relatively low levels in most normal adult tissues, indicating its potential application in cancer treatment. After 30 years of investigation, a large amount of data regarding EphA2 functions have been compiled. Meanwhile, several compounds targeting EphA2 have been evaluated and tested in clinical studies, albeit with limited clinical success. The present review briefly describes the contribution of EphA2-ephrin A1 signaling axis to carcinogenesis. In addition, the roles of EphA2 in resistance to molecular-targeted agents were examined. In particular, we focused on EphA2's potential as a target for cancer treatment to provide insights into the application of EphA2 targeting in anticancer strategies. Overall, EphA2 represents a potential target for treating malignant tumors.

7.
Cancer Res ; 80(20): 4386-4398, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32737118

RESUMO

Overexpression of ANXA1 and EphA2 has been linked to various cancers and both proteins have attracted considerable attention for the development of new anticancer drugs. Here we report that ANXA1 competes with Cbl for binding EphA2 and increases its stability by inhibiting Cbl-mediated EphA2 ubiquitination and degradation in nasopharyngeal carcinoma (NPC). Binding of ANXA1 to EphA2 promoted NPC cell growth and metastasis in vitro and in vivo by elevating EphA2 levels and increasing activity of EphA2 oncogenic signaling (pS897-EphA2). Expression of ANXA1 and EphA2 was positively correlated and both were significantly higher in NPC tissues than in the normal nasopharyngeal epithelial tissues. Patients with high expression of both proteins presented poorer disease-free survival and overall survival relative to patients with high expression of one protein alone. Furthermore, amino acid residues 20-30aa and 28-30aa of the ANXA1 N-terminus bound EphA2. An 11 amino acid-long ANXA1-derived peptide (EYVQTVKSSKG) was developed on the basis of this N-terminal region, which disrupted the connection of ANXA1 with EphA2, successfully downregulating EphA2 expression and dramatically suppressing NPC cell oncogenicity in vitro and in mice. These findings suggest that ANXA1 promotes NPC growth and metastasis via binding and stabilization of EphA2 and present a strategy for targeting EphA2 degradation and treating NPC with a peptide. This therapeutic strategy may also be extended to other cancers with high expression of both proteins. SIGNIFICANCE: These findings show that EphA2 is a potential target for NPC therapeutics and an ANXA1-derived peptide suppresses NPC growth and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4386/F1.large.jpg.

8.
Cell Death Dis ; 11(8): 709, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32848131

RESUMO

EphA2 is an important oncogenic protein and emerging drug target, but the oncogenic role and mechanism of ligand-independent phosphorylation of EphA2 at tyrosine 772 (pY772-EphA2) is unclear. In this study, we established nasopharyngeal carcinoma (NPC) cell lines with stable expression of exogenous EphA2 and EphA2-Y772A (phosphorylation inactivation) using endogenous EphA2-knockdown cells, and observed that pY772A EphA2 was responsible for EphA2-promoting NPC cell proliferation and anchorage-independent and in vivo growth in mice. Mechanistically, EphA2-Y772A mediated EphA2-activating Shp2/Erk-1/2 signaling pathway in the NPC cells, and Gab1 (Grb2-associated binder 1) and Grb2 (growth factor receptor-bound protein 2) were involved in pY772-EphA2 activating this signaling pathway. Our results further showed that Shp2/Erk-1/2 signaling mediated pY772-EphA2-promoting NPC cell proliferation and anchorage-independent growth. Moreover, we observed that EphA2 tyrosine kinase inhibitor ALW-II-41-27 inhibited pY772-EphA2 and EphA2-Y772A decreased the inhibitory effect of ALW-II-41-27 on NPC cell proliferation. Collectively, our results demonstrate that pY772-EphA2 is responsible for EphA2-dependent NPC cell growth in vitro and in vivo by activating Shp2/Erk-1/2 signaling pathway, and is a pharmacologic target of ALW-II-41-27, suggesting that pY772-EphA2 can serve as a therapeutic target in NPC and perhaps in other cancers.

9.
Cell Death Dis ; 11(5): 322, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376822

RESUMO

HDAC7 plays a crucial role in cancers, and is the main drug target of several HDAC inhibitors. However, the role and mechanism of HDAC7 in nasopharyngeal carcinoma (NPC) are still unclear. In this study, we observed that HDAC7 was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa (NNM) tissues, HDAC7 expression levels were positively correlated with NPC progression and negatively correlated with patient prognosis, and HDAC7 knockdown dramatically inhibited the in vitro proliferation, migration, and invasion of NPC cells, and the growth of NPC xenografts in mice, indicating the HDAC7 promotes the oncogenicity of NPC. Mechanistically, HDAC7 promoted the in vitro proliferation, migration, and invasion of NPC cells by upregulating EphA2, in which miR-4465 mediated HDAC7-regulating EphA2, a direct target gene of miR-4465. We further showed that miR-4465 was significantly downregulated in the NPC tissues relative to NNM tissues, and inhibited the in vitro proliferation, migration, and invasion of NPC cells by targeting EphA2 expression. Moreover, we observed that the expressions of HDAC7, miR-4465, and EphA2 in NPC tissues were correlated. The results suggest that HDAC7 promotes the oncogenicity of NPC by downregulating miR-4465 and subsequently upregulating EphA2, highlighting HDAC7 as a potential therapeutic target for NPC.

10.
Oncogene ; 39(21): 4183-4197, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32291412

RESUMO

CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a transmembrane glycoprotein that is highly expressed in tumor cells, particularly melanoma cells, and plays critical roles in tumor cell metastasis through the regulation of matrix metalloprotease (MMP) expression. In this study, we identified Fyn as a novel interacting protein of CD147. Fyn is a member of the Src family of nonreceptor tyrosine kinases that regulates diverse physiological processes, such as T lymphocyte differentiation, through the TCR signaling pathway. Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Two phosphospecific antibodies against Y140 and Y183 were developed to validate the phosphorylation of CD147 by Fyn. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment. In addition, CD147-FF significantly blocked MMP-9 expression as well as cell migration. Moreover, we found that Fyn is overexpressed in clinical melanoma tissues as well as in melanoma cell lines. Knockdown of Fyn expression markedly attenuated the malignant phenotype of melanoma cells in vitro and in vivo through downregulation of CD147 phosphorylation, indicating that Fyn/CD147 is a potential target molecule in melanoma treatment. Finally, through virtual screening, we identified amodiaquine as a potential inhibitor targeting the Fyn/CD147 axis. Amodiaquine treatment dramatically inhibited the phosphorylation of CD147 by Fyn, thus attenuating melanoma cell growth and invasion in vitro and in vivo, suggesting that amodiaquine is a promising inhibitor for melanoma treatment.


Assuntos
Basigina/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Transdução de Sinais , Substituição de Aminoácidos , Basigina/genética , Linhagem Celular Tumoral , Glicosilação , Humanos , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Melanoma/genética , Melanoma/patologia , Mutação de Sentido Incorreto , Metástase Neoplásica , Fosforilação/genética , Proteínas Proto-Oncogênicas c-fyn/genética
11.
Cancer Lett ; 444: 162-174, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30583071

RESUMO

Our phosphoproteomics identified that phosphorylation of EphA2 at serine 897 (pS897-EphA2) was significantly upregulated in the high metastatic nasopharyngeal carcinoma (NPC) cells relative to non-metastatic NPC cells. However, the role and underlying mechanism of pS897-EphA2 in cancer metastasis and stem properties maintenance remain poorly understood. In this study, we established NPC cell lines with stable expression of exogenous EphA2 and EphA2-S897A using endogenous EphA2 knockdown cells, and observed that pS897-EphA2 maintained EphA2-dependent NPC cell in vitro migration and invasion, in vivo metastasis and cancer stem properties. Using phospho-kinase antibody array to identify signaling downstream of pS897-EphA2, we found that AKT/Stat3 signaling mediated pS897-EphA2-promoting NPC cell invasion, metastasis and stem properties, and Sox-2 and c-Myc were the effectors of pS897-EphA2. Immunohistochemistry showed that pS897-EphA2 was positively correlated with NPC metastasis and negatively correlated with patient overall survival. Moreover, ERK/RSK signaling controlled serum-induced pS897-EphA2 in NPC cells. Collectively, our results demonstrate that pS897-EphA2 is indispensable for EphA2-dependent NPC cell invasion, metastasis and stem properties by activating AKT/Stat3/Sox-2 and c-Myc signaling pathway, suggesting that pS897-EphA2 can serve as a therapeutic target in NPC and perhaps in other cancers.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Nasofaríngeas/patologia , Células-Tronco Neoplásicas/patologia , Receptor EphA2/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Fosforilação , Prognóstico , Receptor EphA2/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cell Death Dis ; 9(12): 1148, 2018 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-30451832

RESUMO

RACK1 is upregulated in the various types of human cancers, and considered to play a role in the development and progression of human cancer. However, the role and mechanism of RACK in the colon cancer are poorly understood. In this study, we detected RACK1 expression in 63 normal colonic mucosa, 60 colonic inflammatory polyps, 60 colonic adenomas, 180 colon adenocarcinomas, and 40 lymph node metastases by immunohistochemistry, and observed that RACK1 expression was progressively elevated in the carcinogenic process of human colonic epithelium, and RACK1 expressional levels were positively correlated with the malignant degree and lymph node metastasis of colon cancers, and negatively correlated with the patient survival. With a combination of loss-of-function and gain-of-function approaches, we observed that RACK1 promoted colon cancer cell proliferation, inhibited colon cancer cell apoptosis, and enhanced the anchorage-independent and xenograft growth of colon cancer cells. Moreover, we found that RACK1-induced autophagy of colon cancer cells; RACK1-induced autophagy promoted colon cancer cell proliferation and inhibited colon cancer cell apoptosis. Our data suggest that RACK1 acts as an oncogene in colon cancer, and RACK1-induced autophagy promotes proliferation and survival of colon cancer, highlighting the therapeutic potential of autophagy inhibitor in the colon cancer with high RACK1 expression.


Assuntos
Carcinogênese/genética , Neoplasias do Colo/genética , Proteínas de Neoplasias/genética , Receptores de Quinase C Ativada/genética , Apoptose/genética , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias do Colo/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Transdução de Sinais/genética
14.
Cell Death Dis ; 9(12): 1154, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30459351

RESUMO

Annexin A1 (ANXA1) is dysregulated in the various tumors. However, the role and mechanism of ANXA1 in the cancers are poorly understood. In this study, we first showed a clinically positive correlation between ANXA1 and autophagy-associated protein SQSTM1 expression in nasopharyngeal carcinoma (NPC) and ANXA1-regulating SQSTM1 expression through autophagy, and further demonstrated that ANXA1 inhibited BECN1 and ATG5-dependent autophagy in the NPC cells. Using phospho-kinase antibody array to identify signaling through which ANXA1 regulated NPC cell autophagy, we found that ANXA1-suppressed autophagy was associated with PI3K/AKT signaling activation. We also showed that ANXA1 expression was significantly increased in the NPCs with metastasis relative to NPCs without metastasis and positively correlated with lymphonode and distant metastasis; high ANXA1 expression in the NPC cells promoted in vitro tumor cell migration and invasion and in vivo metastasis. Lastly, we showed that inhibition of autophagy restored the ability of tumor cell migration and invasion, epithelial-mesenchymal transition (EMT)-like alterations and in vivo metastasis in the ANXA1 knockdown NPC cells with autophagy activation; ANXA1-suppresed autophagy induced EMT-like alterations possibly by inhibiting autophagy-mediated degradation of Snail. Our data suggest that ANXA1-suppressed autophagy promotes NPC cell migration, invasion and metastasis by activating PI3K/AKT signaling pathway, highlighting that the activation of autophagy may inhibit metastasis of NPC with high ANXA1 expression.


Assuntos
Anexina A1/genética , Autofagia/genética , Carcinoma Nasofaríngeo/genética , Proteína Sequestossoma-1/genética , Proteína 5 Relacionada à Autofagia/genética , Proteína Beclina-1/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/genética , Proteólise , Proteínas Proto-Oncogênicas c-akt/genética , Fatores de Transcrição da Família Snail/genética
15.
Oncogenesis ; 7(2): 17, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29463844

RESUMO

TRAF6, a well-known adapter molecule, plays pivotal role in TLR/IL-1R associated signaling pathway. Although TRAF6 has been shown to have oncogenic activity in various malignant tumors, the details remain unclear. In this study, we demonstrated that TRAF6 facilitates Ras (G12V) and EGF-induced cellular transformation through EGFR. Silencing of TRAF6 expression significantly downregulated AP-1 activity, as well as MMP-2,9 expression after EGF stimulation. Furthermore, we found that TRAF6 plays an essential role in cutaneous squamous cell carcinoma (cSCC) malignant phenotypes, affecting cell growth and migration. CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is over-expressed in tumors and induces tumorigenesis. Our results showed that CD147 formed complex with EGFR and TRAF6. Knockdown of TRAF6 disrupted the CD147-EGFR complex, thereby inducing EGFR endocytosis. Therefore, TRAF6 might be a novel molecular target for cSCC prevention or therapy.

16.
Mol Cancer Ther ; 16(10): 2094-2106, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28698199

RESUMO

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-125b in NPC radioresistance, one of upregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-125b was frequently upregulated in the radioresistant NPCs, and its increment was significantly correlated with NPC radioresistance, and was an independent predictor for poor patient survival. In vitro radioresponse assays showed that miR-125b inhibitor decreased, whereas miR-125b mimic increased NPC cell radioresistance. In a mouse model, therapeutic administration of miR-125b antagomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we confirmed that A20 was a direct target of miR-125b and found that miR-125b regulated NPC cell radioresponse by targeting A20/NF-κB signaling. With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 overexpression decreased while A20 knockdown increased NPC cell radioresistance both in vitro and in vivo Moreover, A20 was significantly downregulated while p-p65 (RelA) significantly upregulated in the radioresistant NPCs relative to radiosensitive NPCs, and miR-125b expression level was negatively associated with A20 expression level, whereas positively associated with p-p65 (RelA) level. Our data demonstrate that miR-125b and A20 are critical regulators of NPC radioresponse, and high miR-125b expression enhances NPC radioresistance through targeting A20 and then activating the NF-κB signaling pathway, highlighting the therapeutic potential of the miR-125b/A20/NF-κB axis in clinical NPC radiosensitization. Mol Cancer Ther; 16(10); 2094-106. ©2017 AACR.


Assuntos
Carcinoma/radioterapia , MicroRNAs/genética , Neoplasias Nasofaríngeas/radioterapia , Tolerância a Radiação/genética , Fator de Transcrição RelA/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Animais , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , NF-kappa B/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cell Death Dis ; 8(6): e2855, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28569771

RESUMO

MiR-125b is aberrantly expressed and has a role in the various types of tumors. However, the role and mechanism of miR-125b in nasopharyngeal carcinoma (NPC) are unclear. In this study, we investigated the role and mechanism of miR-125b in NPC. We observed that miR-125b was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa (NNM), and its increment was correlated with poor patient survival, and was an independent predictor for reduced patient survival; miR-125b promoted NPC cell proliferation and inhibited NPC cell apoptosis; in a mouse model, administration of miR-125b antagomir significantly reduced the growth of NPC xenograft tumors. Mechanistically, we confirmed that A20 was a direct target of miR-125b, and found that activation of nuclear factor κB (NF-κB) signaling pathway by A20 mediated miR-125b-promoting NPC cell proliferation and -inhibiting NPC cell apoptosis. With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 inhibited NPC cell proliferation, induced NPC cell apoptosis, and reduced the growth of NPC xenograft tumors. Moreover, A20 was significantly downregulated, whereas p-p65(RelA) was significantly upregulated in the NPC tissues relative to normal nasopharyngeal mucosa, and miR-125b level was negatively associated with A20 level, whereas positively associated with p-p65 level. Our data demonstrate that miR-125b regulates NPC cell proliferation and apoptosis by targeting A20/NF-κB signaling pathway, and miR-125b acts as oncogene, whereas A20 functions as tumor suppressor in NPC, highlighting the therapeutic potential of miR-125b/A20/NF-κB signaling axis in the NPC.


Assuntos
Apoptose/genética , Carcinoma/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Nasofaríngeas/genética , Fator de Transcrição RelA/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Animais , Antagomirs/genética , Antagomirs/metabolismo , Carcinoma/metabolismo , Carcinoma/mortalidade , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Transplante de Neoplasias , Transdução de Sinais , Análise de Sobrevida , Fator de Transcrição RelA/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo
18.
Oncotarget ; 7(10): 11463-77, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26862850

RESUMO

Raf kinase inhibitory protein (RKIP) functions as a chemo-immunotherapeutic sensitizer of cancers, but regulation of RKIP on tumor radiosensitivity remains largely unexplored. In this study, we investigate the role and mechanism of RKIP in nasopharyngeal carcinoma (NPC) radioresistance. The results showed that RKIP was frequently downregulated in the radioresistant NPC tissues compared with radiosensitive NPC tissues, and its reduction correlated with NPC radioresistance and poor patient survival, and was an independent prognostic factor. In vitro radioresponse assay showed that RKIP overexpression decreased while RKIP knockdown increased NPC cell radioresistance. In the NPC xenografts, RKIP overexpression decreased while RKIP knockdown increased tumor radioresistance. Mechanistically, RKIP reduction promoted NPC cell radioresistance by increasing ERK and AKT activity, and AKT may be a downstream transducer of ERK signaling. Moreover, the levels of phospho-ERK-1/2 and phospho-AKT were increased in the radioresistant NPC tissues compared with radiosensitive ones, and negatively associated with RKIP expression, indicating that RKIP-regulated NPC radioresponse is mediated by ERK and AKT signaling in the clinical samples. Our data demonstrate that RKIP is a critical determinant of NPC radioresponse, and its reduction enhances NPC radioresistance through increasing ERK and AKT signaling activity, highlighting the therapeutic potential of RKIP-ERK-AKT signaling axis in NPC radiosensitization.


Assuntos
Carcinoma/enzimologia , Carcinoma/radioterapia , Sistema de Sinalização das MAP Quinases/genética , Neoplasias Nasofaríngeas/enzimologia , Neoplasias Nasofaríngeas/radioterapia , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Animais , Carcinoma/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Proteína Oncogênica v-akt , Tolerância a Radiação , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Tumour Biol ; 37(3): 2941-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26409455

RESUMO

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment. Clinical tumor-node-metastasis (TNM) staging has limited accuracy in predicting NPC radioresponse and determining its therapeutic regimens. To construct a risk score model for predicting NPC radioresistance, immunohistochemistry was used to assess the expression of four proteins (14-3-3σ, Maspin, RKIP, and GRP78) in 149 NPC samples with different radiosensitivity. Sequentially, a logistic regression analysis was performed to identify independent predictors of NPC radioresistance and establish a risk score model. As a result, a risk score model, Z = -3.189 - 1.478 (14-3-3σ) - 1.082 (Maspin) - 1.666 (RKIP) + 2.499 (GRP78) + 2.597 (TNM stage), was constructed, and a patient's risk score was estimated by the formula: e (Z)/(e (Z) + 1) × 100, where "e" is the base of natural logarithm. High-risk score was closely associated with NPC radioresistance, and was observed more frequently in the radioresistant patients than that in the radiosensitive patients. The sensitivity, specificity, and accuracy of the risk score model for predicting NPC radioresistance was 88.00, 86.48, and 87.25 %, respectively, which was clearly superior to each individual protein and TNM stage. Furthermore, Kaplan-Meier survival analysis showed that high-risk score correlated with the markedly reduced overall survival (OS) and disease-free survival (DFS) of the patients, and Cox regression analysis showed that the risk score model was an independent predictor for OS and DFS. This study constructs a risk score model for predicting NPC radioresistance and patient survival, and it may serve as a complement to current radioresistance risk stratification approaches.


Assuntos
Neoplasias Nasofaríngeas/radioterapia , Tolerância a Radiação , Proteínas 14-3-3/análise , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma , Exorribonucleases/análise , Feminino , Proteínas de Choque Térmico/análise , Humanos , Imuno-Histoquímica , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Proteína de Ligação a Fosfatidiletanolamina/análise , Prognóstico , Serpinas/análise
20.
Oncotarget ; 6(29): 28341-56, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26314966

RESUMO

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-23a in NPC radioresistance, one of downregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-23a was frequently downregulated in the radioresistant NPC tissues, and its decrement correlated with NPC radioresistance and poor patient survival, and was an independent predictor for reduced patient survival. In vitro radioresponse assays showed that restoration of miR-23a expression markedly increased NPC cell radiosensitivity. In a mouse model, therapeutic administration of miR-23a agomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we found that reduced miR-23a promoted NPC cell radioresistance by activating IL-8/Stat3 signaling. Moreover, the levels of IL-8 and phospho-Stat3 were increased in the radioresistance NPC tissues, and negatively associated with miR-23a level. Our data demonstrate that miR-23a is a critical determinant of NPC radioresponse and prognostic predictor for NPC patients, and its decrement enhances NPC radioresistance through activating IL-8/Stat3 signaling, highlighting the therapeutic potential of miR-23a/IL-8/Stat3 signaling axis in NPC radiosensitization.


Assuntos
Interleucina-8/genética , MicroRNAs/genética , Neoplasias Nasofaríngeas/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Western Blotting , Carcinoma , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Interleucina-8/metabolismo , Estimativa de Kaplan-Meier , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/radioterapia , Prognóstico , Interferência de RNA , Tolerância a Radiação/genética , Radiação Ionizante , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...