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1.
iScience ; 21: 549-561, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31715498

RESUMO

Multi-targeted kinase inhibitors, such as sorafenib, have been used in various malignancies, but their efficacy in clinical applications varies among individuals and lacks pretherapeutic prediction measures. We applied the concept of "click chemistry" to pathological staining and established a drug-loaded probe staining assay. We stained the cells and different types of pathological sections and demonstrated that the assay was reliable. We further verified in cells, cell-derived xenograft model, and clinical level that the staining intensity of the probe could reflect drug sensitivity. The stained samples from 300 patients who suffered from hepatocellular carcinoma and used the sorafenib probe also indicated that staining intensity was closely related to clinical information and could be used as an independent marker without undergoing sorafenib therapy for prognosis. This assay provided new ideas for multi-target drug clinical trials, pre-medication prediction, and pathological research.

2.
Oncogene ; 38(2): 228-243, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30087438

RESUMO

Hepatocellular carcinoma (HCC) is a typical hypervascular solid tumor. Vasculogenic mimicry (VM) formed by aggressive tumor cells to mimic vasculogenic networks plays an important role in the tumor malignancy of HCC. Hsp90ß promotes endothelial cell-dependent angiogenesis in HCC. However, the relationship between Hsp90ß and VM formation is unclear. In this study, we found that Hsp90ß is positively correlated with VM and EMT marker proteins in HCC tissues and promotes tube formation, cell migration, and invasion in vitro. Hsp90ß interacts with Twist1 and promotes its deubiquitination and stabilization to nuclear translocation and enhances the VE-cadherin promoter activity. Results of in vitro analysis indicate that Hsp90ß enhances the tumor VM in tumor-burdened mice, and the Hsp90 inhibitor NVP-BEP800 suppresses VM formation by releasing Hsp90ß and Twist1 interaction. This study provides a potential antitumor therapy for inhibiting VM by targeting Hsp90ß in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal , Proteínas de Choque Térmico HSP90/metabolismo , Neoplasias Hepáticas/patologia , Animais , Carcinoma Hepatocelular/metabolismo , Xenoenxertos , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica
4.
EBioMedicine ; 38: 25-36, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30396856

RESUMO

BACKGROUND: Hypoxia commonly occurs in solid tumors. The hypoxia in the center of solid tumors considerably decreases the chemosensitivity of tumor cells and induces epithelial-mesenchymal transition (EMT) as well as drug resistance of antitumor drugs. METHODS: Here, the effects of salidroside (Sal) combined with platinum drugs on human hepatocellular carcinoma were examined in vitro and in vivo. We investigated the antitumor effects of Sal by inhibiting the drug resistance and explained its mechanism in inhibiting tumor growth. FINDINGS: The results showed that Sal co-administration reverses the drug resistance of platinum drugs and suppressed metastasis induced by the hypoxic tumor microenvironment. Sal promoted the degradation of HIF-1α. In conclusion, Sal significantly increased the sensitivity to platinum drugs and inhibited hypoxia-induced EMT in hepatocellular carcinoma (HCC) through inhibiting HIF-1α signaling pathway. INTERPRETATION: Therefore, Sal may be an effective platinum drug sensitizer that can improve the chemotherapeutic efficacy in patients with HCC.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glucosídeos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Biologia Computacional/métodos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Perfilação da Expressão Gênica , Glucosídeos/química , Humanos , Hipóxia/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Camundongos , Fenóis/química , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Exp Clin Cancer Res ; 37(1): 185, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081924

RESUMO

BACKGROUND: Tumor cells transfer into endothelial cells by epithelial-endothelial transition (EET), which is characterized by vasculagenic mimicry (VM) in morphology. VM can change tumor microcirculation, progression, and metastasis. However, the molecular mechanisms of endothelial-like transition remain unclear. EET is a subtype of epithelial-mesenchymal transition (EMT). Twist1, a transcriptional regulatory factor of EMT, is an important factor that induces EET in hepatocellular carcinoma(HCC), but the upstream signal of Twist1 is unclear. METHODS: Expression plasmids, Ca mobilization, and three-dimensional cultures were evaluated. Western blot assay, reporter gene assay, and immunofluorescence staining were conducted. A murine xenograft model was established. Analyses of immunohistochemistry, patient samples, and complementary DNA (cDNA) microarrays were also performed. RESULTS: This study demonstrated that protease-activated receptor-1 (PAR1) can increase the expression of endothelial markers and enhance VM formation by upregulating Twist1 both in vitro and in vivo through thrombin binding. Thrombin not only activates PAR1 but also promotes PAR1 internalization in a time-dependent manner. Clinical pathological analysis further confirms that PAR1 expression is directly correlated with the endothelial marker expression, VM formation, and metastasis and indicates poor survival rate of patients with tumors. CONCLUSION: PAR1 promotes EET through Twist1 in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Nucleares/metabolismo , Receptor PAR-1/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Nucleares/genética , Receptor PAR-1/biossíntese , Receptor PAR-1/genética , Proteína 1 Relacionada a Twist/genética
6.
Cancer Res ; 78(15): 4150-4162, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29844124

RESUMO

Twist is a critical epithelial-mesenchymal transition (EMT)-inducing transcription factor that increases expression of vimentin. How Twist1 regulates this expression remains unclear. Here, we report that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of vimentin in EMT. Twist1 bound the Cul2 promoter to activate its transcription and to selectively promote expression of Cul2 circular RNA (circ-10720), but not mRNA. circ-10720 positively correlated with Twist1, tumor malignance, and poor prognosis in hepatocellular carcinoma (HCC). Twist1 promoted vimentin expression by increasing levels of circ-10720, which can absorb miRNAs that target vimentin. circ-10720 knockdown counteracted the tumor-promoting activity of Twist1 in vitro and in patient-derived xenograft and diethylnitrosamine-induced TetOn-Twist1 transgenic mouse HCC models. These data unveil a mechanism by which Twist1 regulates vimentin during EMT. They also provide potential therapeutic targets for HCC treatment and provide new insight for circular RNA (circRNA)-based diagnostic and therapeutic strategies.Significance: A circRNA-based mechanism drives Twist1-mediated regulation of vimentin during EMT and provides potential therapeutic targets for treatment of HCC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4150/F1.large.jpg Cancer Res; 78(15); 4150-62. ©2018 AACR.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas Culina/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , RNA/genética , Proteína 1 Relacionada a Twist/genética , Vimentina/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética
7.
Sci Transl Med ; 10(442)2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29794062

RESUMO

The co-silencing of multiple tumor suppressor genes can lead to escalated malignancy in cancer cells. Given the limited efficacy of anticancer therapies targeting single tumor suppressor genes, we developed small circular single-stranded DNA (CSSD) that can up-regulate the expression of co-silenced tumor suppressor genes by sequestering microRNAs (miRNAs) that negatively regulate these genes. We found that cancer patients with low tumor expression of the tumor suppressor genes KLF17, CDH1, and LASS2 had shortened survival times. The up-regulation of these genes upon transfection of artificial CSSD-9 inhibited tumor proliferation and metastasis and promoted apoptosis in vitro as well as in ex vivo and patient-derived xenograft models. In addition, CSSD is more stable and effective than current miRNA inhibitors, and transfecting CSSDs via nanoparticles substantially improved delivery efficiency. The use of a single CSSD can promote the inhibition of multiple tumor suppressor genes. This study provides evidence for the possibility of using CSSDs as therapeutic miRNA inhibitors to target the co-silencing of multiple tumor suppressor genes.


Assuntos
DNA de Cadeia Simples/metabolismo , Inativação Gênica , Genes Supressores de Tumor , Nanopartículas/química , Neoplasias/genética , Neoplasias/patologia , Antineoplásicos/farmacologia , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , DNA Circular/metabolismo , DNA Circular/ultraestrutura , DNA de Cadeia Simples/ultraestrutura , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Neoplásicos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , MicroRNAs/genética , MicroRNAs/metabolismo , Nanopartículas/ultraestrutura , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Oncotarget ; 8(59): 100216-100226, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29245972

RESUMO

Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. Here, we investigated the effects of apigeninin inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Apigenin effectively inhibited ulcerative colitis, a type of IBD, and CAC. Apigenin decreased myeloperoxidase (MPO), inflammatory cytokine and COX-2 levels, and it attenuated inflammatory cell infiltration in treated colon tissues as compared to untreated model colon tissues. Apigenin also reduced NF-κB and STAT3 activity in vitro and in vivo, thereby inhibiting inflammation and inflammation-induced carcinogenesis. Thus apigenin appears to inhibit inflammation and inflammation-induced carcinogenesisin IBD and CAC by suppressing STAT3-NF-κB signaling.

9.
Oncotarget ; 8(61): 103815-103827, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262602

RESUMO

Artemisinin and its derivatives exhibit a high activity against a range of cancer cell types both in vitro and in vivo. In clinical practice, platinum-based anti-cancer chemotherapy is widely used to treat tumors. However, a large proportion of patients receiving these treatments will relapse because of metastasis and drug resistance. The purpose of this study is to explore the combinational anti-metastatic effect of platinum-based drugs and dihydroartemisinin (DHA). Both DDP and oxaliplatin (OXA) at low doses could induce epithelial-mesenchymal transition (EMT) in HCC. Meanwhile, co-administration of DHA could enhance DDP and OXA chemosensitivity in HCC and reverse drug resistance. DHA reversed the morphological changes induced by DDP or OXA and reversed the changes in EMT biomarkers induced by DDP and OXA in HCC in vitro and in vivo via AKT-Snail signaling. DHA significantly increased platinum-based drug sensitivity and suppressed EMT induced by platinum-based drugs via AKT-Snail signaling in HCC. DHA is expected to become the new adjuvant for chemotherapy.

10.
Oncotarget ; 8(41): 70192-70203, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-29050271

RESUMO

Sesquiterpene lactones (SL) have a wide range of applications in anti-tumor and anti-inflammatory therapy. However, the pharmacological mechanism of such substances is not clear. In this study, parthenolide (PTL) was used as an example to explore the anti-tumor effect of natural molecules and their common mechanism. We showed that PTL inhibited the proliferation and migration by reverse EMT via the ERK2/NF-κB/Snail pathway in vivo and in vitro. Interestingly, Multiple potential targets of PTL contain a Gly-Leu-Ser/Lys-"co-adaptation pocket". This inspiring us analogies of PTL may also bind to these target proteins and play a similar function. Significantly, the Concept of co-adaptation pocket may help to increase the selectivity of drug research and development.

11.
Oncotarget ; 8(32): 52901-52912, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28881781

RESUMO

Multidrug resistance is a major problem in colon cancer treatment. However, its molecular mechanisms remain unclear. Recently, the epithelial-mesenchymal transition (EMT) in anticancer drug resistance has attracted increasing attention. This study investigated whether vincristine treatment induces EMT and promotes multidrug resistance in colon cancer. The result showed that vincristine treatment increases the expression of several ATP-binding cassette transporters in invasive human colon adenocarcinoma cell line (HCT-8). Vincristine-resistant HCT-8 cells (HCT-8/V) acquire a mesenchymal phenotype, and thus its migratory and invasive ability are increased both in vitro and in vivo. The master transcriptional factors of EMT, especially Twist1, were significantly increased in the HCT-8/V cell line. Moreover, the ectopic expression of Twist1 increased the chemoresistance of HCT-8 cells to vincristine and increased the expression levels and promoter activities of ABCB1 and ABCC1. Furthermore, Twist1 silencing reverses the EMT phenotype, enhances the chemosensitivity of HCT-8/ V cells to anticancer agents in vitro and in vivo, and downregulates the expression of ABCB1 and ABCC1. Twist1-mediated promotion of ABCB1 and ABCC1 expression levels plays an important role in the drug resistance of colon cancer cells.

13.
Oncotarget ; 7(27): 41421-41431, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27203387

RESUMO

Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. In this study, we investigated the effects of apigenin on migration and metastasis in experimental human hepatocellular carcinoma (HCC) cell lines in vitro and in vivo. Apigenin dose-dependently inhibited proliferation, migration, and invasion by PLC and Bel-7402 human HCC cells. It also suppressed tumor growth in PLC cell xenografts without altering body weight, thereby prolonging survival. Apigenin reduced Snai1 and NF-κB expression, reversed increases in epithelial-mesenchymal transition (EMT) marker levels, increased cellular adhesion, regulated actin polymerization and cell migration, and inhibited invasion and migration by HCC cells. Apigenin may therefore inhibit EMT by inhibiting the NF-κB/Snail pathway in human HCC.


Assuntos
Apigenina/farmacologia , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Hepáticas/patologia , NF-kappa B/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos
14.
J Clin Lab Anal ; 30(6): 892-896, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27040325

RESUMO

BACKGROUND: Filaggrin gene (FLG) plays an important role in skin barrier function, and loss-of-function mutations of FLG have been shown to be a predisposing factor for atopic dermatitis (AD). The c.3321delA mutation is the most common FLG mutation in Chinese population. We aim to develop a rapid, cost-efficiency, and reliable closed-tube method that has not been described for the detection of c.3321delA mutation. METHODS: Recombinant wild-type and mutant plasmids of c.3321delA mutation were constructed, heterozygous mutant plasmids were prepared by mixing the mutant plasmids and wild-type plasmids at 1:1 ratio. High-resolution melting analysis (HRMA) coupled with an unlabeled DNA probe was employed to identify the shift in melting temperature of the probe-template complex, which reflects the presence of c.3321delA mutation. RESULTS: Unlabeled probe based HRMA was able to distinguish all three genotypes (wild-type, heterozygote, and mutant) of c.3321delA mutation. Then, we applied this method to genotype 1,317 clinical samples. Genotyping results obtained from unlabeled probe HRMA were 100% concordant with the results from direct sequencing. CONCLUSION: We developed a fast and high-throughput method to detect the c.3321delA mutation.


Assuntos
Doença de Alzheimer/genética , Análise Mutacional de DNA/métodos , Proteínas de Filamentos Intermediários/genética , Deleção de Sequência/genética , Doença de Alzheimer/diagnóstico , Feminino , Genótipo , Humanos , Masculino , Técnicas de Amplificação de Ácido Nucleico
15.
Oncotarget ; 6(38): 40667-79, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26512779

RESUMO

The gelatinase inhibitor doxycycline is the prototypical antitumor antibiotic. We investigated the effects of doxycycline on the migration, invasion, and metastasis of human lung cancer cell lines and in a mouse model. We also measured the effect of doxycycline on the transcription of epithelial-mesenchymal transition (EMT) markers, and used immunohistochemistry to determine whether EMT reversal was associated with doxycycline inhibition. Doxycycline dose-dependently inhibited proliferation, migration, and invasion of NCI-H446 human small cell lung cancer cells. It also suppressed tumor growth from NCI-H446 and A549 lung cancer cell xenografts without altering body weight, inhibited Lewis lung carcinoma cell migration, and prolonged survival. The activities of the transcription factors Twist1/2, SNAI1/2, AP1, NF-κB, and Stat3 were suppressed by doxycycline, which reversed EMT and inhibited signal transduction, thereby suppressing tumor growth and metastasis. Our data demonstrate functional targeting of transcription factors by doxycycline to reverse EMT and suppress tumor proliferation and metastasis. Thus, doxycycline selectively targets malignant tumors and reduces its metastatic potential with less cytotoxicity in lung cancer patients.


Assuntos
Antibacterianos/farmacologia , Carcinoma Pulmonar de Lewis/prevenção & controle , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxiciclina/farmacologia , Neoplasias Pulmonares/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Transição Epitelial-Mesenquimal , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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