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1.
J Am Chem Soc ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32363868

RESUMO

The design and development of robust and porous supported catalysts with high activity and selectivity is extremely significant but very challenging for eco-friendly synthesis of fine chemicals and pharmaceuticals. We report here the design and synthesis of highly stable chiral Zr(IV)-based MOFs with different topologies to support Ir complexes and demonstrate their network structures-dependent asymmetric catalytic performance. Guided by the modulated synthesis and isoreticular expansion strategy, five chiral Zr-MOFs with a flu or ith topology are constructed from enantiopure 1,1'-biphenol-derived tetracarboxylate linkers and Zr6, Zr9, or Zr12 clusters. The obtained MOFs all show high chemical stability in boiling water, strongly acidic, and weakly basic aqueous solutions. The two flu MOFs featuring the dihydroxyl groups of biphenol in open and large cages, after sequential postsynthetic modification with P(NMe2)3 and [Ir(COD)Cl]2, can be highly efficient and recyclable heterogeneous catalysts for hydrogenation of α-dehydroamino acid esters with up to 98% ee, whereas the three ith MOFs featuring the dihydroxyl groups in small cages cannot be installed with P(NMe2)3 to support the Ir complex. Incorporation of Ir-phosphorus catalysts into Zr-MOFs leads to great enhancement of their chemical stability, durability, and even stereoselectivity. This work therefore not only advances Zr-MOFs as stable supports for labile metal catalysts for heterogeneous asymmetric catalysis but also provides a new insight into how highly active chiral centers can result due to the framework topology.

3.
Cancer Lett ; 483: 66-74, 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32142917

RESUMO

Endometrial cancer, a type of primary epithelial malignant tumor in the endometrium, is one of the three most common malignant tumors of the female reproductive system. While the incidence of endometrial cancer has been recently rising, its etiology remains unclear. In this study we found that EM2D9, an independently developed monoclonal antibody, specifically recognized endometrial cancer cells; we further determined that EM2D9 target protein was α5ß1. In vitro and in vivo experiments showed that EM2D9 inhibited the migration of endometrial cancer cells. Real-time quantitative PCR results showed that the expression of CD151 mRNA in endometrial carcinoma cells significantly decreased after EM2D9 treatment. We also found that EM2D9 affected the FAK signaling pathway. Collectively, these results shed light on a new mechanism for the development of endometrial carcinoma.

6.
Am J Transl Res ; 11(6): 3438-3449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312356

RESUMO

Acute graft-versus-host disease (aGVHD) is one of the major complications after liver transplantation (LTx), which is induced by over-activation of T helper lymphocytes. Cenicriviroc (CVC) exerts its anti-inflammatory effect through inhibition of C-C chemokine receptor 5 (CCR5). However, whether CVC ameliorates aGVHD after liver transplantation remains unknown. In the present study, a rat aGVHD liver transplantation model (LTx-aGVHD) was constructed. CVC was intravenously injected from day 7 to day 14 after LTx. Liver and intestine samples were harvested to evaluate GVHD severity. Peripheral blood mononuclear cells (PBMCs) were collected and CCR5 antibodies were prepared to further explore the molecular mechanism in vitro. CVC significantly decreased the severity of GVHD associated skin and intestine injury. Quality of life of the LTx-GVHD rats was improved after CVC treatment. Flow cytometry further confirmed diminished peripheral donor-derived Th cells after CVC treatment. Molecularly, CVC treatment showed similar anti-inflammatory effects to CCR5 antibody injection. The level of CCR5, C-C motif chemokine ligand 5 (CCL5), and pro-inflammatory cytokines in the liver and intestines were inhibited after CVC treatment. Thus, CVC deactivated Th lymphocytes and decreased the severity of LTx-aGVHD through inhibition of CCR5.

7.
Cardiovasc J Afr ; 30(4): e1-e3, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31140542

RESUMO

Wellens' syndrome is a relatively common clinical entity; however, it is often missed, especially in young patients. Without prompt diagnosis and aggressive intervention, patients with Wellens' syndrome may rapidly go on to develop extensive anterior wall myocardial infarction and possibly sudden death. In this case report, we present a 33-year-old male patient with atypical chest pain, and discuss the significance of a prompt recognition of Wellens' syndrome.

8.
Artif Cells Nanomed Biotechnol ; 47(1): 1961-1970, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31116036

RESUMO

Alantolactone (Ala), a major sesquiterpene lactone extracted from Inula helenium, exerts potent anti-tumour activities in various cancers. However, the underlying mechanism of such activities is still ambiguous. This study focused on evaluating the anti-tumour effects and molecular mechanisms of Ala on HepG2 cells. Our results demonstrated that Ala might inhibit cellular proliferation, induce G2/M phase arrest and apoptosis in HepG2 cells. Specifically, this study confirmed that Ala induced G2/M phase arrest by upregulating p21, downregulating cyclin A1 and cyclin B1, and promoting cellular apoptosis by increasing the expression of cleaved caspase-3 and PARP. Furthermore, Ala caused an increase in reactive oxygen species (ROS) level and inhibition of ROS production significantly prevented Ala-induced apoptosis. Interestingly, the accumulation of ROS, in turn, suppressed the downstream AKT signalling. Finally, mitophagy of Ala-treated HepG2 cells was observed by Mito/Lyso staining. Mitophagy was significantly inhibited by downregulation of the expression of PINK1 and Parkin proteins. The inhibition of mitophagy by a mitophagy inhibitor was found to markedly enhance Ala-mediated apoptosis and growth inhibition in HepG2 cells. Consequently, Ala induced cellular apoptosis via ROS-mediated suppression of AKT signalling and inhibition of PINK1-mediated mitophagy. Thus, Ala has potential to be used for the treatment of liver cancer.


Assuntos
Apoptose/efeitos dos fármacos , Lactonas/farmacologia , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Fosfoproteínas/metabolismo
9.
Cancer Lett ; 453: 1-9, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928385

RESUMO

Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer. Anesthetic regimens possibly influence cancer development. Exploration of novel, effective targets for liver cancer is the current hotspot in cancer treatment. A previous study conducted by us has demonstrated that enhanced expression of the µ-opioid receptor (MOR) promotes cell proliferation, adhesion, migration, and tumorigenesis. The current study investigates whether MOR regulates self-renewal of hepatocellular carcinoma stem cells (HCSCs). We utilize cell function assays, siRNA, shRNA, flow cytometry sorting, and other molecular biology techniques for this purpose. The results indicate that MOR expression is positively related to hepatocarcinoma progression. Silencing MOR greatly reduce HCC-related tumorigenesis both in vitro and in vivo and significantly extend the survival of tumor-bearing mice. Moreover, MOR silencing will greatly reduce colony formation by HCC cells, indicating down-regulation of cancer initiation. In conclusion, these results establish that MOR can be a novel and reliable HCSC marker and a potential therapeutic target against HCC via MOR-NFAT signaling.

10.
Cancer Med ; 8(4): 1806-1816, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30907072

RESUMO

Bladder cancer (BC) is a complex disease and could be classified into nonmuscle-invasive BC (NMIBC) or muscle-invasive BC (MIBC) subtypes according to the distinct genetic background and clinical prognosis. Until now, the golden standard and confirmed diagnosis of BC is cystoscopy and the major problems of BC are the high rate of recurrence and high costs in the clinic. Recent molecular and genetic studies have provided perspectives on the novel biomarkers and potential therapeutic targets of BC. In this article, we provided an overview of the traditional diagnostic approaches of BC, and introduced some new imaging, endoscopic, and immunological diagnostic technology in the accurate diagnosis of BC. Meanwhile, the minimally invasive precision treatment technique, immunotherapy, chemotherapy, gene therapy, and targeted therapy of BC were also included. Here, we will overview the diagnosis and therapy methods of BC used in clinical practice, focusing on their specificity, efficiency, and safety. On the basis of the discussion of the benefits of precision medicine in BC, we will also discuss the challenges and limitations facing the non-invasive methods of diagnosis and precision therapy of BC. The molecularly targeted and immunotherapeutic approaches, and gene therapy methods to BC treatment improved the prognosis and overall survival of BC patients.

11.
Artif Cells Nanomed Biotechnol ; 47(1): 626-635, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30873870

RESUMO

Shikonin, a botanical drug extracted from Lithospermum erythrorhizon, exhibits anti-cancer effects in various cancer cell lines. However, the mechanisms underlying these effects have not been completely elucidated yet. Here, we showed that Shikonin induces apoptosis and autophagy in A375 cells and inhibits their proliferation. Shikonin caused G2/M phase arrest through upregulation of p21 and downregulation of cyclin B1. Shikonin significantly triggered ER stress-mediated apoptosis by upregulating the expression of p-eIF2α, CHOP, and cleaved caspase-3. It also induced protective autophagy by activating the p38 pathway, followed by an increase in the levels of p-p38, LC3B-II, and Beclin 1. Upon suppression of autophagy by 3-methyladenine, Shikonin-induced apoptosis was enhanced in A375 cells. Moreover, after pretreatment with N-acetyl-cysteine, Shikonin increased the production of reactive oxygen species that are involved in regulating ER stress-mediated apoptosis and p38-activated autophagy, as evidenced by the reversion of cell viability and apoptosis and a decrease in p-eIF2α, CHOP, p-p38, LC3B-II, and Beclin 1 levels. Thus, we demonstrated that Shikonin induced apoptosis and autophagy in A375 cells via the activation of ROS-mediated ER stress and p38 pathways, indicating that Shikonin can serve as a potential agent for human melanoma therapy.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/patologia , Naftoquinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Melanoma/metabolismo , Estrutura Molecular , Naftoquinonas/química , Fosforilação/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Mol Cancer ; 18(1): 27, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782157

RESUMO

BACKGROUND: Circular RNA (circRNA) represents a broad and diverse endogenous RNAs that can regulate gene expression in cancer. However, the regulation and function of bladder cancer (BC) circRNAs remain largely unknown. METHODS: Here we generated circRNA microarray data from three BC tissues and paired non-cancerous matched tissues, and detected circular RNA-cTFRC up-regulated and correlated with tumor grade and poor survival rate of BC patients. We subsequently performed functional analyses in cell lines and an animal model to support clinical findings. Mechanistically, we demonstrated that cTFRC could directly bind to miR-107 and relieve suppression for target TFRC expression. RESULTS: We detected circular RNA-cTFRC up-regulated and correlated with tumor grade and poor survival rate of BC patients. Knock down of cTFRC inhibited invasion and proliferation of BC cell lines in vitro and tumor growth in vivo. Furthermore, the expression of cTFRC correlated with TFRC and negatively correlated with miR-107 both in BC cell lines and BC clinical samples. In addition, up-regulation of cTFRC promoted TFRC expression and contributed to an epithelial to mesenchymal transition phenotype in BC cells. Finally, we found that cTFRC acts as a competing endogenous RNA (ceRNA) for miR-107 to regulate TFRC expression. CONCLUSIONS: cTFRC may exert regulatory functions in BC and may be a potential marker of BC diagnosis or progression.


Assuntos
Antígenos CD/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA/genética , Receptores da Transferrina/genética , Neoplasias da Bexiga Urinária/genética , Idoso , Animais , Antígenos CD/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , RNA/antagonistas & inibidores , RNA/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores da Transferrina/metabolismo , Transdução de Sinais , Análise de Sobrevida , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cell Death Dis ; 9(10): 948, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237423

RESUMO

Anoikis is a type of programmed cell death induced by detachment from the extracellular matrix. In cancer cells, anoikis resistance is essential for cancer cell survival in blood circulation and distant metastasis. However, the mechanisms behind anoikis resistance of gastric cancer remain largely unknown. Herein, we demonstrate that NADPH oxidase 4 (NOX4) expression and reactive oxygen species (ROS) generation are upregulated in suspension gastric cell cultures compared with adherent cultures. Silencing of NOX4 decreases ROS generation and downregulates EGFR, sensitizing cells to anoikis. NOX4 overexpression upregulates ROS and EGFR levels and promotes anoikis resistance. NOX4 depletion inhibits gastric cancer survival in blood circulation and attenuates distant metastasis. NOX4 expression is correlated with EGFR expression in patients. In conclusion, induction of NOX4 expression by detachment promotes anoikis resistance of gastric cancer through ROS generation and downstream upregulation of EGFR, which is critical for the metastatic progression of gastric cancer.


Assuntos
Anoikis/fisiologia , Receptores ErbB/metabolismo , NADPH Oxidase 4/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Anoikis/genética , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Imunofluorescência , Humanos , Imuno-Histoquímica , Lentivirus/genética , Masculino , Camundongos , Camundongos Nus , Microscopia Eletrônica de Varredura , NADPH Oxidase 4/genética , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/genética
14.
Inorg Chem ; 57(16): 9786-9789, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30080035

RESUMO

A chiral porous metal-organic framework (MOF) decorated with radicals has been successfully constructed by cocrystallizing achiral (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)-substituted tricarboxylate and enantiopure VO(salen)-derived dipyridine ligands. The chiral MOF can function as an efficient heterogeneous catalyst for the sequential alcohol oxidation/asymmetric cyanation of aldehyde reactions with enhanced activity and enantioselectivity compared to the homogeneous counterpart.

15.
Pharmacogenomics ; 19(12): 961-977, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30019995

RESUMO

AIM: Cytochrome P450 enzymes CYP2S1, CYP2J2 and CYP2R1 are of interest due to their unknown enzymatic function and disease-specific expression property. The aim of this study was to investigate the genetic variations of CYP2S1, CYP2J2 and CYP2R1 genes, and their polymorphic distribution in different Chinese populations. MATERIALS & METHODS: All of the exons, exon-intron boundaries and 1 kb 5'-flanking region of the three genes were sequenced in 150 Chinese subjects. RESULTS: There were 21, 15 and nine genetic variants identified in CYP2S1, CYP2J2 and CYP2R1 genes, respectively. The genetic polymorphisms of CYP2S1 and CYP2J2 showed significant difference. Thr353Ala variant in CYP2S1 protein was predicted to be consistently damaged. The hydrogen bond interactions were decreased in two mutants: Thr353Ala and Cys372Ser. -177C >T in CYP2S1 affected transcription factor EGR1 binding site. CONCLUSION: This study highlights the importance of genetic polymorphism information on the CYP2S1, CYP2J2  and CYP2R1 genes in Chinese populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Colestanotriol 26-Mono-Oxigenase/genética , Sistema Enzimático do Citocromo P-450/genética , Família 2 do Citocromo P450/genética , Polimorfismo de Nucleotídeo Único/genética , Vigilância da População , Variação Genética/genética , Humanos , Tibet/epidemiologia
16.
EBioMedicine ; 35: 198-203, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29941343

RESUMO

The administration of neoadjuvant chemotherapy (NAC) preceding radical cystectomy benefits overall survival for patients with muscle-invasive bladder cancer (MIBC). However, the relationship between the genetic profiling of MIBC and NAC response remains unclear. Here, a mutation panel of six cancer-associated genes (TSC1, FGFR3, TERT, TP53, PIK3CA and ERBB2) and an immunohistochemistry (IHC) panel containing eight bladder cancer (BC) biomarkers (EGFR, RRM1, PD-L1, BRCA1, TUBB3, ERCC, ERCC1, aberrantly glycosylated integrin α3ß1 (AG) and CK5/6) were developed. BC samples from patients who showed a pathologic response (n = 39) and non-response (n = 13) were applied to the panel analysis. ERBB2, FGFR3 and PIK3CA exclusively altered in the responders group (19/39, 48.7%), in which FGFR3 mutations were significantly enriched in patients with a response in the cohort (14/39, 35.9%; P = 0.01). Additionally, strong expression of ERCC1 was associated with a pathologic response (P = 0.01). However, positive lymph node metastasis (P < 0.01) and lymph-vascular invasion (LVI) (P = 0.03) were correlated with a non-response. Overall, the data show that FGFR3 mutations and elevated expression of ERCC1 in MIBCs are potential predictive biomarkers of the response to NAC.


Assuntos
Músculos/patologia , Mutação/genética , Terapia Neoadjuvante , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Análise Mutacional de DNA , Feminino , Genes Neoplásicos , Humanos , Metástase Linfática , Vasos Linfáticos/patologia , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Invasividade Neoplásica
17.
Nan Fang Yi Ke Da Xue Xue Bao ; 38(3): 358-362, 2018 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-29643045

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of 0.9-ms 1064-nm Nd:YAG laser alone or combined with itraconazole for treatment of toenail onychomycosis. METHODS: A total of 37 patients with onychomycosis (178 toenails) were randomly assigned to groups A and B, and each group was further divided into different subgroups according to the Scoring Clinical Index of Onychomycosis (SCIO) and Onychomycosis Severity Index (OSI) scoring. All the patients were treated with 0.9-ms Nd:YAG laser once a week for 8 times. The patients in group A were treated with laser alone, and those in group B were treated with laser combined with itraconazole. The clinical effect, clinical scores, appearance of the toenails and adverse reactions in the two groups were analyzed, and the patients' satisfaction rate was also investigated. RESULTS: At the 12th months of follow-up, the clinical response rate and mycological cure rate in group A were 31.33% and 30.00%, respectively, similar to the rates in group B (35.79% and 41.18%, respectively) (P>0.05). After the treatments, the SCIO and OSI scores showed no significant changes in group A (P>0.05) but both increased significantly in group B (P<0.05). The response rates did not differ significantly among the subgroups with SCIO<12 or with OSI<16 (P>0.05), but showed significant differences among the subgroups with SCIO≥12 or with OSI≥16 (P<0.05). Of the total of 178 toenails, 33.71%, 74.72% and 70.79% toenails showed improvements in terms of clear nail growth, shape and color, respectively. The overall patients' satisfaction rate was 62.16%, and no adverse reactions related with the therapy were recorded in these patients. CONCLUSION: For treatment of toenail onychomycosis, 0.9-ms 1064-nm Nd:YAG laser can effectively improve the aesthetic appearance of the toenails, and a combined treatment with Nd:YAG laser and itraconazole can be better option in severe cases of onychomycosis.


Assuntos
Antifúngicos/uso terapêutico , Itraconazol/uso terapêutico , Lasers de Estado Sólido/uso terapêutico , Unhas/microbiologia , Onicomicose/terapia , Humanos , Unhas/efeitos dos fármacos , Resultado do Tratamento
18.
Front Immunol ; 9: 282, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29497426

RESUMO

How to induce immune tolerance without long-term need for immunosuppressive drugs has always been a central problem in solid organ transplantation. Modulating immunoregulatory cells represents a potential target to resolve this problem. Myeloid-derived suppressor cells (MDSCs) are novel key immunoregulatory cells in the context of tumor development or transplantation, and can be generated in vitro. However, none of current systems for in vitro differentiation of MDSCs have successfully achieved long-term immune tolerance. Herein, we combined dexamethasone (Dex), which is a classic immune regulatory drug in the clinic, with common MDSCs inducing cytokine granulocyte macrophage colony stimulating factor (GM-CSF) to generate MDSCs in vitro. Addition of Dex into GM-CSF system specifically increased the number of CD11b+ Gr-1int/low MDSCs with an enhanced immunosuppressive function in vitro. Adoptive transfer of these MDSCs significantly prolonged heart allograft survival and also favored the expansion of regulatory T cells in vivo. Mechanistic studies showed that inducible nitric oxide sythase (iNOS) signaling was required for MDSCs in the control of T-cell response and glucocorticoid receptor (GR) signaling played a critical role in the recruitment of transferred MDSCs into allograft through upregulating CXCR2 expression on MDSCs. Blockade of GR signaling with its specific inhibitor or genetic deletion of iNOS reversed the protective effect of Dex-induced MDSCs on allograft rejection. Together, our results indicated that co-application of Dex and GM-CSF may be a new and important strategy for the induction of potent MDSCs to achieve immune tolerance in organ transplantation.


Assuntos
Dexametasona/farmacologia , Células Supressoras Mieloides/imunologia , Imunologia de Transplantes/imunologia , Transferência Adotiva , Aloenxertos/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Glucocorticoides/farmacologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Transplante de Coração , Imunoterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/metabolismo , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores de Glucocorticoides/imunologia , Receptores de Glucocorticoides/metabolismo
19.
Am J Transl Res ; 10(1): 274-282, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29423012

RESUMO

Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are involved in diseases such as cancer. However, little is known about the role of lncRNAs in gastrointestinal stromal tumors (GIST). In the present study, we explored the biological function of the lncRNA coiled-coil domain-containing 26 (CCDC26) in imatinib resistance of GIST. We found that human GIST-882 cells with lower CCDC26 expression were less sensitive to imatinib compared with GIST-T1 cells with higher CCDC26 expression. CCDC26 expression decreased in a time-dependent manner in the presence of imatinib. Moreover, small interfering RNA (siRNA) knockdown of CCDC26 increased GIST cell sensitivity to imatinib. The RNA pull-down experiment showed that CCDC26 can interact with c-KIT and that CCDC26 knockdown can upregulate c-KIT expression. We also found that inhibiting c-KIT induced resistance to imatinib. Lastly, we proved that inhibiting c-KIT can reverse CCDC26 knockdown-mediated imatinib resistance in GIST. We suggest that CCDC26 knockdown can induce imatinib resistance in GIST cells by downregulating c-KIT expression. Our results provide a novel insight into imatinib resistance in GIST.

20.
Oncotarget ; 8(55): 94028-94039, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29212207

RESUMO

Chemoresistance limits treatment efficacy in gastric cancer and doxorubicin resistance is common in gastric cancer cells. Dual specificity phosphatase 4 (DUSP4) has been associated with tumor progression. This study aimed to investigate the mechanism of DUSP4 regulating doxorubicin resistance in gastric cancer cells. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay were used to measure cell viability and proliferation in gastric cancer cells treated with doxorubicin. The expression of DUSP4, E-cadherin and Vimentin protein was detected by Western blotting. Overexpression of DUSP4 was more resistant to doxorubicin in gastric cancer cells. Knockdown of DUSP4 increased the sensitivity of gastric cancer cells to doxorubicin. Moreover, up-regulation of DUSP4 promoted the Epithelial-Mesenchymal Transition (EMT) in gastric cancer cells, but blocking the EMT using a Twist siRNA increased the sensitivity of gastric cancer cells to doxorubicin and confirmed the EMT was involved in DUSP4-mediated doxorubicin resistance. These findings demonstrated that DUSP4 could enhance doxorubicin resistance by promoting EMT in gastric cancer cells.

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