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1.
Int J Biol Sci ; 19(3): 831, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36778109

RESUMO

[This corrects the article DOI: 10.7150/ijbs.36429.].

2.
Sci Adv ; 6(12): eaaz3367, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32206724

RESUMO

Mammalian transient receptor potential (TRP) channels are major components of Ca2+ signaling pathways and control a diversity of physiological functions. Here, we report a specific role for TRPC1 in the entry of herpes simplex virus type 1 (HSV-1) into cells. HSV-1-induced Ca2+ release and entry were dependent on Orai1, STIM1, and TRPC1. Inhibition of Ca2+ entry or knockdown of these proteins attenuated viral entry and infection. HSV-1 glycoprotein D interacted with the third ectodomain of TRPC1, and this interaction facilitated viral entry. Knockout of TRPC1 attenuated HSV-1-induced ocular abnormality and morbidity in vivo in TRPC1-/- mice. There was a strong correlation between HSV-1 infection and plasma membrane localization of TRPC1 in epithelial cells within oral lesions in buccal biopsies from HSV-1-infected patients. Together, our findings demonstrate a critical role for TRPC1 in HSV-1 infection and suggest the channel as a potential target for anti-HSV therapy.


Assuntos
Herpes Simples/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Interações Hospedeiro-Patógeno , Canais de Cátion TRPC/metabolismo , Internalização do Vírus , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Ativação do Canal Iônico , Camundongos , Modelos Biológicos , Mutação , Ligação Proteica , Canais de Cátion TRPC/genética , Células Vero
3.
Int J Biol Sci ; 16(1): 162-171, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31892853

RESUMO

Great quantity of intergenic noncoding RNAs (lncRNAs) have been identified in the mammalian genome and involved in various biological processes, especially in the development and metastasis of cancer. In this study, we identified one lncRNA, lncRNA NONHSAT028712 (Lnc712), was highly expressed in breast cancer cell lines and tissues based on microarray screening. Knockdown of Lnc712 largely inhibited breast cancer cell proliferation. Mechanistically, Lnc712 bound specifically to heat-shock protein 90 (HSP90). Interaction between Lnc712 and HSP90 is required for HSP90 binding to cell division cycle 37 (Cdc37). The Lnc712/HSP90/Cdc37 complex regulated cyclin-dependent kinase 2 (CDK2) activation and then triggered breast cancer cell proliferation. In summary, our results identified a new lncRNA regulate breast cancer proliferation though interaction with HSP90.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , RNA Longo não Codificante/metabolismo , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Células MCF-7 , Ligação Proteica , RNA Longo não Codificante/genética
4.
Eur J Cancer Prev ; 27(4): 418-424, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29557800

RESUMO

Cancer is one of the most important health problems today; therefore, many researchers are focusing on exploring the mechanisms underlying its development and treatment. The field of cancer epigenetics has flourished in recent decades, and studies have shown that different epigenetic events, such as DNA methylation, histone modification, and noncoding RNA regulation, work together to influence cancer development and progression. In this short review, we summarize the interactions between methylation and noncoding RNAs that affect cancer development.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , RNA não Traduzido/genética , Humanos , Neoplasias/patologia
5.
Oncol Rep ; 38(6): 3392-3402, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29039577

RESUMO

The expression of estrogen receptor α (ER) in breast cancers may be indicative of a favorable prognosis and most of these cancers respond to anti-estrogens or aromatase inhibitors. However, ER-positive (ER+) breast cancers receiving anti-hormone and/or chemotherapy sometimes lose their ER expression, which leads to the evolution of the disease to higher aggressiveness and drug resistance. In the present study, an ER-modified signature (EMS) was developed from the expression profile of a chemoresistant MCF-7 breast cancer cell line that lost ER expression during long-term treatment with a chemotherapeutic agent. The EMS could discriminate the ER-negative (ER-) breast cancer cells from the ER+ ones, which included seven pathways essential for the ER- cell development. Furthermore, the EMS indicated a more malignant subgroup of the ER- cells by discriminating the chemoresistant ER- cells from the chemosensitive ones. In addition, the classified chemoresistant ER- patients demonstrated worse prognosis. In conclusion, we developed a new method to discriminate subgroups of ER- breast cancer cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/genética , Prognóstico , Antineoplásicos Hormonais/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estrogênios/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7
6.
Clin Sci (Lond) ; 131(3): 227-237, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27895148

RESUMO

Transient receptor potential channel 5 (TrpC5) is a member of the TrpC subgroup, and it forms a receptor-activated, non-selective Ca2+ channel. The architecture of the TrpC5 channel is poorly understood. In the present study, we report that TrpC5 is a key factor in regulating differentiation in colorectal cancer (CRC). Through a study of specimens from a large cohort of patients with CRC, we found that TrpC5 was highly expressed and its cellular level correlated with tumour grade. We showed further that up-regulated TrpC5 caused a robust rise in intracellular calcium concentration [Ca2+]i, increased Wnt5a expression and the nuclear translocation of ß-catenin, leading to a reduction in cancer differentiation and an increase in cancer cell stemness. Notably, patients with tumours that expressed high levels of TrpC5 showed significantly poorer disease-free and overall survival. Therefore, our findings suggest that TrpC5 is an independent adverse prognostic factor for death in CRC, reducing differentiation through the Ca2+/Wnt5a signalling pathway.


Assuntos
Sinalização do Cálcio , Carcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Canais de Cátion TRPC/metabolismo , Proteína Wnt-5a/metabolismo , Animais , Células CACO-2 , Carcinoma/diagnóstico , Carcinoma/patologia , Diferenciação Celular , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Células HT29 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Gradação de Tumores , Prognóstico , beta Catenina/metabolismo
7.
Eur J Pharmacol ; 792: 7-14, 2016 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-27780727

RESUMO

The global gene expression and DNA methylation of genes in adriamycin-resistant human breast cancer cells (MCF-7/ADM cells) are similar to those in paclitaxel-resistant MCF-7 cells (MCF-7/PTX) and are significantly different from those in wild-type MCF-7 cells. DNA methylation is associated with chemoresistance in breast cancer and changes the characteristics of chemoresistant and chemosensitive cells. Here, we showed that the tumor-suppressor gene Notch3 was inactivated due to epigenetic silencing DNA hypermethylation in MCF-7/ADM cells. In addition, the drug efflux pump P-glycoprotein was negatively regulated by Notch3 and highly expressed in MCF-7/ADM cells. Taken together, our findings demonstrated that hypermethylation of Notch3 causes activation of P-glycoprotein in adriamycin-resistant cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Metilação de DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Receptor Notch3/genética , Receptor Notch3/metabolismo , Doxorrubicina/farmacologia , Epigênese Genética/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Paclitaxel/farmacologia
8.
Tumour Biol ; 2016 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-27743379

RESUMO

To define the role of the NOTCH signaling pathway in the development of chemoresistance and the associated epithelial-mesenchymal transition (EMT), we investigated the effect of Notch3 on adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM cells). We found that Notch3 was downregulated and involved in the chemoresistance of MCF-7/ADM cells, while forced expression of Notch3 reversed the chemoresistance. Furthermore, fos-related antigen 1 (Fra1) was negatively regulated by Notch3 and was highly expressed in MCF-7/ADM cells. Increased Fra1 activated the EMT process. Finally, Notch3 expression was confirmed in clinically chemoresistant samples of breast cancers from patients receiving anthracycline-based chemotherapy. Low expression of Notch3 was an unfavorable predictor of distant relapse-free survival in ER positive breast cancers. Taken together, our findings demonstrate that the Notch3-Fra1 signaling pathway mediates chemoresistance via the EMT.

9.
Int J Oncol ; 49(4): 1695-1703, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27633960

RESUMO

Long non-coding RNAs (lncRNAs) are involved in cancer progression. In the present study, we analyzed the lncRNA profiles in adriamycin-resistant and -sensitive breast cancer cells and found a group of dysregulated lncRNAs in the adriamycin-resistant cells. Expression of the dysregulated lncRNAs was correlated with dysregulated mRNAs, and these were enriched in GO and KEGG pathways associated with cancer progression and chemoresistance development. Among these lncRNA-mRNA interactions, some lncRNAs may cis­regulate neighboring protein-coding genes and be involved in chemoresistance. We then validated that the lncRNA NONHSAT028712 regulated nearby CDK2 and interfered with the cell cycle and chemoresistance. Furthermore, we identified another group of lncRNAs that trans-regulated genes by interacting with different transcription factors. For example, NONHSAT057282 and NONHSAG023333 modulated chemoresistance and most likely interacted with the transcription factors ELF1 and E2F1, respectively. In conclusion, in the present study, we report for the first time the lncRNA expression patterns in adriamycin-resistant breast cancer cells, and provide a group of novel lncRNA targets that mediate chemoresistance development in both cis- and trans-action modes.

10.
Clin Sci (Lond) ; 130(24): 2267-2276, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27653744

RESUMO

Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-ß (TGF-ß)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.


Assuntos
Anticoagulantes/uso terapêutico , Neoplasias da Mama/genética , Dicumarol/uso terapêutico , Glicoproteínas beta 1 Específicas da Gravidez/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Glicoproteínas beta 1 Específicas da Gravidez/genética , Glicoproteínas beta 1 Específicas da Gravidez/metabolismo , Taxoides/uso terapêutico , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
11.
Biochem Pharmacol ; 118: 18-30, 2016 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-27520484

RESUMO

It is believed that tumor cells can give rise to endothelial cells and tumor endothelium has a neoplastic origin. Yet, the stimuli and underlying mechanism remain unclear. Here, we demonstrate that adriamycin or paclitaxel, first-line chemotherapy agent, induced breast cancer cells to generate morphological, phenotypical and functional features of endothelial cells in vitro. In xenografts models, challenges from adriamycin or paclitaxel induced cancer cells to generate the majority of microvessels. Importantly, in breast cancer specimens from patients with neoadjuvant anthracycline-based or taxane-based chemotherapy, tumor-derived endothelial microvessels, lined by EGFR-amplified or/and TP53+-CD31+ endothelial cells, was significantly higher in patients with progressive or stable disease (PD/SD) than in those with a partial or complete response (PR/CR). Further, exposure to the Notch signaling inhibitor and gene silencing studies showed that Notch signaling inhibition or silencing Nothc4/Dll3 decreased endothelial markers and function of tumor-derived endothelial cells under chemotherapy treatment, which may be through VEGFR3. Thus, our findings demonstrate that chemotherapy induces functional tumor-derived endothelial microvessels by mediating Notch signaling and VEGF signaling, and may provide new targets for anti-angiogenesis therapy in breast cancer.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Proteínas de Neoplasias/agonistas , Neovascularização Patológica/induzido quimicamente , Receptores Notch/agonistas , Transdução de Sinais/efeitos dos fármacos , Animais , Antraciclinas/efeitos adversos , Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Biomarcadores/metabolismo , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Humanos , Células MCF-7 , Camundongos Nus , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Interferência de RNA , Receptores Notch/antagonistas & inibidores , Receptores Notch/genética , Receptores Notch/metabolismo , Organismos Livres de Patógenos Específicos , Taxoides/efeitos adversos , Taxoides/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Onco Targets Ther ; 9: 1077-84, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27042100

RESUMO

The incidence rate of breast cancers in People's Republic of China has increased in the last decade, and many cases are responsive to hormone therapies. The third-generation aromatase inhibitor letrozole inhibits estrogen production, and is more efficacious than the estrogen receptor inhibitor tamoxifen. In recent years, letrozole has been widely used to treat postmenopausal breast cancers in People's Republic of China. Also, metastatic, premenopausal, and male breast cancers have been effectively treated by a combination of letrozole with cytotoxic, radiation, or other therapies. In this review, we provide a perspective and summary of recent advances in the use of letrozole for breast cancer in Chinese patients.

13.
Sci Rep ; 6: 24706, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-27094684

RESUMO

Cancer chemoresistance is regulated by complex genetic and epigenetic networks. In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX). We found that: ① both of the chemoresistant cell lines had similar, massive changes in gene expression, methylation, and miRNA expression versus chemosensitive controls. ② Pairwise integration of the data highlighted sets of genes that were regulated by either methylation or miRNAs, and sets of miRNAs whose expression was controlled by DNA methylation in chemoresistant cells. ③ By combining the three sets of high-throughput data, we obtained a list of genes whose expression was regulated by both methylation and miRNAs in chemoresistant cells; ④ Expression of these genes was then validated in clinical breast cancer samples to generate a 17-gene signature that showed good predictive and prognostic power in triple-negative breast cancer patients receiving anthracycline-taxane-based neoadjuvant chemotherapy. In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , MicroRNAs/genética , Transcriptoma , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/genética , Biologia Computacional/métodos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Células MCF-7 , Reprodutibilidade dos Testes
14.
Acta Pharmacol Sin ; 37(1): 19-24, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26657058

RESUMO

The transient receptor potential (TRP) superfamily contains at least 28 homologs in mammalian. These proteins form TRP channels are permeable to monovalent and divalent cations and participate in a variety of physiological functions. Dysregulation of TRP channels is responsible for numerous diseases. This review provides a brief short overview of mammalian TRP channels with a focus on TRPC5 and its role in cancers. Dysregulation of TRPC5 interrupts Ca(2+) homeostasis in cancer cells, which activates signaling pathways that are highly associated with cancer progression, especially cancer chemoresistance. Based on the important role of TRPC5, we also discuss the potential of TRPC5 as a target for therapeutic intervention. Either direct targeting of TRPC5 or indirect interruption of TRPC5-related signaling pathways may effectively overcome cancer chemoresistance.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Canais de Cátion TRPC/fisiologia , Animais , Antineoplásicos/uso terapêutico , Cálcio/metabolismo , Homeostase , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/metabolismo , Transdução de Sinais , Canais de Cátion TRPC/genética
15.
Oncotarget ; 7(22): 31814-24, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-26701723

RESUMO

Biotransformation by the endophytes of certain plants changes various compounds, and this 'green' chemistry becomes increasingly important for finding new products with pharmacological activity. In this study, polyphyllin VII (PPL7) was biotransformed by endophytes from the medicinal plant Paris polyphylla Smith, var. yunnanensis. This produced a new compound, ZH-2, with pharmacological activity in vitro and in vivo. ZH-2 was more potent than PPL7 in selectively killing more chemoresistant than chemosensitive breast cancer cells. ZH-2 also re-sensitized chemoresistant breast cancer cells, as evidenced by the improved anti-cancer activity of commonly-used chemotherapeutic agent in vitro, in vivo, and in clinical samples. This anti-chemoresistance effect of ZH-2 was associated with inhibiting the epithelial-mesenchymal transition (EMT) pathway. Taken together, our findings are the first one to link biotransformation with a biomedicine. The results provide insights into developing new pharmacologically-active agents via biotransformation by endophytes.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Descoberta de Drogas/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Saponinas/metabolismo , Saponinas/farmacologia , Animais , Antineoplásicos/metabolismo , Biotransformação , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Delftia acidovorans/metabolismo , Relação Dose-Resposta a Droga , Endófitos/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Química Verde , Humanos , Liliaceae/microbiologia , Células MCF-7 , Camundongos Nus , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Pharm Biomed Anal ; 102: 500-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25459950

RESUMO

Although chemotherapy is widely used to treat human cancers, most chemotherapeutic agents only benefit a small fraction of patients because of the heterogeneity of cancers. Therefore, identifying of the sensitivity of cancers toward various chemotherapies would be important for choosing of chemotherapeutic regime. In this study, a 23-gene chemoresistance signature was developed from chemoresistant breast cancers. Functions of the genes in the signature were related with transcription and translation. The signature was indicative of chemoresistance and associated with poor prognosis in multiple chemotherapeutic agents and cancer types. Furthermore, by applying computational approaches, we identified several compounds that might specifically affect the chemoresistant signature. Decitabine (DAC) was the compound most likely to target the signature. In vitro and clinical analysis confirmed effect of DAC toward both breast cancer cell lines and ovarian cancers respectively. In conclusion, our study identified a chemoresistant signature that is both predictive and prognostic, and the signature-related chemoresistance could be suppressed by DAC treatment.


Assuntos
Antineoplásicos , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/métodos , Biossíntese de Proteínas/genética , Transcrição Gênica/genética , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Células MCF-7 , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Valor Preditivo dos Testes
17.
Mol Biosyst ; 10(12): 3111-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25209432

RESUMO

To date, there is no effective marker to predict chemoresistance in cancers. In this study, we aimed to find a signature that can detect chemoresistance to taxane-based therapies in breast cancer. By studying the gene-expression profiling in discovery cohorts with 92 taxane-resistant and 68 taxane-sensitive patients, a 20-gene taxane-based chemotherapy signature (TAXSig) and a TAXSig equation were developed. The TAXSig and its equation were later validated in five further independent datasets with a total of 659 patients. In general, the TAXSig equation easily and effectively discriminated between chemoresistant and chemosensitive individuals. The TAXSig-identified groups showed significant differences in clinical outcomes both in estrogen-receptor-positive and -negative (ER(-)) breast cancer patients, while the TAXSig was especially powerful in identifying ER(-) patients who had a good prognosis and were chemosensitive. In conclusion, the TAXSig is a reliable, effective, and reproducible means of classifying chemoresistance to taxane-based therapies in breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Taxoides/farmacologia , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Marcadores Genéticos , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Resultado do Tratamento
18.
FEBS J ; 281(20): 4718-30, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25156775

RESUMO

Dysregulation of microRNA is strongly implicated in the chemoresistance of cancer. In this study, we found that miR-149 was downregulated and involved in chemoresistance in adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM). Downregulation of miR-149 was related to hypermethylation of its 5'-UTR; this methylation also affected the expression of the glypican 1 gene, which is both the host and the target gene of miR-149. Furthermore, we found that miR-149 modulated chemoresistance through targeting the expression of GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST1). With downregulated miR-149, NDST1 expression was increased in chemoresistant MCF-7/ADM cells versus control MCF-7 wild-type cells. The increased NDST1 then activated a heparan sulfate-related pathway involving activation of heparanase. Finally, expression of miR-149 and NDST1 was confirmed in clinical chemoresistant samples of breast cancers receiving anthracycline/taxane-based chemotherapies. The high expression of NDST1 was also an unfavorable predictor for distant relapse-free survival in Her2 and basal breast cancers. Taken together, our findings demonstrate that miR-149 is regulated by methylation, and is a modulator of cancer chemoresistance by targeting NDST1.


Assuntos
Neoplasias da Mama/metabolismo , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Sulfotransferases/metabolismo , Regiões 5' não Traduzidas/genética , Antibióticos Antineoplásicos/farmacologia , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Doxorrubicina/farmacologia , Feminino , Heparitina Sulfato/metabolismo , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfotransferases/genética , Células Tumorais Cultivadas
19.
Mol Pharmacol ; 86(5): 536-47, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25159093

RESUMO

We previously demonstrated that the overexpression of transient receptor potential channel C5 (TRPC5) and nuclear factor of activated T-cells isoform c3 (NFATC3) are essential for cancer chemoresistance, but how TRPC5 and NFATC3 are regulated was still unclear. In this study, microRNA 320a (miR-320a) was found to be down-regulated in chemoresistant cancer cells. MiR-320a directly targeted TRPC5 and NFATC3, and down-regulation of miR-320a triggered TRPC5 and NFATC3 overexpression. In chemoresistant cells, down-regulation of miR-320a was associated with regulation by methylation, which implicated promoter methylation of the miR-320a coding sequence. Furthermore, the transcription factor v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS-1), which inhibited miR-320a expression, was activated in chemoresistant cancer cells; such activation was associated with hypomethylation of the ETS-1 promoter. Lastly, the down-regulation of miR-320a and high expression of TRPC5, NFATC3, and ETS-1 were verified in clinically chemoresistant samples. Low expression of MiR-320a was also found to be a significant unfavorable predictor for clinic outcome. In conclusion, miR-320a is a mediator of chemoresistance by targeting TRPC5 and NFATC3. Expression of miR-320a is regulated by methylation of its promoter and that of ETS-1.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Redes Reguladoras de Genes/genética , MicroRNAs/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Feminino , Humanos , Células MCF-7 , Metilação , Fatores de Transcrição NFATC/genética , Regiões Promotoras Genéticas/genética , Proteína Proto-Oncogênica c-ets-1/genética , Canais de Cátion TRPC/genética
20.
FEBS Lett ; 588(11): 2009-15, 2014 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-24786471

RESUMO

To investigate the role of microRNAs in the development of chemoresistance and related epithelial-mesenchymal transition (EMT), we examined the effect of miR-489 in adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM). MiR-489 was significantly suppressed in MCF-7/ADM cells compared with chemosensitive parental control MCF-7/WT cells. Forced-expression of miR-489 reversed chemoresistance. Furthermore, Smad3 was identified as the target of miR-489 and is highly expressed in MCF-7/ADM cells. Forced expression of miR-489 both inhibited Smad3 expression and Smad3 related EMT properties. Finally, the interactions between Smad3, miR-489 and EMT were confirmed in chemoresistant tumor xenografts and clinical samples, indicating their potential implication for treatment of chemoresistance.


Assuntos
Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , MicroRNAs/fisiologia , Regiões 3' não Traduzidas , Animais , Antraciclinas/farmacologia , Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Células MCF-7 , Camundongos , Camundongos Nus , Terapia Neoadjuvante , Interferência de RNA , Proteína Smad3/genética , Proteína Smad3/metabolismo , Taxoides/farmacologia , Taxoides/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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