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1.
Front Oncol ; 10: 217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219060

RESUMO

Background: Patients with metastatic radioiodine-refractory papillary thyroid carcinoma (PTC) have limited treatment options and a poor prognosis. There is an urgent need to develop new drugs targeting PTC for clinical application. Apatinib, a novel small-molecule tyrosine kinase inhibitor (TKI), is highly selective for vascular endothelial growth factor receptor-2 (VEGFR2) and exhibits antitumor effects in a variety of solid tumors. Although apatinib has been shown to be safe and efficacious in radioiodine-refractory differentiated thyroid cancer, the mechanism underlying its antitumor effect is unclear. In this report, we explored the effects of apatinib on PTC in vitro and in vivo. Methods: VEGFR2 expression levels were evaluated by immunohistochemistry (IHC), qPCR, and western blotting (WB). The effects of apatinib on cell viability, colony formation, and migration in the Transwell assay were assessed in vitro, and its effect on tumor growth rate was assessed in vivo. In addition, the levels of proteins in signaling pathways were determined by WB. Finally, the autophagy level was assessed by WB, immunofluorescence (IF), and transmission electron microscopy. Results: We found that high VEGFR2 expression is associated with tumor size, T stage, and lymph node metastasis in patients with PTC and that apatinib inhibits PTC cell growth, promotes apoptosis, and induces cell cycle arrest through the PI3K/Akt/mTOR signaling pathway. Moreover, apatinib induces autophagy, and pharmacological inhibition of autophagy or small interfering RNA (siRNA)-mediated targeting of autophagy-associated gene 5 (ATG5) can further increase PTC cell apoptosis. Conclusion: Our data suggest that apatinib can induce apoptosis and autophagy via the PI3K/Akt/mTOR signaling pathway for the treatment of PTC and that autophagy is a potential novel target for future therapy in resistant PTC.

2.
Cell Rep ; 26(1): 168-181.e4, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30605673

RESUMO

The heat shock protein 70 (Hsp70) is upregulated in response to stress and has been implicated as a stress marker in temporal lobe epilepsy (TLE). However, whether Hsp70 plays a pathologic or protective role in TLE remains unclear. Here we report a deleterious role of Hsp70 in kainic acid (KA)-induced seizures. Hsp70 expression is upregulated in a KA model of TLE, and silencing or inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates acute or chronic epilepsy by enhancing A-type potassium current in hippocampal neurons. Hsp70 upregulation leads to proteosomal degradation of Kv4-KChIP4a channel complexes primarily encoding neuronal A-type current. Furthermore, Hsp70 directly binds to the N terminus of auxiliary KChIP4a and targets Kv4-KChIP4a complexes to proteasome. Taken together, our findings reveal a role of Hsp70 in the pathogenesis of epilepsy through degradation of Kv4-KChIP4a complexes, and pharmacological inhibition of Hsp70 may represent therapeutic potential for epilepsy or hyperexcitability-related neurological disorders.

3.
Cell Death Dis ; 9(6): 703, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899325

RESUMO

Overexpression of the Ca2+-activated chloride channel ANO1/TMEM16A is implicated in tumorigenesis, and inhibition of ANO1 overexpression suppresses xenograft tumor growth and invasiveness. However, the underlying molecular mechanism for ANO1 inhibition in suppression of tumorigenesis remains unknown. Here, we show that silencing or inhibition of endogenous ANO1 inhibits cell growth, induces apoptosis and upregulates TNF-α expression in prostate cancer PC-3 cells. Enhancement of TNF-α signaling by ANO1 knockdown leads to upregulation of phosphorylated Fas-associated protein with death domain and caspase activation. Furthermore, silencing of ANO1 inhibits growth of PC-3 xenograft tumors in nude mice and induces apoptosis in tumors via upregulation of TNF-α signaling. Taken together, our findings provide mechanistic insight into promoting apoptosis in prostate cancer cells by ANO1 inhibition through upregulation of TNF-α signaling.


Assuntos
Anoctamina-1/antagonistas & inibidores , Apoptose , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Animais , Anoctamina-1/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteína de Domínio de Morte Associada a Fas/metabolismo , Inativação Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Fosforilação , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Cell Sci ; 131(4)2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29361540

RESUMO

Unconventional myosin VIIA (Myo7a) is an actin-based motor molecule that normally functions in the cochlear hair cells of the inner ear. Mutations of MYO7A/Myo7a have been implicated in inherited deafness in both humans and mice. However, there is limited information about the functions of Myo7a outside of the specialized cells of the ears. Herein, we report a previously unidentified function of Myo7a by demonstrating that it plays an important role in melanoma progression. We found that silencing Myo7a by means of RNAi inhibited melanoma cell growth through upregulation of cell cycle regulator p21 (also known as CDKN1A) and suppressed melanoma cell migration and invasion through downregulation of RhoGDI2 (also known as ARHGDIB) and MMP9. Furthermore, Myo7a depletion suppressed melanoma cell metastases to the lung, kidney and bone in mice. In contrast, overexpression of Myo7a promoted melanoma xenograft growth and lung metastasis. Importantly, Myo7a levels are remarkably elevated in human melanoma patients. Collectively, we demonstrated for the first time that Myo7a is able to function in non-specialized cells, a finding that reveals the complicated disease-related roles of Myo7a, especially in melanomas.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Melanoma/genética , Miosinas/genética , Inibidor beta de Dissociação do Nucleotídeo Guanina rho/genética , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Orelha Interna/metabolismo , Orelha Interna/patologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Metaloproteinase 9 da Matriz/genética , Melanoma/patologia , Camundongos , Mutação , Miosinas/antagonistas & inibidores , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Oncotarget ; 7(48): 78619-78630, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27732935

RESUMO

ANO1, a calcium-activated chloride channel, has been reported to be amplified or overexpressed in tissues of several cancers. However, reports on its roles in tumor progression obtained from cancer cell lines are inconsistent, suggesting that the role of ANO1 in tumorigenesis is likely dependent on either its expression level or cell-type expressing ANO1. To investigate the biological roles of ANO1 in different tumor cells, we, in this study, selected several cancer cell lines and a normal HaCaT cell line with high expression levels of ANO1, and examined the function of ANO1 in these cells using approaches of lentiviral knockdown and pharmacological inhibition. We found that ANO1 knockdown significantly inhibited cell proliferation and induced cell apoptosis in either tumor cell lines or normal HaCaT cell line. Moreover, silencing ANO1 arrested cancer cells at G1 phase of cell cycle. Treatment with ANO1 inhibitor CaCCinh-A01 reduced cell viability in a dose-dependent manner. Furthermore, both ANO1 inhibitors CaCCinh-A01 and T16Ainh-A01 significantly suppressed cell migration. Our findings show that ANO1 overexpression promotes cancer cell proliferation and migration; and genetic or pharmacological inhibition of ANO1 induces apoptosis and cell cycle arrest at G1 phase in different types of epithelium-originated cancer cells.


Assuntos
Anoctamina-1/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Pirimidinas/farmacologia , Tiazóis/farmacologia , Tiofenos/farmacologia , Anoctamina-1/genética , Anoctamina-1/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção
6.
PLoS One ; 10(8): e0136584, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26305547

RESUMO

Lung cancer or pulmonary carcinoma is primarily derived from epithelial cells that are thin and line on the alveolar surfaces of the lung for gas exchange. ANO1/TMEM16A, initially identified from airway epithelial cells, is a member of Ca2+-activated Cl- channels (CaCCs) that function to regulate epithelial secretion and cell volume for maintenance of ion and tissue homeostasis. ANO1/TMEM16A has recently been shown to be highly expressed in several epithelium originated carcinomas. However, the role of ANO1 in lung cancer remains unknown. In this study, we show that inhibition of calcium-activated chloride channel ANO1/TMEM16A suppresses tumor growth and invasion in human lung cancer. ANO1 is upregulated in different human lung cancer cell lines. Knocking-down ANO1 by small hairpin RNAs inhibited proliferation, migration and invasion of GLC82 and NCI-H520 cancel cells evaluated by CCK-8, would-healing, transwell and 3D soft agar assays. ANO1 protein is overexpressed in 77.3% cases of human lung adenocarcinoma tissues detected by immunohistochemistry. Furthermore, the tumor growth in nude mice implanted with GLC82 cells was significantly suppressed by ANO1 silencing. Taken together, our findings provide evidence that ANO1 overexpression contributes to tumor growth and invasion of lung cancer; and suppressing ANO1 overexpression may have therapeutic potential in lung cancer therapy.


Assuntos
Adenocarcinoma/genética , Proliferação de Células/genética , Canais de Cloreto/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Animais , Anoctamina-1 , Cálcio/metabolismo , Movimento Celular/genética , Canais de Cloreto/biossíntese , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Invasividade Neoplásica/genética , Proteínas de Neoplasias/biossíntese , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
PLoS One ; 10(4): e0124338, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25919292

RESUMO

BACKGROUND: Insulin-like growth factor 2 mRNA binding protein 3 (IMP3) is expressed in metastatic and a subset of primary renal cell carcinoma (RCC). However, the role of IMP3 in RCC progression was poorly understood. We aim to uncover the mechanism of IMP3 in regulating clear cell RCC (CCRCC) progression and validate the prognostic significance of IMP3 in localized CCRCC. METHODS: Caki-1 cells stably overexpressing IMP3 and Achn cells with knockdown of IMP3 were analyzed for cell migration and invasion by Transwell assay. RNA-seq was used to profile gene expression in IMP3-expressing Caki-1 cells. A cohort of 469 localized CCRCC patients were examined for IMP3 expression by immunohistochemistry using tumor tissue array. RESULTS: IMP3 promoted Caki-1 cell migration and invasion, whereas knockdown of IMP3 by RNAi inhibited Achn cell migration and invasion. Enhanced IMP3 expression activated NF-кB pathway and through which, it functioned in promoting the RCC cell migration. IMP3 expression in localized CCRCC was found to be associated with higher nuclear grade, higher T stage, necrosis and sarcomatoid differentiation (p< 0.001). Enhanced IMP3 expression was correlated with shorter recurrence-free and overall survivals. Multivariable analysis validated IMP3 as an independent prognostic factor for localized CCRCC patients. CONCLUSION: IMP3 promotes RCC cell migration and invasion by activation of NF-кB pathway. IMP3 is validated to be an independent prognostic marker for localized CCRCC.


Assuntos
Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Progressão da Doença , Neoplasias Renais/patologia , NF-kappa B/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Prognóstico , Adulto Jovem
8.
FEBS Lett ; 588(17): 2859-66, 2014 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-24997346

RESUMO

Unconventional myosin VIIA (Myo7a) has been known to associate with hereditary deafness. Here we present a novel function of Myo7a by identifying that Myo7a directly interacts with integrin ß5 subunit and regulates cell adhesion and motility in an integrin-dependent manner. We found that Myo7a bound to the cytoplasmic tail of integrin ß5. Further, we pinpointed an integrin-binding domain at F3 of the first FERM domain and F1 of the second FERM domain. Functionally, Myo7a-induced cell adhesion and migration were mediated by integrin αvß5. These findings indicated that Myo7a interacts with integrin ß5 and selectively promotes integrin αvß5-mediated cell migration.


Assuntos
Movimento Celular , Cadeias beta de Integrinas/metabolismo , Miosinas/química , Miosinas/metabolismo , Receptores de Vitronectina/metabolismo , Animais , Adesão Celular , Linhagem Celular , Citoplasma/metabolismo , Humanos , Camundongos , Ligação Proteica , Estrutura Terciária de Proteína
9.
Int J Cancer ; 133(6): 1368-79, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23483548

RESUMO

Kindlin 2, as a focal adhesion protein, controls integrin activation and regulates Wnt signaling in an integrin-binding independent manner. However, the association of Kindlin 2 with cancer-related microRNAs is unknown. Here, we report that Kindlin 2 markedly downregulates the expression of miR-200 family by inducing CpG island hypermethylation. Mechanistically, Kindlin 2 forms a complex with DNMT3A in the cell nucleus and the two proteins co-occupy the promoter of miRNA-200b. Functionally, repression of miR-200b is required for Kindlin 2-induced breast cancer cell invasion and tumor formation. Our data indicate that Kindlin 2 plays a novel role in epigenetic repression of miR-200 family, a mechanism that promotes breast cancer invasion.


Assuntos
Neoplasias da Mama/patologia , Inativação Gênica , Proteínas de Membrana/fisiologia , MicroRNAs/genética , Proteínas de Neoplasias/fisiologia , Animais , Linhagem Celular Tumoral , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferases/fisiologia , Metilação de DNA , Feminino , Humanos , Camundongos , Camundongos SCID , Invasividade Neoplásica
10.
Cancer Lett ; 330(2): 208-16, 2013 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-23211537

RESUMO

Kindlin-2, as a focal adhesion protein, has been found to regulate tumor progression. However, the mechanism underlying Kindlin-2 regulation of tumor progression is largely unknown. Here, we report that Kindlin-2 regulates breast cancer cell proliferation, apoptosis and chromosomal abnormalities in both gain and loss of function assays. Functionally, overexpression of Kindlin-2 promotes tumor formation in implanted xenograft while knockdown of Kindlin-2 inhibits tumor growth in mice. Mechanistically, an array-based comparative genomic hybridization and karyotype analyses indicate that ectopic expression of Kindlin-2 leads to genome instability in breast cancer cells. Our data suggest a novel mechanism that Kindlin-2 regulates breast cancer progression by inducing genome instability.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Instabilidade Genômica/genética , Proteínas de Membrana/fisiologia , Proteínas de Neoplasias/fisiologia , Animais , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Proteínas de Membrana/análise , Camundongos , Proteínas de Neoplasias/análise
11.
Guang Pu Xue Yu Guang Pu Fen Xi ; 30(10): 2676-9, 2010 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-21137398

RESUMO

Using a Dual-View wavelength splitter, double-stained African green monkey kidney COS-7 cells, transfected with pEGFP-Myosin 15a and costained with Rhodamine-filopodia were observed based on an ICCD(intensified charge couple device) fluorescence micro-imaging systems. Total internal reflection fluorescence microscopy was used to observe the overexpression of Myosin 15a to the tips of the elongation filopodia. An approach to collecting fluorescence in two channels and avoiding spectra crosstalk was employed to observe Myosin 15a and filopodia distribution in African green monkey kidney COS-7 cells. High sensitivity TIRF technology and two channels imaging method provided a wide application in bio-medical studies.


Assuntos
Células COS , Microscopia de Fluorescência , Animais
12.
Cancer Lett ; 299(1): 54-62, 2010 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-20813451

RESUMO

Resistance to anticancer drugs is often observed in prostate cancer therapy. Kindlin-2 was recently found overexpressed during cancer progression. In this study, we examined the functional role of Kindlin-2 in cisplatin-induced prostate cancer cell death. Kindlin-2 was highly expressed in the androgen-insensitive (PC-3 and DU-145), but not in the androgen-sensitive cell lines (e.g., LNCaP). Overexpression of Kindlin-2 in LNCaP protected the cells from cisplatin-induced death, while Kindlin-2 knock-down in PC-3 cells enhanced cisplatin sensitivity. Mechanistically, Kindlin-2 regulation of the anti-apoptotic Bcl-xL may explain the increased cell death in the absence of Kindlin-2. Taken together, Kindlin-2 appears to play a functional role in prostate cancer cell sensitivity to cisplatin. Targeting Kindlin-2 may therefore improve drug efficacy and reduce drug doses, and would likely be beneficial for the treatment of prostate cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Proteínas de Membrana/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Masculino , Proteínas de Membrana/análise , Proteínas de Neoplasias/análise , Neoplasias da Próstata/química , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Interferência de RNA
13.
Beijing Da Xue Xue Bao Yi Xue Ban ; 40(4): 347-51, 2008 Aug 18.
Artigo em Chinês | MEDLINE | ID: mdl-18677378

RESUMO

OBJECTIVE: To confirm the nucleolar localization of telomerase-regulation associated protein-human N-acetyltransferase-like protein (hALP) and its associated functions. METHODS: Immunofluoresent staining and immunoelectron microscopy were used to detect the distribution of hALP in HeLa and Saos2 cells, and the co-localization of hALP and rDNA was analyzed by fluorescence in situ hybridization and immunofluoresence. RNAi was performed to further verify the nucleolar localization of hALP. A series of eukaryotic expression plasmids carrying various portions of hALP sequence were constructed and transiently transfected to HeLa and Saos2 cells. The expression of hALP in tumor tissues was stained by immunohistochemistry. RESULTS: hALP distributed predominantly in the nucleoli of HeLa and Saos2 cells, and colocalized with rDNA. Granular component was the precise distribution of hALP in the nucleolus under electron microscope. Nucleolar signals for hALP reduced significantly in cells transfected with hALP siRNA. The carboxy terminus of hALP including residues 549-834 was necessary for its nucleolar localization. hALP could be detected in the nucleoli of many kinds of tumor cells, including leiomyosarcoma, primitive neuroectodermal tumor, neuroblastoma, melanoma, prostatic cancer, and clear cell renal carcinoma. CONCLUSION: hALP is a nucleolar protein, and the nucleolar localization is mediated by its carboxy terminal domain, and hALP could be detected in the nucleoli of many tumor tissues, which is worthy of further investigation.


Assuntos
Asparaginase/metabolismo , Autoantígenos/metabolismo , Nucléolo Celular/metabolismo , Neoplasias/metabolismo , Asparaginase/genética , Autoantígenos/genética , Regulação Enzimológica da Expressão Gênica , Células HeLa , Humanos
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