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1.
Braz. j. biol ; 83: e248746, 2023. graf
Artigo em Inglês | MEDLINE, LILACS, VETINDEX | ID: biblio-1339351

RESUMO

Abstract Colorectal cancer (CRC) is one of the most common cancers leading to comorbidities and mortalities globally. The rational of current study was to evaluate the combined epigallocatechin gallate and quercetin as a potent antitumor agent as commentary agent for therapeutic protocol. The present study investigated the effect of epigallocatechin Gallate (EGCG) (150mg) and quercetin (200mg) at different proportions on proliferation and induction of apoptosis in human colon cancer cells (HCT-116). Cell growth, colonogenic, Annexin V in addition cell cycle were detected in response to phytomolecules. Data obtained showed that, the colony formation was inhibited significantly in CRC starting from the lowest concentration tested of 10 µg/mL resulting in no colonies as visualized by a phase-contrast microscope. Data showed a significant elevation in the annexin V at 100 µg/mL EGCG(25.85%) and 150 µg/mL quercetin (48.35%). Moreover, cell cycle analysis showed that this combination caused cell cycle arrest at the G1 phase at concentration of 100 µg/mL (72.7%) and 150 µg/mL (75.25%). The combined effect of epigallocatechin Gallate and quercetin exert antiproliferative activity against CRC, it is promising in alternative conventional chemotherapeutic agent.


Resumo O câncer colorretal (CCR) é um dos cânceres mais comuns, levando a comorbidades e mortalidade em todo o mundo. O racional do presente estudo foi avaliar a combinação de galato de epigalocatequina e quercetina como um agente antitumoral potente como agente de comentário para protocolo terapêutico. O presente estudo investigou o efeito de galato de epigalocatequina (EGCG) (150 mg) e quercetina (200 mg) em diferentes proporções na proliferação e indução de apoptose em células de câncer de cólon humano (HCT-116). O crescimento celular, colonogênico, anexina V, além do ciclo celular foram detectados em resposta a fitomoléculas. Os dados obtidos mostraram que a formação de colônias foi inibida significativamente no CRC a partir da concentração mais baixa testada de 10 µg/mL, resultando em nenhuma colônia conforme visualizado por um microscópio de contraste de fase. Os dados mostraram uma elevação significativa na anexina V a 100 µg/mL de EGCG (25,85%) e 150 µg/mL de quercetina (48,35%). Além disso, a análise do ciclo celular mostrou que essa combinação causou parada do ciclo celular na fase G1 na concentração de 100 µg/mL (72,7%) e 150 µg/mL (75,25%). O efeito combinado da epigalocatequina galato e quercetina exerce atividade antiproliferativa contra o CCR, é promissor como agente quimioterápico alternativo convencional.


Assuntos
Humanos , Neoplasias Colorretais/tratamento farmacológico , Catequina/análogos & derivados , Catequina/farmacologia , Quercetina/farmacologia , Ciclo Celular , Anexina A5 , Linhagem Celular Tumoral , Proliferação de Células
2.
Cell Biol Int ; 46(4): 599-610, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34957655

RESUMO

In most cases of cervical cancer, the high risk of the disease is caused by the human papilloma virus (HPV). Surgery or radiation usually benefits patients with early cervical cancer, while the metastatic one is uncurable and new therapeutic strategies and approaches are required. In this study, HPV16 E6 silence or overexpression were carried out to evaluate the possible mechanisms of HPV16 E6 function in cervical cancer cells with different HPV16 E6 expression background. HPV16 E6-positive cervical cancer cell Siha exerts significantly stronger cell invasion and migration potentials than the HPV16 E6-negative C33A cells. HPV16 E6 silence significantly weakened the potentials of cell invasion and migration, cell proliferation and stemness characteristic in Siha cells. Meanwhile, the overexpression of HPV16 E6 effectively promoted the cell proliferation and stemness characteristic in C33A cells. Our data also indicated a positive association between HPV16 E6 and the levels of epithelial to mesenchymal transition (EMT), and cell stemness. The ectopic expression of OCT4 could effectively reverse the inhibitory roles of HPV16 E6 silence on cell migration, invasion, and stemness in Siha cells. More interestingly, we found that HPV16 E6 might promote the OCT4 expression by impairing the direct binding of p53 on the promoter and activate its transcription. Taken together, our results indicated that HPV16 E6 could promoted the potential cell proliferation, migration, and invasion of human cervical cancer cells by modulating EMT and cell stemness. Our data provide a novel mechanism for how HPV16 E6 acts as a key risk factor for cervical cancer development and progression.


Assuntos
Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Papillomavirus Humano 16/metabolismo , Humanos , Neoplasias do Colo do Útero/metabolismo
3.
Drug Dev Res ; 83(1): 208-216, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34347904

RESUMO

Breast cancer (BC), which is widely considered as the most common cancer in women around the world, evokes ~1.7 million new BC cases and 522,000 BC-related deaths each year. Triple negative breast cancer (TNBC) is clinically confirmed as one of the most aggressive subtypes of BC. ORY-1001, a clinically used lysine specific demethylase 1 (LSD1/KDM1A) inhibitor, was investigated herein to confirm its role in the progression of TNBC and reveal the potential mechanism. After treatment with ORY-1001 in MDA-MB-231 and BT549 cells, the cell proliferation and apoptosis were respectively measured by CCK-8 and TUNEL assays. The expression of proliferation- and apoptosis-associated proteins was tested by means of western blot analysis. Then, R1881, an androgen receptor (AR) agonist, was used to evaluate whether the effects of ORY-1001 on proliferation and apoptosis of TNBC cells was mediated by regulating AR. Results indicated that ORY-1001 treatment restrained the proliferation while enhanced the apoptosis of BC cells, accompanied by the change of proliferation- and apoptosis-related proteins expression. Furthermore, ORY-1001 reduced the level of AR in BC cells. After the activation of AR by R1881, the decreased proliferation and enhanced apoptosis of BC cells triggered by ORY-1001 intervention were partially abolished. In conclusion, this paper has presented the first evidence to suggest that ORY-1001 inhibits proliferation and promotes apoptosis of TNBC cells by suppressing AR expression, which may constitute the theoretical basis for the clinical use of ORY-1001 in the treatment of this disease.


Assuntos
Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Histona Desmetilases/farmacologia , Humanos , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo
4.
Acta Histochem ; 124(2): 151856, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35077998

RESUMO

Neuroblastoma is a metastatic brain tumor particularly common in children. The cure rate is below 50% for patients of high-risk condition. Novel therapeutic agents and approaches are needed to improve the cure rate. Tumor necrosis factor-related and apoptosis-inducing ligand (TRAIL) is a promising proapoptotic factor that rapidly induces apoptosis preferentially in transformed and cancerous cells. Unfortunately, the common TRAIL resistance in cancers has hampered the clinical application of the ligand. Previously we prepared a novel TRAIL-armed ER derived nanosomal agent (ERN-T) that overcomes TRAIL resistance in some cancer lines when combined with a synthetic antagonist of inhibitors of apoptosis proteins (IAPs), AZD5582. However, how AZD5582 sensitizes cancer cells to ERN-T remains not well understood. In this study we continued to test the therapeutic efficacy of the combinatory therapy of ERN-T and AZD5582 on neuroblastoma, aiming to reveal the molecular mechanism underlying the synergism between AZD5582 and ERN-T. The obtained data revealed that ERN-Ts overcame TRAIL resistance and showed significant cytotoxicity on the resistant neuroblastoma line SH-SH5Y when combined with AZD5582 whilst sparing normal cells. The combination of low doses of ERN-Ts and AZD5582 induced intensive apoptosis in SH-SY5Y but not in normal skin fibroblasts (NSFs). Importantly we discovered that TRAIL sensitization in SH-SY5Y was associated with the concomitant downregulation of antiapoptotic factors cFLIP, MCL-1 and IAPs and upregulation of proapoptotic protein BAX and the death receptor 5 (DR5) by the cotreatment of ERN-T and AZD5582. In vivo study demonstrated that the combination of ERN-T and AZD5582 constituted a highly effective and safe therapy for subcutaneous SH-SY5Y xenograft neuroblastoma in nude mice. In conclusion, we identified that the concomitant regulation of both antiapoptotic and proapoptotic factors and DR5 is an essential molecular mechanism for overcoming TRAIL resistance in SH-SY5Y and the combination of ERN-T and AZD5582 potentially constitutes a novel therapeutic strategy, which is highly effective and safe for neuroblastoma.


Assuntos
Neuroblastoma , Ligante Indutor de Apoptose Relacionado a TNF , Alcinos , Animais , Apoptose , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Oligopeptídeos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico
5.
Horm Metab Res ; 54(2): 113-118, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35130572

RESUMO

The function of miR-551b has been widely reported in various human cancers, and its dysregulation in papillary thyroid cancer (PTC) has also been disclosed, implying its potential regulator role in PTC. The aim of the study was to evaluate the function of miR-551b in PTC development and its potential mechanism. miR-551b was evaluated in PTC tissues and cells by RT-qPCR and associated with the clinicopathological features of patients. The biological effect of miR-551b on cellular processes of PTC was assessed with the CCK8 proliferation assay and the Transwell migration and invasion assay. The potential molecular mechanism was estimated with the dual-luciferase reporter assay. miR-551b was significantly upregulated in PTC, which showed a close relationship with the malignancy and development of PTC patients. miR-551b served as a prognostic biomarker negatively related to patients' survival together with the TNM stage. The overexpression of miR-551b exerted promoted effect on the development-related cellular processes of PTC, which was reversed by the overexpression of ERBB4. In conclusion, miR-551b could predict the poor prognosis of PTC patients and serve as a tumor promoter via suppressing ERBB4.


Assuntos
MicroRNAs , Neoplasias da Glândula Tireoide , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Prognóstico , Receptor ErbB-4/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
6.
Cell Mol Biol Lett ; 27(1): 5, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34991445

RESUMO

BACKGROUND: Osteosarcoma (OS) is a common primary bone malignancy. Long noncoding RNA HCG18 is known to play an important role in a variety of cancers. However, its role in OS and relevant molecular mechanisms are unclear. METHODS: Real-time quantitative PCR was performed to determine the expression of target genes. Function experiments showed the effects of HCG18 and miR-365a-3p on OS cell growth. RESULTS: HCG18 expression was increased in OS cell lines. Moreover, in vitro and in vivo experiments demonstrated that HCG18 knockdown inhibited OS cell proliferation. Mechanistically, HCG18 was defined as a competing endogenous RNA by sponging miR-365a-3p, thus elevating phosphoglycerate kinase 1 (PGK1) expression by directly targeting its 3'UTR to increase aerobic glycolysis. CONCLUSION: HCG18 promoted OS cell proliferation via enhancing aerobic glycolysis by regulating the miR-365a-3p/PGK1 axis. Therefore, HCG18 may be a potential target for OS treatment.


Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , RNA Longo não Codificante , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glicólise/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , Fosfoglicerato Quinase/genética , Fosfoglicerato Quinase/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
7.
Cell Biol Int ; 46(3): 336-343, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34941001

RESUMO

Osteosarcoma is a malignant tumor that often occurs in adolescents. There is an urgent need for new treatment options for osteosarcoma due to its poor prognosis after metastasis. Cancer stem cell (CSC) theory states that CSCs represent a small proportion of cancer cells. These CSC have self-renewal ability and are closely associated with cancer growth and metastasis as well as chemotherapy resistance. Similarly, osteosarcoma stem cells (OSCs) play an important role in the growth, metastasis, and chemotherapy resistance of osteosarcoma cells. Targeting OSCs may represent a future treatment of osteosarcoma. Furthermore, some genes have been shown to regulate the growth, metastasis, and chemotherapy resistance of osteosarcoma cells by altering the stemness of OSCs. Targeting these genes may help in the treatment of osteosarcoma. This review mainly discusses recent advances in the research of OSCs and their related genes.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Adolescente , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Células-Tronco Neoplásicas/patologia , Osteossarcoma/patologia
8.
Methods Mol Biol ; 2418: 363-382, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35119675

RESUMO

Manipulation of protein stability using small molecules has a great potential for both basic research and clinical therapy. Based on our protein knockdown technology, we developed chimeric degrader molecules SNIPER(ER)s that target the estrogen receptor alpha (ERα) for degradation via the ubiquitin-proteasome system. This chapter describes the design and synthesis of SNIPER(ER) compounds and methods for the evaluation of their activity in cellular systems and in a tumor xenograft model.


Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio , Animais , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina/metabolismo , Ubiquitinação
9.
Nanotechnology ; 33(23)2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35193121

RESUMO

We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2µM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.


Assuntos
Neoplasias da Mama , Clorofilídeos , Nanopartículas , Fotoquimioterapia , Porfirinas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Clorofilídeos/uso terapêutico , Células Endoteliais/patologia , Feminino , Glutationa , Humanos , Isoquinolinas , Nanopartículas/química , Fármacos Fotossensibilizantes , Porfirinas/química , Pirazóis , Pirimidinas
10.
Mol Pharm ; 19(2): 720-727, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34936367

RESUMO

Radiolabeled prostate-specific membrane antigen (PSMA) ligands have been rapidly adopted as part of patient care for prostate cancer. In this study, a new series of 18F-labeled PSMA-targeting agents was developed based on the high-affinity Glu-ureido-Lys scaffold and 18F-vinyl sulfones (VSs), the tumor uptake and tumor/major organ contrast of which could be tuned by pharmacokinetic linkers within the molecules. In particular, 18F-PEG3-VS-PSMAi showed the highest tumor uptake (12.1 ± 2.2%ID/g at 0.5 h p.i.) and 18F-PEG2-VS-PSMAi showed the highest tumor-to-liver ratio (T/L = 3.7 ± 1.0, 4.8 ± 1.2, and 6.3 ± 1.1 at 0.5, 1.5, and 3 h p.i. respectively). Significantly, compared with the FDA-approved 68Ga-PSMA-11, the newly developed 18F-PEG3-VS-PSMAi has an almost double tumor uptake (P < 0.0001) when tested in the same animal model. In conclusion, 18F-VS-labeled PSMA ligands are promising PET agents with prominent tumor uptake and high contrast. The lead agents 18F-PEG2-VS-PSMAi and 18F-PEG3-VS-PSMAi warrant further evaluation in prostate cancer patients.


Assuntos
Próstata , Neoplasias da Próstata , Animais , Antígenos de Superfície , Linhagem Celular Tumoral , Radioisótopos de Flúor/farmacocinética , Isótopos de Gálio , Radioisótopos de Gálio , Glutamato Carboxipeptidase II , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Compostos Radiofarmacêuticos/farmacocinética , Sulfonas
11.
Mol Cancer ; 21(1): 37, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35130920

RESUMO

PURPOSE: The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. RESULTS: Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). CONCLUSIONS: Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.


Assuntos
Antineoplásicos , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma de Células de Transição/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
12.
J Adv Res ; 37: 169-184, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35499057

RESUMO

Introduction: The prognosis for cervical cancer (CC) patients with lymph node metastasis (LNM) is extremely poor. Lipid droplets (LDs) have a pivotal role in promoting tumor metastasis. The crosstalk mechanism between LDs and LNM modulated in CC remains largely unknown. Objectives: This study aimed to construct a miRNA-dependent progonostic model for CC patients and investigate whether miR-532-5p has a biological impact on LNM by regualting LDs accumulation. Methods: LASSO-Cox regression was applied to establish a prognostic prediction model. miR-532-5p had the lowest P-value in RNA expression (P < 0.001) and prognostic prediction (P < 0.0001) and was selected for further study. The functional role of the prognostic miR-532-5p-correlated competing endogenous RNA (ceRNA) network was investigated to clarify the crosstalk between LDs and LNM. The underlying mechanism was determined using site-directed mutagenesis, dual luciferase reporter assays, RNA immunoprecipitation assays, and rescue experiments. A xenograft LNM model was established to evaluate the effect of miR-532-5p and orlistat combination therapy on tumor growth and LNM. Results: A novel 5-miRNAs prognostic signature was constructed to better predict the prognosis of CC patient. Further study demonstrated that miR-532-5p inhibited epithelial-mesenchymal transition and lymphangiogenesis by regulating LDs accumulation. Interestingly, we also found that LDs accumulation promoted cell metastasis in vitro. Mechanistically, we demonstrated a miR-532-5p-correlated ceRNA network in which LINC01410 was bound directly to miR-532-5p and effectively functioned as miR-532-5p sponge to disinhibit its target gene-fatty acid synthase (FASN). Combined therapy with miR-532-5p and FASN inhibitor-orlistat further inhibited tumor growth and LNM in vivo. Conclusion: Our findings highlight a LD accumulation-dependent mechanism of miR-532-5p-modulated LNM and support treatment with miR-532-5p/orlistat as novel strategy for treating patients with LNM in CC.


Assuntos
MicroRNAs , Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Gotículas Lipídicas/metabolismo , Metástase Linfática , MicroRNAs/genética , MicroRNAs/metabolismo , Orlistate , Prognóstico , Neoplasias do Colo do Útero/genética
13.
Bioengineered ; 13(5): 11541-11550, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35502827

RESUMO

N6-methyladenosine (m6A) modification acts as the most prevalent internal modification in eukaryotic mRNA. Emerging evidence shows the critical biological roles of m6A key enzymes in human cancers. However, the roles of m6A binding protein IGF2BP2 in gastric cancer (GC) progression are still unclear. In this study, we confirmed that IGF2BP2 was highly expressed in GC cell lines and tumor tissues. Knocking down of IGF2BP2 suppressed cell proliferation and migration, and repressed xenograft tumor growth in vivo, while IGF2BP2 overexpression promoted the proliferation and migration. Mechanistically, we identified that IGF2BP2 regulated GC the proliferation/migration through recognizing the m6A modification sites of SIRT1 mRNA. In general, our findings demonstrated a novel regulatory mechanism that IGF2BP2/SIRT1 axis modulated GC progression in an m6A-dependent manner, suggesting that m6A may be a therapeutic target for GC.


Assuntos
Neoplasias Gástricas , Adenosina/análogos & derivados , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Mensageiro , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Neoplasias Gástricas/patologia
14.
Bioengineered ; 13(5): 11551-11563, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35502885

RESUMO

Laryngeal squamous cell carcinoma (LSCC) is a common malignancy in head and neck. Circular SHKBP1 (circSHKBP) exerts momentous functions in the occurrence of many cancers including LSCC. Thus, we investigated the oncogenic capacities of circSHKBP1 in LSCC, and revealed the underlying mechanism as a competing endogenous RNA. The expression levels of circSHKBP1, miR-766-5p, and high mobility group AT-hook 2 (HMGA2) were examined by quantitative real-time PCR and their influences on the overall survival were measured by Kaplan-Meier method. The correlations between circSHKBP1 and miR-766-5p or HMGA2 were detected by Spearman's rank correlation analysis. In vitro, the influences of circSHKBP1/miR-766-5p/HMGA2 axis on the tumorigenesis of LSCC were examined by CCK-8, transwell, sphere formation, and angiogenesis assays, respectively. circSHKBP1 expression was up-regulated in the LSCC specimens and cell lines. And elevated circSHKBP1 expression was closely linked to poor prognosis. Silencing circSHKBP1 expression restrained cell proliferation, invasion, angiogenesis, stem cell-like properties and tumor growth. We observed that miR-766-5p was down-regulated and negatively correlated to circSHKBP1 in LSCC samples. However, HMGA2 was highly expressed and positively associated with circSHKBP1 in these specimens. Importantly, the levels of circSHKBP1, miR-766-5p, and HMGA2 were closely associated with patients' clinical parameters including lymph nodes metastasis and TNM stages. Mechanistic analysis clarified that circSHKBP1 sponged miR-766-5p to regulate HMGA2, the target of miR-766-5p. Moreover, miR-766-5p inhibition and overexpression of HMGA2 rescued the tumor-suppressing roles of circSHKBP1 downregulation in LSCC. In conclusion, circSHKBP1 accelerated the tumorigenesis of LSCC via modulating HMGA2 by targeting miR-766-5p.


Assuntos
Neoplasias de Cabeça e Pescoço , MicroRNAs , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Células-Tronco/metabolismo
15.
Acta Med Okayama ; 76(2): 203-215, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35503449

RESUMO

The epithelial-mesenchymal transition (EMT), a normal biological process by which epithelial cells acquire a mesenchymal phenotype, is associated with migration, metastasis, and chemoresistance in cancer cells, and with poor prognosis in patients with esophageal cancer. However, therapeutic strategies to inhibit EMT in tumor environments remain elusive. Here, we show the therapeutic potential of telomerase-specific replication- competent oncolytic adenovirus OBP-301 in human esophageal cancer TE4 and TE6 cells with an EMT phenotype. Transforming growth factor-ß (TGF-ß) administration induced the EMT phenotype with spindleshaped morphology, upregulation of mesenchymal markers and EMT transcription factors, migration, and chemoresistance in TE4 and TE6 cells. OBP-301 significantly inhibited the EMT phenotype via E1 accumulation. EMT cancer cells were susceptible to OBP-301 via massive autophagy induction. OBP-301 suppressed tumor growth and lymph node metastasis of TE4 cells co-inoculated with TGF-ß-secreting fibroblasts. Our results suggest that OBP-301 inhibits the TGF-ß-induced EMT phenotype in human esophageal cancer cells. OBP-301-mediated E1A overexpression is a promising antitumor strategy to inhibit EMT-mediated esophageal cancer progression.


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias Esofágicas , Adenoviridae/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/patologia , Humanos , Fator de Crescimento Transformador beta/farmacologia , Fatores de Crescimento Transformadores
16.
Methods Mol Biol ; 2451: 203-210, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35505020

RESUMO

When investigating the promise of novel therapeutic modalities, the choice of an appropriate and reproducible in vivo model is critical to determine the relevance of the findings. In the case of glioblastoma, a high-grade glioma tumor that is clinically characterized by a high infiltrative pattern, no existing model exactly mimics the clinical features of these tumors. However, a syngeneic rat model of glioblastoma in which F98 cells are orthotopically implanted can recapitulate most of the characteristics of glioma as observed in patients, including a highly aggressive nature, a high degree of infiltration of cancer cells into healthy tissue, and a strong resistance to commonly used treatments including radiotherapy and chemotherapy. Here, we provide a detailed protocol to stereotaxically implant F98 cells in the rat brain and obtain a reproducible and clinically representative glioma model in rodents.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Fotoquimioterapia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Ratos , Ratos Endogâmicos F344
17.
Cell Mol Life Sci ; 79(5): 268, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35499593

RESUMO

FBXW2 is a poorly characterized F-box protein, as a tumor suppressor that inhibits growth and metastasis of lung cancer by promoting ubiquitylation and degradation of oncogenic proteins, including SKP2 and ß-catenin. However, what the biological functions of FBXW2 in prostate cancer cells and whether FBXW2 targets other substrates to involve in progression of prostate cancer is still unclear. Here, we reported that overexpression of FBXW2 attenuated proliferation and metastasis of PCa models both in vitro and in vivo, while FBXW2 depletion exhibited the opposite effects. Intriguingly, FBXW2 was an E3 ligase for EGFR in prostate cancer. EGFR protein level and its half-life were extended by FBXW2 depletion, while EGFR protein level was decreased, and its half-life was shortened upon overexpression of FBXW2, but not its dominant-negative mutant. Importantly, FBXW2 bond to EGFR via its consensus degron motif (TSNNST), and ubiquitylated and degraded EGFR, resulting in repression of EGF function. Thus, our data uncover a novel that FBXW2 as a tumor suppressor of prostate cancer, inhibits EGFR downstream by promoting EGFR ubiquitination and degradation, resulting in repression of cell proliferation and metastasis.


Assuntos
Proteínas F-Box , Neoplasias da Próstata , Linhagem Celular Tumoral , Proliferação de Células , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Humanos , Masculino , Neoplasias da Próstata/patologia , Ubiquitinação
18.
BMC Cancer ; 22(1): 488, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35505294

RESUMO

BACKGROUND: Emerging evidence has identified miR-138 as a tumor suppressor that can suppress the proliferation of various cancers. Meanwhile, the cause of abnormal miR-138 expression in cervical cancer remains uncertain. This study clarified the mechanism by which miR-138 regulates proliferation, invasion, metastasis, and EMT in cervical cancer cells. RESULTS: miR-138 expression in human cervical cancer and adjacent normal tissue was measured using qPCR. SiHa and C33A cells were used to determine the function of miR-138 via miR-138 mimic or inhibitor transfection, followed by wound healing, Cell Counting Kit-8, flow cytometry, and Transwell assays. Epithelial and mesenchymal marker expression was analyzed using Western blotting. DNA methylation in the miR-138 promoter was examined using bisulfite sequencing PCR. The downstream target genes of miR-138 were identified via bioinformatics analysis and luciferase reporter assays. A tumor xenograft model was employed to validate DNA methylation-induced miR-138 downregulation and tumor growth inhibition in cervical cancer in vivo. miR-138 levels were significantly lower in cervical cancer tissues than in adjacent control tissues. Furthermore, lower miR-138 expression and higher CpG methylation in the miR-138 promoter were identified in lymph node-positive metastatic cervical cancer tumors versus that in non-metastatic tumor tissues. Upon miR-138 overexpression, cell proliferation, metastasis, invasion, and EMT were suppressed. miR-138 agomir transfection and demethylating drug treatment significantly inhibited cervical tumor growth and EMT in tumor xenograft models. DNA methylation inhibited miR-138 transcription, and enhancer of zeste homolog 2 (EZH2) downregulation mediated the tumor suppressor function of miR-138 in cervical cancer. CONCLUSION: We demonstrated that miR-138 suppresses tumor progression by targeting EZH2 in cervical cancer and uncovered the role of DNA methylation in the miR-138 promoter in its downregulation. These findings demonstrated the potential of miR-138 to predict disease metastasis and/or function as a therapeutic target in cervical cancer.


Assuntos
MicroRNAs , Neoplasias do Colo do Útero , Linhagem Celular Tumoral , Proliferação de Células/genética , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias do Colo do Útero/patologia
19.
BMC Gastroenterol ; 22(1): 215, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35505304

RESUMO

BACKGROUND: CircRNA circ-ATAD1 has been characterized as an oncogenic circRNA in gastric cancer, while its role in colorectal cancer (CRC) is unknown. This study was carried out to explore the role of circ-ATAD1 in CRC. METHODS: Paired CRC and adjacent non-tumor tissue samples collected from 64 CRC patients were subjected to RNA extractions and RT-qPCRs to analyze the expression of circ-ATAD1, premature miR-618, and mature miR-618 in CRC. The effects of circ-ATAD1 overexpression on miR-618 maturation were analyzed by transfecting circ-ATAD1 expression vector into CRC cells, followed by determining the expression of premature miR-618 and mature miR-618 using RT-qPCR. The subcellular location of circ-ATAD1 was analyzed by nuclear fractionation assay, and the interaction between circ-ATAD1 and premature miR-618 was analyzed by RNA pull-down assay. The roles of circ-ATAD1, premature miR-618, and mature miR-618 in regulating CRC cell proliferation were explored by CCK-8 assay. RESULTS: Circ-ATAD1 was upregulated in CRC and predicted poor survival. In addition, circ-ATAD1 was inversely correlated with mature miR-618 but not premature miR-618. In CRC cells, circ-ATAD1 overexpression decreased the level of mature miR-618 but not premature miR-618. Circ-ATAD1 was detected in both the nucleus and cytoplasm. A direct interaction between circ-ATAD1 and miR-618 was observed. Moreover, circ-ATAD1 overexpression reduced the inhibitory effects of miR-618 overexpression on cell proliferation. CONCLUSION: Circ-ATAD1 is overexpressed in CRC and may suppress miR-618 maturation to participate in CRC.


Assuntos
Neoplasias Colorretais , MicroRNAs , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
20.
Proc Natl Acad Sci U S A ; 119(19): e2202439119, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35512094

RESUMO

SignificanceMesothelin (MSLN) is a cell-surface protein that is a popular target for antibody-based therapies. We have identified shed MSLN as a major obstacle to successful antibody therapies and prepared a monoclonal antibody that inhibits shedding and makes very active CAR T cells whose activity is not blocked by shed MSLN and merits further preclinical development.


Assuntos
Receptores de Antígenos Quiméricos , Anticorpos Monoclonais/metabolismo , Linhagem Celular Tumoral , Proteínas Ligadas por GPI/metabolismo , Linfócitos T
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