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1.
Oncol Rep ; 47(2)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34958116

RESUMO

Mutations of p53 tumor suppressors occur more frequently in cancers at advanced stages or in more malignant cancer subtypes such as triple­negative breast cancer. Thus, restoration of p53 tumor suppressor function constitutes a valuable cancer therapeutic strategy. In the present study, it was revealed that a specific inhibitor of histone deacetylase 6, ACY­1215, caused increased acetylation of p53 in breast cancer cells with mutated p53, which was accompanied by increased expression of p21. These results suggested that ACY­1215 may lead to enhanced transcriptional activity of p53. It was also determined that ACY­1215 treatment resulted in G1 cell cycle arrest and apoptosis in these cancer cells. Furthermore, ACY­1215 displayed a synergistic effect with specific inhibitors of ATM, an activator of Akt, in inducing cancer cell apoptosis and inhibiting their motility. More importantly, it was observed that combination of ACY­1215 and ATM inhibitors exhibited markedly more potent antitumor activity than the individual compound in xenograft mouse models of breast cancer with mutant p53. Collectively, our results demonstrated that ACY­1215 is a novel chemotherapeutic agent that could restore mutant p53 function in cancer cells with strong antitumor activity, either alone or in combination with inhibitors of the ATM protein kinase.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Quimioterapia Combinada , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Camundongos
2.
Gene ; 807: 145964, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34530087

RESUMO

AIMS: We aimed to investigate the role of G protein subunit alpha Z(GNAZ) in the progression and prognosis of patients with hepatocellular carcinoma (HCC). METHODS: Oncomine, GEO, TCGA, GEPIA2, Kaplan-Meier Plotter, TIMER2, Metascape, CCLE, LinkedOmics, and UALCAN databases were used to analyze the differential expression of GNAZ in HCC and normal liver tissues, relationship between GNAZ expression and prognosis of patients with HCC, and expression of GNAZ in common human HCC cell lines. Western blotting was performed to analyze GNAZ expression, while the Cell Counting Kit 8 assay was used to determine cell proliferation, and flow cytometry was used to evaluate the cell cycle and apoptosis. Wound healing and transwell invasion assays were used to investigate cell metastasis and invasion. RESULTS: Using Oncomine, Gene Expression Omnibus (GEO), and GEPIA2 databases, GNAZ was found to be overexpressed in HCC tissues compared with that in adjacent normal liver tissues, and western blotting analysis showed GNAZ overexpression in seven patients with HCC who underwent surgical resection of HCC and para-cancerous tissues (p < 0.01). Survival analysis revealed that high GNAZ expression was negatively associated with overall survival (OS), recurrence-free survival, progression-free survival, and disease-specific survival in patients with HCC (p < 0.05). GNAZ overexpression was associated with worse 4- month, 6- month, 12- month, 24- month, 36- month, 48- month, and 60-month OS, as well as with different clinicopathological characteristics of patients with HCC, including hepatitis virus infection state; alcohol consumption state; male; female; Asian; microvascular invasion, Stage I-II, Stage II-III, and Stage III-IV; and grade II (Cox regression, p < 0.05). KEGG/GO biological process enrichment indicated that the genes similar to GNAZ in HCC were mainly enriched in the cell cycle, cell cycle phase transition, DNA replication checkpoint, and regulation of G0 to G1 transition. siRNA-GNAZ significantly reduced the viability of JHH-2 and SNU-761 cells from 12 to 96 h; increased the percentage of cells in the G0/G1 phase and decreased that of cells in the S and G2/M phases (p < 0.05); and markedly downregulated the expression of cyclin D, cyclin E, and CDK2 protein. siRNA-GNAZ also significantly increased the percentage of JHH-2 and SNU-761 cell apoptosis at late stages, while the number of surviving cells decreased (p < 0.05), and upregulated the expression of apoptosis-related proteins Bax and caspase 3 protein. Furthermore, siRNA-GNAZ remarkably reduced the healing of scratch wounds in JHH-2 and SNU-761 cells and the number of invasive cells compared with that in the control group (p < 0.001). CONCLUSION: Our study demonstrated that GNAZ plays a pivotal role as a potential oncogene and predicts poor prognosis in patients with HCC. It promotes tumor proliferation via cell cycle arrest, apoptosis, migration, and invasion. Thus, GNAZ may be a potential candidate biomarker providing useful insight into hepatocarcinogenesis and aggressiveness.


Assuntos
Carcinoma Hepatocelular/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Idoso , Apoptose/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transcriptoma/genética
3.
Anticancer Res ; 41(11): 5461-5468, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732415

RESUMO

BACKGROUND/AIM: This study aimed to assess the effects of telmisartan (TEL), a potential antitumor agent, and its mechanism of action in the regulation of apoptosis, autophagy, and cell cycle in scirrhous gastric cancer (SGC). MATERIALS AND METHODS: The effect of TEL on the viability and chromatin condensation of OCUM-2M and OCUM-12 cells was assessed. Protein expression and the cell cycle were analysed using western blotting and flow cytometry, respectively. RESULTS: TEL inhibited cell proliferation in a dose-dependent manner and increased chromatin condensation and autophagy marker LC3-II levels in OCUM-12 cells. TEL also increased the proportion of cells in the G0/G1 phase transition. CONCLUSION: Apoptosis and autophagy are partially involved in the inhibitory effect of TEL on cell proliferation. Additionally, TEL caused G0/G1 cell cycle arrest. Therefore, TEL could be a promising treatment for SGC.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Telmisartan/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
4.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638959

RESUMO

Though Morusin isolated from the root of Morus alba was known to have antioxidant, anti-inflammatory, antiangiogenic, antimigratory, and apoptotic effects, the underlying antitumor effect of Morusin is not fully understood on the glycolysis of liver cancers. Hence, in the current study, the antitumor mechanism of Morusin was explored in Hep3B and Huh7 hepatocellular carcninomas (HCC) in association with glycolysis and G1 arrest. Herein, Morusin significantly reduced the viability and the number of colonies in Hep3B and Huh7 cells. Moreover, Morusin significantly increased G1 arrest, attenuated the expression of cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) and upregulated p21 and p27 in Hep3B and Huh7 cells. Interestingly, Morusin significantly activated phosphorylation of the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) but attenuated the expression of the p-mammalian target of protein kinase B (AKT), rapamycin (mTOR), c-Myc, hexokinase 2(HK2), pyruvate kinases type M2 (PKM2), and lactate dehydrogenase (LDH) in Hep3B and Huh7 cells. Consistently, Morusin suppressed lactate, glucose, and adenosine triphosphate (ATP) in Hep3B and Huh7 cells. Conversely, the AMPK inhibitor compound C reduced the ability of Morusin to activate AMPK and attenuate the expression of p-mTOR, HK2, PKM2, and LDH-A and suppressed G1 arrest induced by Morusin in Hep3B cells. Overall, these findings suggest that Morusin exerts an antitumor effect in HCCs via AMPK mediated G1 arrest and antiglycolysis as a potent dietary anticancer candidate.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Flavonoides/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Extratos Vegetais/farmacologia , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Hexoquinase/metabolismo , Humanos , Lactato Desidrogenase 5/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/metabolismo , Morus/química , Raízes de Plantas/química , Serina-Treonina Quinases TOR/metabolismo , Hormônios Tireóideos/metabolismo
5.
BMC Cancer ; 21(1): 1088, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625047

RESUMO

BACKGROUND: The aminoisoquinoline FX-9 shows pro-apoptotic and antimitotic effects against lymphoblastic leukemia cells and prostate adenocarcinoma cells. In contrast, decreased cytotoxic effects against non-neoplastic blood cells, chondrocytes, and fibroblasts were observed. However, the actual FX-9 molecular mode of action is currently not fully understood. METHODS: In this study, microarray gene expression analysis comparing FX-9 exposed and unexposed prostate cancer cells (PC-3 representing castration-resistant prostate cancer), followed by pathway analysis and gene annotation to functional processes were performed. Immunocytochemistry staining was performed with selected targets. RESULTS: Expression analysis revealed 0.83% of 21,448 differential expressed genes (DEGs) after 6-h exposure of FX-9 and 0.68% DEGs after 12-h exposure thereof. Functional annotation showed that FX-9 primarily caused an activation of inflammatory response by non-canonical nuclear factor-kappa B (NF-κB) signaling. The 6-h samples showed activation of the cell cycle inhibitor CDKN1A which might be involved in the secondary response in 12-h samples. This secondary response predominantly consisted of cell cycle-related changes, with further activation of CDKN1A and inhibition of the transcription factor E2F1, including downstream target genes, resulting in G1-phase arrest. Matching our previous observations on cellular level senescence signaling pathways were also found enriched. To verify these results immunocytochemical staining of p21 Waf1/Cip1 (CDKN1A), E2F1 (E2F1), PAI-1 (SERPNE1), and NFkB2/NFkB p 100 (NFKB2) was performed. Increased expression of p21 Waf1/Cip1 and NFkB2/NFkB p 100 after 24-h exposure to FX-9 was shown. E2F1 and PAI-1 showed no increased expression. CONCLUSIONS: FX-9 induced G1-phase arrest of PC-3 cells through activation of the cell cycle inhibitor CDKN1A, which was initiated by an inflammatory response of noncanonical NF-κB signaling.


Assuntos
Antineoplásicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , NF-kappa B/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Fator de Transcrição E2F1/antagonistas & inibidores , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Células PC-3 , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Pontos de Checagem da Fase S do Ciclo Celular , Fatores de Tempo , Análise Serial de Tecidos
6.
BMC Cancer ; 21(1): 1061, 2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34565342

RESUMO

BACKGROUND: Neuroblastoma (NB) patients with MYCN amplification or overexpression respond poorly to current therapies and exhibit extremely poor clinical outcomes. PI3K-mTOR signaling-driven deregulation of protein synthesis is very common in NB and various other cancers that promote MYCN stabilization. In addition, both the MYCN and mTOR signaling axes can directly regulate a common translation pathway that leads to increased protein synthesis and cell proliferation. However, a strategy of concurrently targeting MYCN and mTOR signaling in NB remains unexplored. This study aimed to investigate the therapeutic potential of targeting dysregulated protein synthesis pathways by inhibiting the MYCN and mTOR pathways together in NB. METHODS: Using small molecule/pharmacologic approaches, we evaluated the effects of combined inhibition of MYCN transcription and mTOR signaling on NB cell growth/survival and associated molecular mechanism(s) in NB cell lines. We used two well-established BET (bromodomain extra-terminal) protein inhibitors (JQ1, OTX-015), and a clinically relevant mTOR inhibitor, temsirolimus, to target MYCN transcription and mTOR signaling, respectively. The single agent and combined efficacies of these inhibitors on NB cell growth, apoptosis, cell cycle and neurospheres were assessed using MTT, Annexin-V, propidium-iodide staining and sphere assays, respectively. Effects of inhibitors on global protein synthesis were quantified using a fluorescence-based (FamAzide)-based protein synthesis assay. Further, we investigated the specificities of these inhibitors in targeting the associated pathways/molecules using western blot analyses. RESULTS: Co-treatment of JQ1 or OTX-015 with temsirolimus synergistically suppressed NB cell growth/survival by inducing G1 cell cycle arrest and apoptosis with greatest efficacy in MYCN-amplified NB cells. Mechanistically, the co-treatment of JQ1 or OTX-015 with temsirolimus significantly downregulated the expression levels of phosphorylated 4EBP1/p70-S6K/eIF4E (mTOR components) and BRD4 (BET protein)/MYCN proteins. Further, this combination significantly inhibited global protein synthesis, compared to single agents. Our findings also demonstrated that both JQ1 and temsirolimus chemosensitized NB cells when tested in combination with cisplatin chemotherapy. CONCLUSIONS: Together, our findings demonstrate synergistic efficacy of JQ1 or OTX-015 and temsirolimus against MYCN-driven NB, by dual-inhibition of MYCN (targeting transcription) and mTOR (targeting translation). Additional preclinical evaluation is warranted to determine the clinical utility of targeted therapy for high-risk NB patients.


Assuntos
Acetanilidas/farmacologia , Azepinas/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazóis/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Regulação para Baixo , Sinergismo Farmacológico , Fator de Iniciação 4E em Eucariotos/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Esferoides Celulares/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo
7.
Cell Prolif ; 54(11): e13111, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34520051

RESUMO

OBJECTIVES: Among gynaecologic malignancies, ovarian cancer (OC) represents the leading cause of death for women worldwide. Current OC treatment involves cytoreductive surgery followed by platinum-based chemotherapy, which is associated with severe side effects and development of drug resistance. Therefore, new therapeutic strategies are urgently needed. Herein, we evaluated the anti-tumour effects of Vitamin E-derived δ-tocotrienol (δ-TT) in two human OC cell lines, IGROV-1 and SKOV-3 cells. MATERIALS AND METHODS: MTT and Trypan blue exclusion assays were used to assess δ-TT cytotoxicity, alone or in combination with other molecules. δ-TT effects on cell cycle, apoptosis, ROS generation and MAPK phosphorylation were investigated by flow cytometry, Western blot and immunofluorescence analyses. The synergism between δ-TT and chemotherapy was evaluated by isobologram analysis. RESULTS: We demonstrated that δ-TT could induce cell cycle block at G1-S phase and mitochondrial apoptosis in OC cell lines. In particular, we found that the proapoptotic activity of δ-TT correlated with mitochondrial ROS production and subsequent JNK and p38 activation. Finally, we observed that the compound was able to synergize with cisplatin, not only enhancing its cytotoxicity in IGROV-1 and SKOV-3 cells but also re-sensitizing IGROV-1/Pt1 cell line to its anti-tumour effects. CONCLUSIONS: δ-TT triggers G1 phase cell cycle arrest and ROS/MAPK-mediated apoptosis in OC cells and sensitizes them to platinum treatment, thus representing an interesting option for novel chemopreventive/therapeutic strategies for OC.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Vitamina E/análogos & derivados , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Feminino , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vitamina E/farmacologia
8.
Exp Cell Res ; 407(2): 112826, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34508742

RESUMO

INTS6 (integrator complex subunit 6) has been reported as a tumor suppressor in many cancers. However, the expression and biological function of INTS6 in colorectal cancer (CRC) has not been investigated yet. In this study, we found that INTS6 expression was significantly increased in CRC tissues when compared with normal tissues and was associated with poor prognosis. Downregulation of INTS6 induced G1/S-phase cell cycle arrest, and markedly suppressed the growth of CRC cells and the derived tumors, while overexpression of INTS6 showed opposite effect. Mechanism study revealed that INTS6 increased the levels of phosphorylated AKT (p-AKT) and ERK (p-ERK), and the growth-promoting effect of INTS6 was inhibited by AKT and ERK inhibitors. Besides, INTS6 also affected the expression of two targets of PI3K/AKT and MAPK signaling, c-Myc and CDK2, which contributed to cell cycle alteration. Altogether, the present study has revealed the oncogenic role of INTS6 in CRC, providing a novel therapeutic target for this malignant cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Masculino , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas de Ligação a RNA/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Sci Rep ; 11(1): 17997, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504274

RESUMO

Nucleotide excision repair (NER) and cell cycle checkpoints impact the ability of the anti-cancer drug cisplatin to inhibit cell proliferation and induce cell death. Genetic studies have shown that both NER and cell cycle progression are impacted by the circadian clock, which has emerged as a novel pharmacological target for the treatment of various disease states. In this study, cultured human cell lines were treated with combinations of cisplatin and the circadian clock modulating compounds KS15 and SR8278, which enhance circadian clock transcriptional output by inhibiting the activities of the cryptochrome and REV-ERB proteins, respectively. Treatment of cells with KS15 and SR8278 protected cells against the anti-proliferative effects of cisplatin and increased the expression of NER factor XPA and cell cycle regulators Wee1 and p21 at the mRNA and protein level. Correlated with these molecular changes, KS15 and SR8278 treatment resulted in fewer unrepaired cisplatin-DNA adducts in genomic DNA and a higher fraction of cells in the G1 phase of the cell cycle. Thus, the use of pharmacological agents targeting the circadian clock could be a novel approach to modulate the responses of normal and cancer cells to cisplatin chemotherapy regimens.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Criptocromos/antagonistas & inibidores , Adutos de DNA/efeitos dos fármacos , Adutos de DNA/farmacologia , Reparo do DNA/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Células A549 , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relógios Circadianos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HaCaT , Humanos , Isoquinolinas/farmacologia , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiofenos/farmacologia , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo
10.
FASEB J ; 35(10): e21923, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34551143

RESUMO

Our recent studies have shown that haspin, a protein kinase imperative for mitosis, is engaged in the interphase progression of HeLa and U2OS cancer cells. In this investigation, we employed the Fucci reporter system and time-lapse imaging to examine the impact of haspin gene silencing on cell cycle progressions at a single-cell level. We found that the loss of haspin induced multiple cell cycle defects. Specifically, the S/G2 duration was greatly prolonged by haspin gene depletion or inhibition in synchronous HeLa cells. Haspin gene depletion in asynchronous HeLa and U2OS cells led to a similarly protracted S/G2 phase, followed by mitotic cell death or postmitotic G1 arrest. In addition, haspin deficiency resulted in robust induction of the p21CIP1/WAF1 checkpoint protein, a target of the p53 activation. Also, co-depleting haspin with either p21 or p53 could rescue U2OS cells from postmitotic G1 arrest and partially restore their proliferation. These results substantiate the haspin's capacity to regulate interphase and mitotic progression, offering a broader antiproliferative potential of haspin loss in cancer cells.


Assuntos
Ciclo Celular , Proliferação de Células , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Neoplasias/patologia , /deficiência , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Corantes Fluorescentes , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Humanos , Interfase/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mitose/efeitos dos fármacos , Neoplasias/genética , /genética , Fase S/efeitos dos fármacos , Tubercidina/análogos & derivados , Tubercidina/farmacologia , Proteína Supressora de Tumor p53/genética , Ubiquitinação , Regulação para Cima/efeitos dos fármacos
11.
J Med Chem ; 64(16): 12075-12088, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34375106

RESUMO

The dysfunctional bromodomain PHD finger transcription factor (BPTF) exerts a pivotal influence in the occurrence and development of many human diseases, particularly cancers. Herein, through the structural decomposition of the reported BPTF inhibitor TP-238, the effective structural fragments were synthetically modified to obtain our lead compound DC-BPi-03. DC-BPi-03 was identified as a novel BPTF-BRD inhibitor with a moderate potency (IC50 = 698.3 ± 21.0 nM). A structure-guided structure-activity relationship exploration gave rise to two BPTF inhibitors with much higher affinities, DC-BPi-07 and DC-BPi-11. Notably, DC-BPi-07 and DC-BPi-11 show selectivities 100-fold higher than those of other BRD targets. The cocrystal structures of BPTF in complex with DC-BPi-07 and DC-BPi-11 demonstrate the rationale of chemical efforts from the atomic level. Further study showed that DC-BPi-11 significantly inhibited leukemia cell proliferation.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Pirimidinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Antígenos Nucleares/química , Antígenos Nucleares/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Indóis/síntese química , Indóis/metabolismo , Estrutura Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , Domínios Proteicos , Pirimidinas/síntese química , Pirimidinas/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
12.
J Med Chem ; 64(16): 12022-12048, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34351741

RESUMO

We herein report the identification, structural optimization, and structure-activity relationship of thieno[2,3-d]pyrimidine derivatives as a novel kind of selective vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors. N-(4-Chloro-3-(trifluoromethyl)phenyl)-4-(6-(4-(4-methylpiperazin-1-yl)phenyl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide (38k) was the most potent VEGFR3 inhibitor (IC50 = 110.4 nM) among developed compounds. Compared with VEGFR1 and VEGFR2, VEGFR3 was approximately 100 times more selective. Here, compound 38k significantly inhibited proliferation and migration of VEGF-C-induced human dermal lymphatic endothelial cells (HDLEC), MDA-MB-231, and MDA-MB-436 cells by inactivating the VEGFR3 signaling pathway. Additionally, 38k induced cell apoptosis and a prolonged G1/S-phase in MDA-MB-231 and MDA-MB-436 cells. It also presented acceptable pharmacokinetic characteristics in Sprague-Dawley (SD) rats with an oral bioavailability of 30.9%. In the xenograft model in vivo, 38k effectively inhibited breast cancer growth by suppressing the VEGFR3 signaling pathway. 38k pronouncedly resisted the formation of pulmonary metastatic nodules in mice. Collectively, 38k may be a promising therapeutic agent of metastatic breast cancer.


Assuntos
Antineoplásicos/uso terapêutico , Pirimidinas/uso terapêutico , Tiofenos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/metabolismo , Tiofenos/farmacocinética , Neoplasias de Mama Triplo Negativas/patologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Food Sci ; 86(9): 4209-4222, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34392532

RESUMO

Red-fleshedapples are preferredbecause of their high content of phenolics and antioxidants in peel and pulp. Herein, we evaluated the mechanisms of apple peel polyphenolic extracts (APP) and apple flesh polyphenolic extracts (AFP) from the new red-fleshed apple in inhibiting cell proliferation and inducing apoptosis on human breast cancer MDA-MB-231 cells. The antiproliferative activities were determined by the CCK8 assay. The expression of proteins was determined using Western blot. We found that the content of polyphenols and flavonoids in APP was significantly higher than that in AFP, and 14 main phenolic compounds in APP and AFP were quantified using UPLC-MS/MS techniques. Besides, the significant inhibition effects of APP and AFP were achieved through Akt pathway by inducing apoptosis (significantly upregulating reactive oxygen species [ROS] levels, and downregulating expression of pAkt, pBad, Bcl-2, promoting Cytochrome c release, activating Cle-Caspase 9, and inducing expressions of Cle-Caspase 3 and Cle-PARP), and inducing G0/G1 cell cycle arrest (increased expressions of p-p53 and p21 and decreased expressions of PCNA and Cyclin D1). And the inhibition effect of APP was stronger than that of AFP. These results suggest that AFP and APP may be excellent sources of natural chemicals for treating triple-negative breast cancer MDA-MB-231 cells. PRACTICAL APPLICATION: The effects of antiproliferation of phenolic extracts from red-fleshed apple peels and flesh on human breast cancer MDA-MB-231 cells were evaluated. The data may clarify the functional parts of red-fleshed apple and provide some basis for scientific researchers and consumers to recognize and exploit red-fleshed apple.


Assuntos
Frutas , Pontos de Checagem da Fase G1 do Ciclo Celular , Malus , Extratos Vegetais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Feminino , Frutas/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Malus/química , Fenóis/química , Extratos Vegetais/farmacologia , Espectrometria de Massas em Tandem
14.
Ecotoxicol Environ Saf ; 222: 112518, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34271501

RESUMO

Copper (Cu), as a common chemical contaminant in environment, is known to be toxic at high concentrations. The current research demonstrates the effects of copper upon hepatocyte cell-cycle progression (CCP) in mice. Institute of cancer research (ICR) mice (n = 240) at an age of four weeks were divided randomly into groups treated with different doses of Cu (0, 4, 8, and 16 mg/kg) for 21 and 42 days. Results showed that high Cu exposure caused hepatocellular G0/G1 cell-cycle arrest (CCA) and reduced cell proportion in the G2/M phase. G0/G1 CCA occurred with down-regulation (p < 0.05) of Ras, p-PI3K (Tyr458), p-Akt (Thr308), p-forkhead box O3 (FOXO3A) (Ser253), p-glycogen synthase kinase 3-ß (GSK3-ß) (Ser9), murine double minute 2 (MDM2) protein, and mRNA expression levels, and up-regulation (p < 0.05) of PTEN, p-p53 (Ser15), p27, p21 protein, and mRNA expression levels, which subsequently suppressed (p < 0.05) the protein and mRNA expression levels of CDK2/4 and cyclin E/D. These results indicate that Cu exposure suppresses the Ras/PI3K/Akt signaling pathway to reduce the level of CDK2/4 and cyclin E/D, which are essential for the G1-S transition, and finally causes hepatocytes G0/G1 CCA.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Animais , Linhagem Celular Tumoral , Proliferação de Células , Cobre/toxicidade , Pontos de Checagem da Fase G1 do Ciclo Celular , Quinase 3 da Glicogênio Sintase , Camundongos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
15.
Eur J Med Chem ; 223: 113661, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34237636

RESUMO

Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). In vitro studies revealed that FD223 displays high potency (IC50 = 1 nM) and selectivity (29-51 fold over other PI3K isoforms) against PI3Kδ, and exhibits efficient inhibition of the proliferation of AML cell lines (MOLM-16, HL-60, EOL-1 and KG-1) by suppressing p-AKT Ser473 thus causing G1 phase arrest during the cell cycle. Further given the favorable pharmacokinetic (PK) profiles of FD223, in vivo studies were evaluated using xenograft model in nude mice, confirming its significant antitumor efficacy meanwhile with no observable toxicity. All these results are comparable to the positive group of Idelalisib (CAL-101), indicating that FD223 has potential for further development as a promising PI3Kδ inhibitor for the treatment of leukemia such as AML.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Desenho de Fármacos , Indóis/química , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Meia-Vida , Humanos , Indóis/metabolismo , Indóis/farmacologia , Indóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Transplante Heterólogo
16.
Sci Rep ; 11(1): 14862, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290382

RESUMO

Cell proliferation and cell death abnormalities are strongly linked to the development of cancer, including lung cancer. The purpose of this study was to investigate the effect of pterostilbene on cell proliferation and cell death via cell cycle arrest during the transition from G1 to S phase and the p53 pathway. A total of 24 female Balb/C mice were randomly categorized into four groups (n = 6): N-nitroso-tris-chloroethyl urea (NTCU) induced SCC of the lungs, vehicle control, low dose of 10 mg/kg PS + NTCU (PS10), and high dose of 50 mg/kg PS + NTCU (PS50). At week 26, all lungs were harvested for immunohistochemistry and Western blotting analysis. Ki-67 expression is significantly lower, while caspase-3 expression is significantly higher in PS10 and PS50 as compared to the NTCU (p < 0.05). There was a significant decrease in cyclin D1 and cyclin E2 protein expression in PS10 and PS50 when compared to the NTCU (p < 0.05). PS50 significantly increased p53, p21, and p27 protein expression when compared to NTCU (p < 0.05). Pterostilbene is a potential chemoprevention agent for lung SCC as it has the ability to upregulate the p53/p21 pathway, causing cell cycle arrest.


Assuntos
Anticarcinógenos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Estilbenos/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/genética , Proliferação de Células/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclinas/genética , Ciclinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Camundongos Endogâmicos BALB C , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
17.
J Biochem Mol Toxicol ; 35(9): e22858, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34309953

RESUMO

The cyclin-dependent kinases 4 and 6 have led to a significant improvement in the treatment of hormone-receptor-positive breast cancer. However, the therapeutic potential of abemaciclib in triple-negative breast cancer (TNBC) has not been definitively elucidated. Therefore, the objective of this study was to investigate abemaciclib mediated antiproliferative effects on MDA-MB-231 and MDA-MB-468 TNBC and MCF-10A cell line through annexin V, cell cycle, caspase-3, reverse transcription-polymerase chain reaction analysis, acridine orange, and DAPI staining, for the first time. In addition, the autophagy-related cell death was assessed by autophagy-LC3 assay and acidic vesicular organelles staining. Our findings demonstrated that abemaciclib treatment resulted in significant apoptotic cell death in TNBC cells via G0/G1 arrest, chromatin condensation, the upregulation of caspase-3 and Bax levels, and the downregulation of Bcl-2. However, the formation of a large number of cytoplasmic vacuoles was not associated with autophagy. Therefore, abemaciclib treatment could be an effective treatment for TNBC. However, further studies are needed to elucidate the molecular mechanism of abemaciclib-induced apoptotic as well as atypical cell death derived from lysosomes in TNBC.


Assuntos
Aminopiridinas/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzimidazóis/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Feminino , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
18.
Int J Mol Sci ; 22(9)2021 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-34065149

RESUMO

Ovarian cancer is a fatal gynecological cancer because of a lack of early diagnosis, which often relapses as chemoresistant. Trichodermin, a trichothecene first isolated from Trichoderma viride, is an inhibitor of eukaryotic protein synthesis. However, whether trichodermin is able to suppress ovarian cancer or not was unclear. In this study, trichodermin (0.5 µM or greater) significantly decreased the proliferation of two ovarian cancer cell lines A2780/CP70 and OVCAR-3. Normal ovarian IOSE 346 cells were much less susceptible to trichodermin than the cancer cell lines. Trichodermin predominantly inhibited ovarian cancer cells by inducing G0/G1 cell cycle arrest rather than apoptosis. Trichodermin decreased the expression of cyclin D1, CDK4, CDK2, retinoblastoma protein, Cdc25A, and c-Myc but showed little effect on the expression of p21Waf1/Cip1, p27Kip1, or p16Ink4a. c-Myc was a key target of trichodermin. Trichodermin regulated the expression of Cdc25A and its downstream proteins via c-Myc. Overexpression of c-Myc attenuated trichodermin's anti-ovarian cancer activity. In addition, trichodermin decelerated tumor growth in BALB/c nude mice, proving its effectiveness in vivo. These findings suggested that trichodermin has the potential to contribute to the treatment of ovarian cancer.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Tricodermina/farmacologia , Animais , Biomarcadores Tumorais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias Ovarianas , Tricodermina/química , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070493

RESUMO

5-Aminolevulinic acid (5-ALA) is a naturally occurring non-proteinogenic amino acid, which contributes to the diagnosis and therapeutic approaches of various cancers, including glioblastoma (GBM). In the present study, we aimed to investigate whether 5-ALA exerted cytotoxic effects on GBM cells. We assessed cell viability, apoptosis rate, mRNA expressions of various apoptosis-related genes, generation of reactive oxygen species (ROS), and migration ability of the human U-87 malignant GBM cell line (U87MG) treated with 5-ALA at different doses. The half-maximal inhibitory concentration of 5-ALA on U87MG cells was 500 µg/mL after 7 days; 5-ALA was not toxic for human optic cells and NIH-3T3 cells at this concentration. The application of 5-ALA led to a significant increase in apoptotic cells, enhancement of Bax and p53 expressions, reduction in Bcl-2 expression, and an increase in ROS generation. Furthermore, the application of 5-ALA increased the accumulation of U87MG cells in the SUB-G1 population, decreased the expression of cyclin D1, and reduced the migration ability of U87MG cells. Our data indicate the potential cytotoxic effects of 5-ALA on U87MG cells. Further studies are required to determine the spectrum of the antitumor activity of 5-ALA on GBM.


Assuntos
Ácido Aminolevulínico/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
20.
BMC Cancer ; 21(1): 657, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078310

RESUMO

BACKGROUND: Long non-coding RNAs exert vital roles in several types of cancer. The objective of this study was to explore the role of LINC_00355 in gastric cancer (GC) progression and its potential mechanism. METHODS: The expression levels of LINC_00355 in GC tissues and cells were detected by quantitative real-time PCR, followed by assessing the effects of LINC_00355 knockdown or overexpression on cell properties. Dual-luciferase reporter assay was utilized to identify the relationship between LINC_00355 and microRNA (miR)-15a-5p and miR-15a-5p and PHD finger protein 19 (PHF19), followed by the rescue experiments. RESULTS: The results showed that LINC_00355 was highly expressed in GC tissues and cells compared with the corresponding control. LINC_00355 knockdown decreased the viability, migration, and invasion and increased the accumulation of GC cells in G1 phase and apoptosis. Meanwhile, LINC_00355 downregulation markedly increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase protein levels, whereas decreased cyclin D1, cyclin E, matrix metalloproteinase (MMP) 9, MMP2, and N-cadherin protein levels in GC cells. However, LINC_00355 overexpression had the opposite effects. It was verified that LINC_00355 upregulated the expression of PHF19 through sponging miR-15a-5p. Furthermore, PHF19 overexpression reversed the effect of LINC_00355 knockdown on GC cell properties, including cell viability, migration, invasion, and apoptosis. CONCLUSIONS: Collectively, these results suggest that LINC_00355 promotes GC progression by up-regulating PHF19 through sponging miR-15a-5p. Our findings may provide an important clinical basis for reversing the malignant phenotype of GC.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/genética , Fatores de Transcrição/genética , Apoptose/genética , Biópsia , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Mucosa Gástrica/patologia , Técnicas de Silenciamento de Genes , Humanos , RNA Longo não Codificante/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Ativação Transcricional , Regulação para Cima
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