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1.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445110

RESUMO

Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different cancer cell types. Here, we aimed to investigate the apoptotic and anticancer effects of SH003 in combination with DTX, in human non-small-cell lung cancer (NSCLC). SH003, with DTX, induced apoptotic cell death, with increased expression of cleaved caspases and cleaved poly (ADP-ribose) polymerase in NSCLC cells. Moreover, SH003 and DTX induced the apoptosis of H460 cells via the suppression of the EGFR and signal transducer and activator of transcription 3 (STAT3) signaling pathways. In H460 tumor xenograft models, the administration of SH003 or docetaxel alone diminished tumor growth, and their combination effectively killed cancer cells, with increased expression of apoptotic markers and decreased expression of p-EGFR and p-STAT3. Collectively, the combination of SH003 and DTX may be a novel anticancer strategy to overcome the challenges that are associated with conventional lung cancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células A549 , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
BMC Med Genomics ; 14(1): 121, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952249

RESUMO

BACKGROUND: ABL1 is primarily known as a leukemia-related oncogene due to translocation, but about 2.2% of ABL1 mutations have been identified in bladder cancer, and high expression in solid cancer has also been detected. METHODS: Here, we used the NCBI database, UCSC genome browser gateway and Tandem repeat finder program to investigate the structural characterization of the ABL1 breakpoint region and to identify the variable number of tandem repeats (VNTR). To investigate the relationship between ABL1-MS1 and bladder cancer, a case-controlled study was conducted in 207 controls and 197 bladder cancer patients. We also examined the level of transcription of the reporter gene driven by the ABL1 promoter to determine if the VNTR region affects gene expression. RESULTS: In our study, one VNTR was identified in the breakpoint region, the intron 1 region of ABL1, and was named ABL1-MS1. In the control group, only two common alleles (TR13, TR15) were detected, but an additional two rare alleles (TR14, TR16) were detected in bladder cancer. A statistically significant association was identified between the rare ABL1-MS1 allele and bladder cancer risk: P = 0.013. Investigating the level of transcription of the reporter gene driven by the ABL1 promoter, VNTR showed inhibition of ABL1 expression in non-cancer cells 293 T, but not in bladder cancer cells. In addition, ABL1-MS1 was accurately passed on to offspring according to Mendelian inheritance through meiosis. CONCLUSIONS: Therefore, the ABL1-MS1 region can affect ABL1 expression of bladder cancer. This study provides that ABL1-MS1 can be used as a DNA fingerprinting marker. In addition, rare allele detection can predict susceptibility to bladder cancer.

3.
Int J Mol Sci ; 21(23)2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33261027

RESUMO

DNA repair defects are important factors in cancer development. High DNA repair activity can affect cancer progression and chemoresistance. DNA double-strand breaks in cancer cells caused by anticancer agents can be restored by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Our previous study has identified E2F1 as a key gene in bladder cancer progression. In this study, DNA repair genes related to E2F1 were analyzed, and RAD54L involved in HRR was identified. In gene expression analysis of bladder cancer patients, the survival of patients with high RAD54L expression was shorter with cancer progression than in patients with low RAD54L expression. This study also revealed that E2F1 directly binds to the promoter region of RAD54L and regulates the transcription of RAD54L related to the HRR pathway. This study also confirmed that DNA breaks are repaired by RAD54L induced by E2F1 in bladder cancer cells treated with MMC. In summary, RAD54L was identified as a new target directly regulated by E2F1. Our results suggest that, E2F1 and RAD54L could be used as diagnostic markers for bladder cancer progression and represent potential therapeutic targets.


Assuntos
DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Fator de Transcrição E2F1/metabolismo , Reparo de DNA por Recombinação , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Sequência de Bases , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mitomicina/farmacologia , Prognóstico , Reparo de DNA por Recombinação/genética , Ativação Transcricional/genética
4.
Cancers (Basel) ; 12(6)2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32486251

RESUMO

Although the 5-year survival rate of patients diagnosed with nonmuscle invasive bladder cancer (NMIBC) has reached 85%, more than 50% of patients suffer from frequent recurrences. To identify molecular targets associated with recurrence of NMIBC, we analyzed gene expression data and found that FOXM1 and FANCD2 were involved in recurrence. Therefore, we investigated how these genes were involved in the mechanism of recurrence and confirmed their usefulness as biomarkers. Investigation have shown that FOXM1 directly regulated the transcription of FANCD2, which is the key gene of the Fanconi anemia (FA) pathway. Depletion of FOXM1 resulted in DNA repair defects in the FA pathway and in decreased resistance to chemotherapy. Thus, the FANCD2-associated FA pathway activated by FOXM1 is an important mechanism involved in chemotherapy-related recurrence. In conclusion, FOXM1 and FANCD2 can be used as prognostic factors that are associated with high risk of recurrence and with anticancer drug resistance properties in NMIBC patients.

5.
Cancers (Basel) ; 12(2)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093417

RESUMO

The standardized uptake value (SUV), an indicator of the degree of glucose uptake in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used for predicting the clinical behavior of malignant tumors. However, its characteristics have been insufficiently explored at the genomics level. Here, we aim to identify genomic signatures reflecting prognostic SUV characteristics in breast cancer (BRC). Through integrative genomic profiling of 3710 BRC patients, including 254 patients who underwent preoperative FDG-PET, we identified an SUV signature, which showed independent clinical utility for predicting BRC prognosis (hazard ratio [HR] 1.27, 95% confidence interval [CI] = 1.12 to 1.45, p = 2.23 × 10-4). The risk subgroups classified by the signature exhibited mutually exclusive mutation patterns of TP53 and PIK3CA and showed significantly different responsiveness to immunotherapy. Experimental assays revealed that a signaling axis defined by TP53-FOXM1 and its downstream effectors in glycolysis-gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our molecular characterizations support an understanding of glucose metabolism and poor prognosis in BRC with a high SUV, utilizable in clinical practice to assist other diagnostic tools.

6.
Genes Genomics ; 41(12): 1517-1525, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31691174

RESUMO

BACKGROUND: hTERT contains a high density of minisatellites, of which rare alleles of hTERT-VNTR2-2nd have been reported to be associated with prostate cancer. This shows an association between VNTR and cancer, but this repeat sequence is likely to be associated with genomic instability. Therefore, we investigated the effects of hTERT-VNTR2-2nd on gastrointestinal cancer and the relationship between repeated sequence and chromosome instability. METHODS: A case-control study was performed using DNA from 818 cancer-free controls, 539 cases with gastric cancer, 275 cases with colon cancer and 274 cases with rectal cancer. To determine whether minisatellites affect gene expression, expression levels were examined using TERT-reporter vectors in cell lines. In addition, the length of the hTERT-VNTR2-2nd alleles were determined in blood and cancer tissues from 107 gastric cancers, 112 colon cancers and 76 rectal cancers patients to determine whether the repeat sequence was associated with genomic instability during cancer development. RESULTS: No statistically significant association between hTERT-VNTR2-2nd and risk of gastrointestinal cancer was detected. However, it has been shown that VNTRs inserted into the enhancer region can regulate the expression of TERT in gastrointestinal cancer cells. Moreover, hTERT-VNTR2-2nd was analyzed in matched blood and cancer tissue from patients with gastrointestinal cancer and in seven among 294 subjects, and hTERT-VNTR2-2nd was found to be rearranged. CONCLUSIONS: We suggest that minisatellites are associated with genomic instability in cancer and that the hTERT-VNTRs region may increase hTERT expression in gastrointestinal cancer cells.


Assuntos
Neoplasias Gastrointestinais/genética , Instabilidade Genômica , Repetições Minissatélites , Telomerase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto Jovem
7.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141941

RESUMO

Tristetraprolin (TTP), a well-characterized AU-rich element (ARE) binding protein, functions as a tumor suppressor gene. The purpose of this study was to investigate whether a bioactive substance derived from a natural medicinal plant affects the induction of TTP and to elucidate its mechanism. We examined the effects of natural bioactive materials including Resveratrol (RSV), thymoquinone (TQ) and curcumin on the expression of TTP in cancer cell. TQ derived from a natural plant Nigella sativa increased the expression levels of TTP mRNA and proteins in a dose-dependent manner in gastric and breast cancer cells. TQ-induced TTP increased the instability of MUC4 mRNA by direct binding of TTP to ARE in the 3'UTR of MUC4 mRNA. The induction of TTP by TQ also reduced the proliferation, migration and invasion of cancer cells. The expression of the epithelial-mesenchymal (EMT)-related genes, which were target genes of TTP, was also decreased by the TQ treatment. In the in vivo experiments using mouse melanoma cells, TQ-induced TTP inhibited metastasis of tumor cells. We have found that TQ-induced TTP might inhibit metastasis by reducing tumor cell migration and invasion through destabilization of MUC4 mRNA, which suggest the MUC4 as a novel target to TTP.


Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Mucina-4/genética , Neoplasias Experimentais/tratamento farmacológico , Tristetraprolina/metabolismo , Animais , Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Mucina-4/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
8.
Genes Genomics ; 41(2): 249-256, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30499053

RESUMO

BACKGROUND: BORIS/CTCFL, a paralog of CTCF and member of the cancer-testicular antigen family, is abnormally activated in multiple cancers. OBJECTIVE: We investigated the relationship between polymorphic variants of the BORIS minisatellite 2 (BORIS-MS2), located within the 5' upstream promoter region of BORIS, and bladder cancer. METHODS: We used case-control study with 516 controls and 113 bladder cancer patients. To evaluate whether minisatellite variants play a role in BORIS expression, we examined the transcript levels of a reporter gene linked to these minisatellites in cell lines. We also examined BORIS expression in cancerous and non-cancerous bladder tissue. RESULTS: A statistically significant association was identified between the short rare allele (13-repeat) and bladder cancer incidence (odds ratio (OR) 2.97, 95% confidence interval (CI) [1.14, 7.74]; P = 0.020). In particular, short rare alleles in the younger group (aged < 65) were associated with statistically significant increase in bladder cancer risk (OR 5.38, CI [1.32, 21.87]; P = 0.01). The BORIS-MS2 region acted as a negative regulator, and the expression level of the luciferase reporter in bladder cancer cells was less effectively inhibited than in normal cells. Furthermore, the expression of BORIS mRNA significantly differed (P < 0.05) between normal and cancerous muscle-invasive bladder cancer tissues, and relationship to clinical parameters was observed. CONCLUSIONS: The short rare allele of BORIS-MS2 could be used to identify bladder cancer risk. BORIS expression levels have been shown to increase with the progression of bladder cancer, could be used as a biomarker for its progression.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Polimorfismo Genético , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Regiões Promotoras Genéticas , Neoplasias da Bexiga Urinária/patologia
9.
BMB Rep ; 51(2): 98-103, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29397866

RESUMO

Recurrence is a serious problem in patients with bladder cancer. The hypothesis for recurrence was that the proliferation of drug-resistant cells was reported, and this study focused on drug resistance due to drug efflux. Previous studies have identified FOXM1 as the key gene for recurrence. We found that FOXM1 inhibition decreased drug efflux activity and increased sensitivity to Doxorubicin. Therefore, we examined whether the expression of ABC transporter gene related to drug efflux is regulated by FOXM1. As a result, ABCG2, one of the genes involved in drug efflux, has been identified as a new target for FOXM1. We also demonstrated direct transcriptional regulation of ABCG2 by FOXM1 using ChIP assay. Consequently, in the presence of the drug, FOXM1 is proposed to directly activate ABCG2 to increase the drug efflux activation and drug resistance, thereby involving chemoresistance of bladder cancer cells. Therefore, we suggest that FOXM1 and ABCG2 may be useful targets and important parameters in the treatment of bladder cancer. [BMB Reports 2018; 51(2): 98-103].


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteína Forkhead Box M1/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Doxorrubicina , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Forkhead Box M1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética
10.
DNA Cell Biol ; 36(3): 227-236, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28055236

RESUMO

The dopamine transporter SLC6A3 (DAT1) mediates uptake of dopamine into presynaptic terminals. In addition, in previous reports, hypertensive rats were associated with DAT gene, but the genetic association with SLC6A3 and hypertension is still unknown. We examined the distribution of variable number of tandem repeats (VNTRs) and conducted polymorphic analysis of the entire region of SLC6A3. Ten VNTR regions (MS1-10) were revealed throughout the intronic and UTRs; seven VNTR regions were newly isolated and three VNTRs were previously reported. Four VNTR regions (SLC6A3-MS1, -MS4, -MS8 [rs3836790], and -MS9 [rs28363170]) showed polymorphism and these loci were found to be transmitted through meiosis following Mendelian inheritance. These VNTR polymorphisms may be useful markers for paternity mapping and DNA fingerprinting. Furthermore, we also conducted a case-control study between the controls and essential hypertensive cases. Analysis of the genotypes of SLC6A3-MS8 (rs3836790) revealed that having an 8/6-repeat allele, which was only detected in hypertensive cases, was associated with hypertension (p < 0.05). Additional significant association was identified between the short 7-repeat allele of SLC6A3-MS9 (rs28363170) and the occurrence of hypertension (odds ratio 2.02; p < 0.05). These results revealed the genetic association between SLC6A3 and hypertension, and the specific VNTR alleles of SLC6A3 may be a risk factor for hypertension.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Predisposição Genética para Doença/genética , Hipertensão/genética , Repetições Minissatélites/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Saúde da Família , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Linhagem , Fatores de Risco
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