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1.
Mol Genet Genomic Med ; 8(2): e1079, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31867841

RESUMO

BACKGROUND: One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated the utility of ctDNA to reflect the efficacy of treatment and to monitor resistance mechanisms. METHODS: Targeted next-generation sequencing (NGS) of 416 cancer-relevant genes was performed on 41 plasma biopsy samples of 19 HER2+ and 12 HER2- BC patients. Longitudinal ctDNA samples were analyzed in three BC patients over the treatment course for detecting acquired mutations. RESULTS: In HER2+ BC patients, ERBB2 somatic copy numbers in ctDNA samples were significantly higher in patients progressed on HER2-targeted therapy than those who were still responding to the treatment. Recurrent acquired mutations were detected in genes including ERBB2, TP53, EGFR, NF1, and SETD2, which may contribute to trastuzumab resistance. In longitudinal analyses, the observed mutation allele frequencies were tracked closely in concordance with treatment responses. A novel ERBB2 p.(Leu869Arg) mutation was acquired in one patient upon resistant to trastuzumab therapy, which was further validated as an oncogenic mutation in vitro and contributed to resistance. In HER2- BC patients with chemotherapy resistance, genetic alterations on TP53, PIK3CA, and DNA damage repair genes were frequently observed. CONCLUSIONS: In summary, ctDNA monitoring, particularly longitudinal analyses, provides valuable insights into the assessment of targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2- BC patients, respectively.

2.
Cancer Cell Int ; 19: 277, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708688

RESUMO

Background: CKS1 is highly expressed in colon cancer tissues, and is essential for cancer cell proliferation. The downstream molecular mechanism of CKS1 has been fully studied, but the upstream regulatory mechanism of it is still unclear. Earlier research found that PADI3 plays its anti-tumor roles via suppress cell proliferation, in this study, we found that the expression pattern of PADI3 and CKS1 are negatively correlated in colon cancer tissues, and overexpression of PADI3 can partly reverse CKS1 induced cancer cell proliferation. However, the regulatory mechanism of PADI3 and CKS1 in the tumorigenesis of colon cancer is still unclear and need to do further research. Methods: Western blot and real-time PCR were used to detect the expression levels of genes. CCK-8 and colony formation assays were used to examine cell proliferation and colony formation ability. Overexpression and rescue experiments were used to study the molecular mechanism of CKS1 in colon cancer cells, BALB/c nude mice were used to study the function of CKS1 in vivo. Results: CKS1 is highly expressed in colon cancer tissues, and the overexpression of CKS1 promotes cell proliferation and colony formation in both HCT116 (originating from primary colon cancer) and SW620 (originating from metastatic tumor nodules of colon cancer) cells. CKS1-expressing HCT116 cells produced larger tumors than the control cells. The expression pattern of PADI3 and CKS1 are negatively correlation in clinical samples of colon cancer, further study indicates that PADI3 can significantly decrease Hsp90 and CKS1 expression, and Hsp90 is essential for PADI3 to downregulate CKS1expression in colon cancer cells. Conclusions: PADI3 exerts its antitumor activity by inhibiting Hsp90 and CKS1 expression, and Hsp90 is essential for PADI3 to suppress CKS1 expression.

3.
Cancer Med ; 8(12): 5544-5553, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385461

RESUMO

BACKGROUND: Previous case reports have shown the promising antitumor activity of everolimus in solid tumors containing molecular aberrations in PI3K/ATK/mTOR pathway, however, whether it is effective in patients with breast cancer remains unknown. Therefore, we conducted this retrospective cohort study to compare the efficacy of molecularly matched targeted therapy with everolimus to conventional therapy in refractory breast cancer patients harboring PI3K/ATK/mTOR pathway activating mutations. METHODS: Refractory metastatic breast cancer patients who have received molecular screening using next-generation sequencing (NGS) between September 8, 2015 and October 30, 2017 in two sites were screened for this study. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall response rate (ORR), disease control rate (DCR), and safety profile. RESULTS: A total of 78 patients were screened for analysis, amongst all, 52 (66.7%) had at least one gene mutation in PI3K/AKT/mTOR pathway. The most common mutation fell in PIK3CA (76.9%, 40/52) with a mutational prevalence of 51.3%. Of the 32 patients who were eligible for efficacy analysis, patients in the everolimus group (n = 19) exhibited shorter PFS than those in the conventional group (n = 13) (median, 1.9 vs 6.1 months; HR, 3.6; 95% CI, 1.48-8.81; P = .0005). ORR was 15.4% (2/13) in the everolimus group and 23.1% (3/13) in the conventional group (P = 1.000), and DCR was 30.8% (4/13) and 100% (13/13) for each group, respectively (P = .000). The incidence of grade 3-5 adverse events was relatively higher in the conventional group (38.5%, 5/13) than that in the everolimus group (26.3%, 5/19). CONCLUSIONS: Our findings suggested that everolimus might not be effective for cancer patients harboring mutations in PI3K/ATK/mTOR pathway and physicians should be cautious about its off-label use in clinical practice.

4.
BMC Cancer ; 19(1): 551, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174498

RESUMO

BACKGROUND: Mutated BRCA1/2 genes are associated with hereditary breast and ovarian cancer (HBOC). So far most of the identified BRCA1/2 pathogenic variants are single nucleotide variants (SNVs) or insertions/deletions (Indels). However, large genomic rearrangements (LGRs) such as copy number variants (CNVs) are also playing an important role in HBOC predisposition. Their frequency and spectrum have been well studied in western populations but remain largely unknown for Chinese population. METHODS: Peripheral blood samples were collected from 218 unrelated familial breast and/or ovarian cancer (FBOC) patients living in Eastern China. PCR-based Sanger sequencing and panel-based next-generation sequencing (NGS) were performed to detect pathogenic SNVs and Indels in BRCA1/2 genes. For the patients lacking small pathogenic variants, multiplex ligation dependent probe amplification (MLPA) assay was conducted to screen for LGRs. RESULTS: In total, we identified 44 samples (20.1%) carrying small pathogenic variants (26 in BRCA1 and 18 in BRCA2, respectively). Among the rest of 174 samples, five were found carrying novel deleterious LGRs in BRCA1 which are exon5-7dup (1 patient), exon13-14dup (2 patients), and exon1-22del (2 patients). No LGR was found in BRCA2. Overall, LGRs accounted for 16.1% (5/31) of BRCA1 pathogenic variants, and were detected in 2.3% (5/218) of all FBOC patients. , CONCLUSIONS: LGR variants in BRCA1 gene play a significant role in Chinese HBOC patients. MLPA or other similar LGR-detecting methods should be recommended along with nucleotide sequencing as the initial screening approach for Chinese HBOC women.


Assuntos
Rearranjo Gênico , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Genômica , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Mutação , Alelos , Substituição de Aminoácidos , China , Feminino , Genômica/métodos , Genótipo , Humanos , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
5.
Onco Targets Ther ; 12: 2931-2936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118664

RESUMO

Metastatic breast cancer (MBC) is the most life-threatening disease in women worldwide. HER2-mutated breast carcinoma has been reported to benefit from HER2-targeted tyrosine kinase inhibitors recently. Here, we presented a heavy pretreated and harbored HER2 V777L mutation de novo stage IV Luminal B (HER2 unamplified) breast cancer patient who achieved an unexpected good response to trastuzumab combined with vinorelbine therapy. Although HER2-unamplified MBC patients do not regularly benefit from anti-HER2 target therapy, HER2 V777L mutation detected by next-generation sequencing from ctDNA may present as a predictive biomarker for anti-HER2-based strategy therapy in HER2-negative MBC patients.

6.
Clin Lab ; 65(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775882

RESUMO

BACKGROUND: Recent studies have established non-coding RNAs, which include microRNAs and lncRNAs, are aberrantly expressed in breast cancer. In this study, we explore the expression profile of microRNAs and lncRNAs in ER positive (ER+) breast and paracancerous tissues and define their possible correlations. METHODS: We collected ER+ breast cancer patients' and paracancerous tissues from the specimen bank of Zhejiang Cancer Hospital to extract total RNA for obtaining the expression level of microRNAs and lncRNAs by qRT-PCR. RESULTS: The relative expression results indicated that microRNAs such as MIR-191, MIR-213, MIR-122A had significantly higher expression and MIR-125B-1, MIR-125B-2, MIR-145 had lower expression in ER positive breast cancer compared to normal breast. The interaction of microRNA and lncRNA results exhibited upregulated MIR382-5P and lncRNA 362 in ER+ breast cancer compared to non-cancerous breast. By contrast, MIR222 and NFIA-AS1 are down-regulated. Furthermore, MIR222 and NFIA-AS1 showed different expressions in different TNM stages. CONCLUSIONS: MicroRNAs and lncRNAs are aberrantly expressed in ER+ breast cancer. It is inferred that these microRNAs and lncRNAs may be promising biomarkers for ER positive breast cancer.


Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Receptores Estrogênicos/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Regulação para Baixo , Feminino , Humanos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Longo não Codificante/metabolismo , Receptores Estrogênicos/metabolismo , Regulação para Cima
7.
Neurochem Res ; 43(10): 2008-2015, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30155805

RESUMO

Alzheimer's disease (AD) is a well-known neurodegenerative disease. Deposition of ß-amyloid protein (Aß) oligomers plays a crucial role in the disease progression. Previous studies showed that toxicity induced by Aß oligomers in cultured neurons and adult rat brain was partially mediated by activation of glutamatergic N-methyl-D-aspartate receptors (NMDAR). Additionally, memantine, a noncompetitive NMDAR antagonist, can significantly improve cognitive functions in some AD patients. However, little is currently known about the potential role of NMDAR antagonist on the regulation of P-MARCKS protein to Aß1-42 oligomers induced neurotoxicity. The protective effect and mechanism of NMDAR antagonist on primary neurons exposed to Aß1-42 oligomers were investigated in the study. We have defined that the Aß1-42 treatment decreased cell viability and increased apoptosis. Moreover, Aß1-42 oligomers exposure increased P-MARCKS and PIP2 expressions, while decreased SYP expression. However, NMDAR antagonist pretreatment ameliorates Aß1-42 oligomers induced neuronal apoptosis and partially reverses the expression of P-MARCKS, PIP2 and SYP. In conclusion, NMDAR antagonist may ameliorate neurotoxicity induced by Aß1-42 oligomers through reducing neuronal apoptosis and protecting synaptic plasticity in rat primary neurons. The mechanism involved may be mediated by the variation of protein P-MARCKS.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Substrato Quinase C Rico em Alanina Miristoilada/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Masculino , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/metabolismo , Fragmentos de Peptídeos/toxicidade , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo
8.
Oncol Lett ; 14(5): 6156-6162, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29113261

RESUMO

It has been hypothesized that single nucleotide polymorphisms in CYP19A1 gene may alter aromatase activity and circulating steroid hormone levels in females. Therefore, it is biologically reasonable that CYP19A1 rs1008805 (A/G) polymorphism may be associated with the clinical outcome of hormone therapy. Genotyping for the CYP19A1 rs1008805 polymorphism was performed for 287 females with hormone receptor (HR)-positive early breast cancer, and potential associations were evaluated between CYP19A1 rs1008805 genotypes and disease-free survival (DFS). Based on the analysis of the whole cohort, no significant differences were observed between rs1008805 genotypes and DFS. However, in postmenopausal females, rs1008805 variants were significantly associated with DFS (AA vs. AG vs. GG, 89.2 vs. 58.2 vs. 32.7 months; P=0.019). In addition, when the population was divided into two cohorts, females with the GG variant exhibited a significantly poorer DFS [GG vs. AA or AG, 32.7 vs. 70.6 months; hazard ratio (HR), 3.613; 95% confidence interval (CI), 1.380-9.457; P=0.005]. Furthermore, when adjusted for other patient features in multivariate analyses, GG genotype remained an independent prognostic marker for DFS (HR, 3.439; 95% CI, 1.251-9.456; P=0.017). However, there were no significant differences in DFS between patients harboring the minor allele and those with the homozygous common allele (AG or GG vs. AA, 52.4 vs. 89.2 months; HR, 1.288; 95% CI, 0.705-2.353; P=0.408). There were also no associations between rs1008805 polymorphism and DFS for premenopausal females. In conclusion, the homozygous minor allele (GG) of CYP19A1 rs1008805 was identified to be significantly associated with an inferior clinical outcome of hormone therapy in postmenopausal hormone receptor-positive patients with early breast cancer. If confirmed by further study, genotyping for CYP19A1 rs1008805 polymorphism may provide predictive information to improve the selection of endocrine treatment.

9.
Medicine (Baltimore) ; 96(27): e7340, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28682882

RESUMO

RATIONALE: Breast cancer is the most prevalent malignancy in women worldwide. Our patient presented with a history of breast liposarcoma (LPS) and was found to have pleural metastasis during the initial workup. PATIENT CONCERNS: The patient was complaining about chest pain and dyspnea that had persisted for a week. DIAGNOSES: After a full evaluation and histological diagnosis, she was diagnosed as metastatic breast LPS. INTERVENTIONS: We adopted 6 cycles of pegylated liposomal doxorubicin (PLD) plus ifosfamide as 1st-line palliative chemotherapy, combined with local pleural effusion management. OUTCOMES: The patient's symptoms were notably relieved, and both malignant metastatic lesions and pleural effusion were controlled. LESSONS: Although metastatic breast LPS is rarely reported and incurable, more clinical experience and use of next-generation sequencing should be helpful in finding the effective treatment for metastatic LPS.


Assuntos
Neoplasias da Mama/patologia , Lipossarcoma/patologia , Neoplasias Pleurais/secundário , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Diagnóstico Diferencial , Feminino , Humanos , Lipossarcoma/diagnóstico por imagem , Lipossarcoma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/tratamento farmacológico
10.
Oncol Lett ; 13(5): 3599-3607, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28521460

RESUMO

N-myc downstream-regulated gene 1 (NDRG1) is a multifunctional protein associated with carcinogenesis and tumor progression. The function of NDRG1 in hepatocellular carcinoma (HCC) cells remains controversial. The present study investigated the role of NDRG1 in HCC as well as its molecular mechanism using a range of techniques, including western blot analysis, cellular proliferation test, wound healing assay and Transwell assay. In HCC, the levels of NDRG1 expression were highest in the cytoplasm, followed by the membrane, and were lowest in the nucleus. NDRG1 was revealed to inhibit the proliferation and invasion of BEL7402 cells, which facilitated the hypothesis that NDRG1 expression levels may be lower in cell line with a high metastatic potential compared with those in cell lines with a low metastatic potential. However, the present study identified that NDRG1 expression was higher in detached BEL7402 cells and MHCC-97H cells compared with that in attached BEL7402 cells and MHCC-97L cells. Thus, this finding was contrary to what was expected, suggesting that NDRG1 overexpression in the HCC with a high metastatic potential may be the compensatory mechanism. The human HCC BEL7402 cell line demonstrated a significant increase in the capability of motility, invasion and cellular proliferation following NDRG1-short hairpin RNA transfection. Integrin ß3 (ITGB3) protein expression was increased in NDRG1-downregulated BEL7402 cells and SMMC7721 cells compared with that in the control cells. The present study suggested that NDRG1 may be a potential anti-tumor target for the treatment of patients with HCC. A potential mechanism for these roles of NDRG1 is by regulating ITGB3 expression; however, this requires additional investigation.

11.
Onco Targets Ther ; 10: 1475-1485, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28331341

RESUMO

BACKGROUND: Peptidylarginine deiminase (PAD) catalyzes the conversion of arginine residues to citrulline residues, termed citrullination. Recent studies have suggested that PAD isoform 2 (PADI2) plays an important role in tumors, although its tumorigenic effect and mechanism are largely unknown. MATERIALS AND METHODS: Immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were used to investigate the expression level of PADI2 in various tumor tissues and patient blood samples, respectively. MNK-45 and Bel-7402 tumor cell lines originating from gastric and liver tumors, respectively, were treated with anti-PADI2 siRNA, and the subsequent cell proliferation, apoptosis and migration were observed. Polymerase chain reaction (PCR) arrays, including Cancer PathwayFinder, Oncogenes and Tumor Suppressor Genes, p53 Signaling Pathway, Signal Transduction Pathway and Tumor Metastasis PCR arrays, were used to investigate the tumorigenic pathway of PADI2 in the siRNA-treated tumor cells. This analysis was verified by real-time PCR. RESULTS: Immunohistochemistry detected significantly increased expression of PADI2 in invasive breast ductal carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma, liver hepatocellular carcinoma, lung cancer, ovarian serous papillary adenocarcinoma and papillary thyroid carcinoma samples. ELISA detected a twofold increase in PADI2 expression in the blood of 48.3% of patients with liver cancer, 38% of patients with cervical carcinoma and 32% of patients with gastric carcinoma. Increased apoptosis and decreased cell proliferation and migration were observed in the anti-PADI2 siRNA-treated MNK-45 cells, and increased cell proliferation and migration and decreased apoptosis were observed in the treated Bel-7402 cells with suppressed PADI2 expression. PCR arrays and real-time PCR detected significantly decreased CXCR2 and EPO expression in the MNK-45 cells and Bel-7402 cells, respectively, with the anti-PADI2 siRNA treatments. CONCLUSION: PADI2 expression is increased in many types of tumor tissues and patient blood samples. PADI2 may advance abnormal cell behavior in gastric cancers by mediating CXCR2, a well-known gene that stimulates cell proliferation and invasion. However, PADI2 might have deleterious effects on tumor growth and metastasis in liver tumor cells by regulating the expression of EPO, a gene with controversial functions in tumor growth. The results suggest that the effect of PADI2 on tumorigenesis is multifactorial, depending on the tumor type.

12.
Oncotarget ; 8(2): 2069-2075, 2017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-27906683

RESUMO

We examined the long-term clinical tolerance and cardiac safety of trastuzumab treatment in ninety-four female patients diagnosed with breast cancer with human epidermal growth factor receptor 2 (HER-2) overexpression. Electrocardiography (ECG) was monitored throughout trastuzumab treatment, and left ventricular ejection fractions (LVEFs) were estimated using echocardiography prior to treatment with trastuzumab and every 3 months after its first application. The duration of trastuzumab treatments ranged from 3 to 60 months. Declines in LVEF ≥ 15% were seen mainly after 3-15 months of trastuzumab treatment, and LVEF was lowest at 15 months, which coincided with the largest decline in LVEF from baseline. Spearman correlation coefficients indicated that accumulation of anthracycline, the use of cyto/cardioprotective drugs (CPD) and the duration of trastuzumab treatment were all associated with the change of LVEF, and there was a strong correlation between these factors and the change of LVEF (ρ=0.81, ρ=0.734 and ρ=0.777 respectively). These results indicate that significant decreases of LVEF may be seen after 3-15 months of trastuzumab treatment, but that there is a favorable benefit-risk ratio for patients undergoing long-term trastuzumab treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Coração/efeitos dos fármacos , Trastuzumab/uso terapêutico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/fisiopatologia , Cardiotoxicidade/epidemiologia , Monitoramento de Medicamentos/métodos , Ecocardiografia , Feminino , Seguimentos , Coração/fisiopatologia , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Fatores de Tempo , Trastuzumab/efeitos adversos , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico , Função Ventricular Esquerda/efeitos dos fármacos
13.
Oncotarget ; 7(38): 62159-62176, 2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27556695

RESUMO

PADI4 (peptidyl deiminase isoform 4) is overexpressed in many tumor tissues and converts arginine residues to citrulline residues. This study used an Illumina SNP microarray and a TaqMan assay to determine the possible association of the PADI4 gene with various tumor risks. Both genotyping methods demonstrated significant associations between the tag SNPs rs1635566 and rs882537 in the PADI4 locus with gastric carcinoma in two independent cohorts. Based on this genotyping result, we used the Cancer Pathway Finder, p53 Signaling, Signal Transduction and Tumor Metastasis PCR arrays to investigate the tumorigenic pathway of PADI4 in MNK-45 cells derived from gastric carcinoma. We detected significantly decreased expression levels of CXCR2, KRT14 and TNF-α in MNK-45 cells that were treated with anti-PADI4 siRNA. We also detected increased expression of these three genes in MNK-45 cells transfected with a pcDNA3.1 plasmid overexpressing PADI4. A highly similar result was also obtained for SGC 7901 cells, which also originate from gastric carcinoma. Our result indicates that the PADI4 gene has genetic susceptibility in gastric carcinoma. PADI4 contributes to gastric tumorigenesis by upregulating CXCR2, KRT14 and TNF-α expression, which are well known to activate angiogenesis, cell proliferation, cell migration and the immune microenvironment in tumors.


Assuntos
Carcinogênese/genética , Carcinoma/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Desiminases de Arginina em Proteínas/genética , Neoplasias Gástricas/genética , Apoptose , Arginina/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células , Citrulina/metabolismo , Técnicas de Genotipagem , Humanos , Queratina-14/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Polimorfismo de Nucleotídeo Único , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Interleucina-8B , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
14.
Cancer Cell Int ; 16: 61, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27478411

RESUMO

BACKGROUND: Peptidylarginine deiminase (PAD) post-translationally converts arginine residues to citrulline residues. Recent studies have suggested that PADI2 (PAD isoform 2), a member of the PAD family, is involved in the tumorigenic process of some tumors, especially breast cancer. However, little is known about the mechanisms of PADI2 in tumorigenesis. This study aimed to elucidate the tumorigenic role and regulatory pathway of PADI2 in breast tumors. METHODS: The Sequenom MassARRAY and TaqMan genotyping methods were used to investigate the correlation between PADI2 gene SNPs and various tumor risks. PCR array analyses, including cancer pathway finder and signal transduction PCR arrays, were performed to investigate the tumorigenic pathway of PADI2 in the MCF-7 breast cancer cell line following treatment with anti-PADI2 siRNA. Cell proliferation, apoptosis and transwell migration assays were performed to observe the effect of PADI2 in MCF-7 cells treated with anti-PADI2 siRNA. RESULTS: Both Sequenom MassARRAY and TaqMan genotyping assays demonstrated that SNP rs10788656 in the PADI2 gene was significantly associated with breast cancer. PCR arrays indicated that inhibiting PADI2 expression significantly increased expression of CA9 and decreased expression of ACSL4 and BIRC3 in MCF-7 cells, which was verified using real-time PCR. Inhibiting PADI2 expression also significantly decreased the migration ability of MCF-7 cells but did not affect cell proliferation or apoptosis. CONCLUSIONS: The PADI2 gene confers susceptibility to breast cancer. PADI2 expression contributes to abnormal migration of breast tumor cells. PADI2 affects tumorigenesis in breast tumor cells by regulating the expression of ACSL4, BINC3 and CA9, which are known to promote abnormal lipid metabolism and cell invasion of tumors.

15.
Inflamm Res ; 65(10): 815-25, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27342824

RESUMO

BACKGROUND: Some studies have indicated that glucose metabolism plays an important role in the pathogenesis of rheumatoid arthritis (RA). This study aimed to find the novel genes affecting glucose metabolism in RA. MATERIALS/METHODS: Synovial tissues of collagen-induced arthritis (CIA) were analyzed with Rat Glucose Metabolism RT(2) Profiler™ PCR Array to screen those genes with special expressions in glucose metabolism. Real-time PCR, western blotting, and ELISA were used to confirm the result in synovial tissues and blood of human RA. Culture synovial fibroblast cells (RASF) was treated with siRNA to suppress expressions of the target genes. CCK-8 cell proliferation assay and two-compartment transwell system were performed to examine cell proliferation and cell migration of the treated RASF. RESULTS: Both PCR array and real-time PCR detected the up-regulation of ENO1, HK2, and PGK1 and the down-regulation of PCK1 and PDK4 in synovial tissues of CIA rats. Real-time PCR and western blotting detected the increased expression of ENO1 and PGK1 in RA synovial tissues. ELISA detected a high level of PGK1 in the blood of RA patients. Decreased cell proliferation and cell migration capabilities were significantly detected in RASF following treatment of anti-PGK1 siRNA. IL-1ß and IFN-γ rather than TNF-α and IL-1α levels were significantly declined in supernatants of the treated RASF. CONCLUSIONS: PGK1, a glycolytic enzyme catalyzing the conversion of 3-phosphoglycerate into 2-phosphoglycerate, has increased expression in synovial tissues and blood of RA, which may be involved in pro-inflammation and synovial hyperplasia of the disease.


Assuntos
Artrite Reumatoide/metabolismo , Fosfoglicerato Quinase/metabolismo , Membrana Sinovial/metabolismo , Adulto , Idoso , Animais , Artrite , Artrite Experimental/genética , Artrite Experimental/metabolismo , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Colágeno , Citocinas/metabolismo , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Glucose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinesina/sangue , Cinesina/genética , Cinesina/metabolismo , Masculino , Pessoa de Meia-Idade , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Fosfoglicerato Quinase/sangue , Fosfoglicerato Quinase/genética , Fosfopiruvato Hidratase/sangue , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Proteínas Serina-Treonina Quinases/sangue , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Wistar , Proteínas Supressoras de Tumor/sangue , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
16.
Mol Med Rep ; 13(5): 4046-50, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27035558

RESUMO

The aim of the present study was to establish the underlying regulatory mechanism of estrogen receptor (ER) in breast cancer cell gene expression. A gene expression profile (accession no. GSE11324) was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) from an estrogen treatment group and a control group were identified. Chromatin immunoprecipitation with high­throughput sequencing data (series GSE25710) was obtained from the GEO for the ER binding sites, and binding and expression target analysis was performed. A total of 3,122 DEGs were obtained and ER was demonstrated to exhibit inhibition and activation roles during the regulation of its target gene expression. Motif analysis revealed that the upregulated target genes that demonstrated interactions with ER were meis homeobox 1 (MEIS1) and forkhead box P3 (FOXP3). The downregulated target genes, which demonstrated interactions with ER, were thyroid hormone receptor, ß (THRB) and grainyhead­like 1 (GRHL1). Thus, it was observed that ER stimulated gene expression by interacting with MEIS1 and FOXP3, and ER inhibited gene expression by interacting with THRB and GRHL1. However, additional experiments are required to provide further confirmation of these findings.


Assuntos
Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/metabolismo , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Feminino , Humanos , Proteínas de Neoplasias/genética , Receptores Estrogênicos/genética
17.
Cancer Invest ; 34(3): 123-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26934461

RESUMO

Human epidermal growth factor receptor 2 (HER2/neu or HER2) has long been recognized as an attractive therapeutic target for breast cancer. The YVMA in-frame insertion at the residue G776 (G776(YVMA)) of HER2 kinase domain is a frequently observed mutation that can largely shift drug sensitivity in targeted therapy of HER2-positive breast cancer. Here, the molecular mechanism and biological significance of tyrosine kinase inhibitor (TKI) response to HER2 G776(YVMA) insertion were investigated in detail. An established protocol that integrated bioinformatics modeling and kinase inhibition assay was employed to examine the structural basis, energetic property, and biological implication underlying the intermolecular interaction between HER2 kinase domain and three representative TKIs, i.e. two FDA-approved drugs lapatinib and gefitinib as well as a pan-kinase inhibitor staurosporine. It was found that the insertion mutation can moderately sensitize lapatinib, but cannot influence the inhibitory capability of staurosporine essentially, suggesting that the two inhibitors exhibit differentiated selectivity between the wild-type HER2 (HER2(WT)) and HER2 G776(YVMA) (HER2(YVMA)) variant. In addition, the gefitinib, which was originally developed as EGFR inhibitor, only possesses modest potency against its noncogate target HER2(WT), and the insertion can further impair the potency, causing a strong resistance for the agent to HER2(YVMA) variant.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Quinazolinas/química , Receptor ErbB-2/química , Sítios de Ligação , Neoplasias da Mama/genética , Feminino , Humanos , Lapatinib , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutagênese Insercional , Ligação Proteica , Estrutura Secundária de Proteína , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética
18.
Cell Mol Immunol ; 13(6): 839-849, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26166764

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by abnormal inflammation, angiogenesis, and cartilage destruction. Our previous study demonstrated an increased expression of thioredoxin domain containing 5 (TXNDC5) in the synovial tissues of RA, and its overexpression was implicated in RA pathology. Although TXNDC5 variation is linked to genetic susceptibility to RA, the regulation of its abnormal expression has not been well defined. Here, we show that TXNDC5 is directly targeted by microRNA (miR)-573, and TXNDC5, in turn, mediates the suppressive effect of miR-573 on the invasion of synovial fibroblasts of RA (RASFs). miR-573 overexpression suppressed the expression of interleukin 6 (IL-6) and cyclooxygenase 2 in RASFs, as well as the production of tumor necrosis factor-alpha and interleukin-1 beta by activated THP-1 cells in response to lipopolysaccharide (LPS) stimulation. Moreover, treatment with conditioned medium of RASFs transfected with miR-573 mimic inhibited the angiogenic ability of human umbilical vein endothelial cells (HUVECs). Of note, epidermal growth factor receptor and Toll-like receptor 2 were validated as new direct targets of miR-573, and mediate the regulation of miR-573 on IL-6 production as well as the angiogenesis of HUVECs. In addition, exogenous miR-573 expression suppressed the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3, and phosphatidylinositol-3 kinase/activate protein kinase B in RASFs in response to LPS. Indeed, MAPK signaling was essential to ensure the function of miR-573. Taken together, our study points toward the protective roles of miR-573 in the pathological process of RA and suggests a potential target in the treatment of RA.


Assuntos
Artrite Reumatoide/genética , MicroRNAs/metabolismo , Adulto , Idoso , Artrite Reumatoide/patologia , Sequência de Bases , Citocinas/biossíntese , Receptores ErbB/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Inativação Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/patologia , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Modelos Biológicos , Neovascularização Fisiológica/efeitos dos fármacos , Isomerases de Dissulfetos de Proteínas/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/patologia , Receptor 2 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Oncol Rep ; 35(2): 683-90, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26572075

RESUMO

MicroRNAs are emerging as critical regulators of the initiation and progression of multiple types of human cancers, including breast cancer. In the present study, the expression of miR-181b in breast cancer patient serum and breast cancer cell lines was evaluated. It was demonstrated that the miR-181b level was significantly upregulated in patient serum and breast cancer cell lines compared with that in normal controls. The results of in vitro 3H thymidine incorporation and Transwell migration assay indicated that miR-181b overexpression markedly promoted the proliferation and metastasis of breast cancer cells. These data suggest that miR-181b is a tumor promoter in breast cancer. Furthermore, miR-181b expression was found to be upregulated in doxorubicin (DOX)-resistant T-47D cells (T-47D-R) compared with that in the parental T-47D cells, and upregulation of miR-181b expression decreased the anticancer effect of DOX in the T-47D cells. Mechanistic studies demonstrated that the Bim gene, an essential initiator of apoptosis, was inhibited by miR-181b overexpression. We observed that knockdown of miR-181b by its specific inhibitors significantly re-sensitized the T-47D-R cells to the cytotoxicity of DOX. Importantly, we demonstrated that miR-181b inhibitors increased the level of Bim in the T-47D-R cells, resulting in the loss of mitochondrial membrane potential (MMP) and the activation of caspases caused by DOX. In summary, the results of the present study suggest that miR-181b functions as an oncogene during breast cancer development, and the miR-181b/Bim pathway may be a novel target used to overcome the chemoresistance in breast cancer.


Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Membrana/biossíntese , MicroRNAs/genética , Proteínas Proto-Oncogênicas/biossíntese , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Western Blotting , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Proteínas de Membrana/genética , Oncogenes/genética , Proteínas Proto-Oncogênicas/genética , Reação em Cadeia da Polimerase em Tempo Real , Transfecção
20.
Tumour Biol ; 37(4): 5375-83, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26563365

RESUMO

Peptidylarginine deiminase 4 (PADI4) is an enzyme that converts both histone arginine and mono-methyl arginine residues to citrulline, and it has been detected in various subtypes of ovarian cancer. However, the mechanism of action of PADI4 in ovarian carcinogenesis remains unknown. To examine the function of PADI4, we transfected two ovarian cancer cell lines, wild-type p53 A2780 and p53-null SKOV3, with PADI4-siRNA and negative control siRNA. The proliferation of both A2780 and SKOV3 cells decreased significantly following PADI4-siRNA treatment (P A2780 < 0.01; P SKOV3 < 0.001). The invasion and migration ability of A2780 cells also significantly decreased in response to PADI4-siRNA treatment (P < 0.001), but SKOV3 cells showed no such decrease. The apoptotic rate of A2780 cells increased in the presence of PADI4-siRNA, but there was no such increase in SKOV3 cells (P > 0.05). PCR arrays of A2780 cells treated with PADI4-siRNA revealed the up-regulated expression of six genes, including cell death-inducing DFFA-like effector a (CIDEA) and tumor necrosis factor receptor superfamily member 9 (TNFRSF9), and the down-regulation of seven genes, including integrin beta 3 (ITGB3) and BCL2-antagonist/killer 1 (BAK1). These results suggest an important role for PADI4 in the p53 pathway and the regulation of the proliferation, apoptosis, invasion and migration of ovarian cancer cells. Our study also demonstrated that PADI4 contributes to tumor metastasis by regulating the gene expression of insulin-like growth factor 1 (IGF1) and WAS/WASL-interacting protein family member 1 (WIPF1).


Assuntos
Carcinogênese/genética , Proliferação de Células/genética , Hidrolases/genética , Neoplasias Ovarianas/genética , Apoptose/genética , Linhagem Celular Tumoral , Proteínas do Citoesqueleto/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hidrolases/biossíntese , Fator de Crescimento Insulin-Like I/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Neoplasias Ovarianas/patologia , Desiminases de Arginina em Proteínas
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