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1.
J Cell Biochem ; 121(3): 2139-2149, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31595560

RESUMO

Matrine, a natural product extracted from the root of Sophora flavescens Ait, was the main chemical ingredient of compounds of Kushen injection, which has been widely used for its remarkable anticancer effects for years. The underlying mechanisms for Matrine regulations of human breast cancer stem cells (BrCSCs) are barely known. LIN28, a well-characterized suppressor of Let-7 microRNA biogenesis, playing vital roles in regulations of stem cells' renewal and tumorigenesis. Here we show that the compounds of Kushen injection derived Matrine could suppress the BrCSCs differentiation and self-renewal through downregulating the expression of Lin28A, resulting in the inactivation of Wnt pathway through a Let-7b-dependent way. In opposite to Matrine, Cisplatin treatment increases the ability of tumorsphere formation and the expression of BrCSCs markers, which was partially blocked by either Let-7b overexpression or CCND1 inhibition. Furthermore, Matrine sensitized BrCSCs to cisplatin's suppression of cancer expansion in vitro and in vivo. Our study uncovers the role of the LIN28A/Let-7 in BrCSCs renewal, and more importantly, elucidated a novel mechanism by which Matrine induces breast cancer involution.

2.
J Cell Biochem ; 120(6): 10587-10595, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30816573

RESUMO

MicroRNAs plays an important role in the ccurrence and development of non-small-cell lung cancer (NSCLC). miR-497-5p has been reported to function as a tumor suppressor in various cancers. However, the role of miR-497-5p in NSCLC remains poorly understood. In this study, we aimed to investigate the biological role and potential molecular mechanism of miR-497-5p in NSCLC. Our results showed that the messenger RNA (mRNA) expression level of miR-497-5p was notably downregulated in human NSCLC tissues and cell lines. miR-497-5p overexpression remarkably inhibited NSCLC cell proliferation and increased cell apoptosis in A549 and H460 cells, whereas inhibition of miR-497-5p had an opposite effect. The ability of cell migration and invasion was inhibited by miR-497-5p overexpression but was increased by miR-497-5p inhibition. Moreover, our findings indicated that SOX5 was a direct target of miR-497-5p. The protein and mRNA expression levels of SOX5 in A549 cells were remarkably inhibited by miR-497-5p overexpression but was upregulated by miR-497-5p inhibition. Furthermore, SOX5 overexpression notably reversed the effect of miR-497-5p mimic on NSCLC cell proliferation, cell apoptosis, cell migration, and invasion. Taken together, these results indicated that miR-497-5p overexpression inhibited NSCLC cell proliferation, migration and invasion, and induced cell apoptosis through inhibiting SOX5 gene expression. It was conceivable that miR-497-5p might serve as a potential molecular target for NSCLC treatment.

3.
Cell Prolif ; 52(1): e12534, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30338598

RESUMO

OBJECTIVES: Breast cancer stem-like cells (BrCSCs) are the major reason for tumour generation, resistance and recurrence. The turbulence of their self-renewal ability could help to constrain the stem cell expansion. The way BrCSCs divided was related to their self-renewal capacity, and the symmetric division contributed to a higher ability. Non-coding long RNA of H19 was involved in multiple malignant procedures; the role and mechanistic proof of non-coding long RNA of H19 in controlling the divisions of BrCSCs were barely known. MATERIALS AND METHODS: Indicative functions of H19 in preclinical study were analysed by using the TCGA data base. Division manners were defined by using fluorescence staining. RESULTS: We identified the stimulation of H19 on symmetric division of BrCSCs, which subsequently resulted in self-renewing increasing. H19 inhibited the Let-7c availability by acting as its specific molecular sponge, and with Let-7c inhibition, oestrogen receptor activated Wnt signalling was unconstrained. Similarly, restoring Let-7c constrained oestrogen receptor activated Wnt factors, which sequentially inhibited the H19 decreasing of Let-7 bioavailability. Let-7c is reactivated in vitro where H19 was knockdown, and later inhibited the symmetric division of BrCSCs. Reciprocally, Wnt pathway activation leads to H19 increasing, which in turn decreased Let-7c bioavailability. CONCLUSIONS: Our results revealed a previously undescribed double negative feedback loop between sponge H19 and targeted Let-7c through oestrogen activated Wnt signalling that dominated in stem cells' division.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , RNA Longo não Codificante/genética , Axitinibe/farmacologia , Mama/patologia , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Proliferação de Células/genética , Estrogênios/metabolismo , Feminino , Células HEK293 , Humanos , Células MCF-7 , MicroRNAs/antagonistas & inibidores , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Via de Sinalização Wnt/fisiologia
4.
J Cell Mol Med ; 22(12): 6262-6274, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30324719

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with a poor prognosis. The microRNA-200 (miR-200) family has been associated with breast cancer metastasis. However, the epigenetic mechanisms underlying miR-200b repression in TNBC are not fully elucidated. In this study, we found that MYC proto-oncogene, bHLH transcription factor (MYC) and DNA methyltransferase 3A (DNMT3A) were highly expressed in TNBC tissues compared with other breast cancer subtypes, while miR-200b expression was inhibited significantly. We demonstrated that MYC physically interacted with DNMT3A in MDA-MB-231 cells. Furthermore, we demonstrated that MYC recruited DNMT3A to the miR-200b promoter, resulting in proximal CpG island hypermethylation and subsequent miR-200b repression. MiR-200b directly inhibited DNMT3A expression and formed a feedback loop in TNBC cells. MiR-200b overexpression synergistically repressed target genes including zinc-finger E-box-binding homeobox factor 1, Sex determining region Y-box 2 (SOX2), and CD133, and inhibited the migration, invasion and mammosphere formation of TNBC cells. Our findings reveal that MYC can collaborate with DNMT3A on inducing promoter methylation and miR-200b silencing, and thereby promotes the epithelial to mesenchymal transition and mammosphere formation of TNBC cells.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias de Mama Triplo Negativas/genética , Idoso , Movimento Celular/genética , Proliferação de Células/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Transdução de Sinais/genética , Transfecção , Neoplasias de Mama Triplo Negativas/patologia
5.
Ann Surg Oncol ; 25(12): 3647-3659, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30229416

RESUMO

OBJECTIVE: This study was designed to evaluate the prognostic value of the preoperative albumin-globulin score (AGS) in the patients with non-small cell lung cancer (NSCLC) after pulmonary lobectomy. METHODS AND RESULTS: The optimal cutoff level was 40.00 and 27.05 g/L for Alb and Glb, respectively. Based on this and the previous study, patients with both an hypoalbuminemia (< 40.00 g/L) and an elevated Glb level (≥ 27.05 g/L) were assigned a score of 2, and patients with one or neither were assigned a score of 1 or 0, respectively. We investigated the correlations between the AGS and the clinicopathological characteristics of patients and found that AGS was significantly associated with TNM stage (P = 0.016). Multivariate Cox analyses indicated that the AGS was an independent prognostic indicator for NSCLC for disease-free survival (DFS) (P = 0.001) and overall survival (OS) (P = 0.004). Kaplan-Meier analysis and log-rank test demonstrated that there were significant differences in DFS (P < 0.001) and OS (P < 0.001) among the three AGS groups. Furthermore, our study showed that DFS and OS are significantly different in three groups of patients with different AGS, in both Squamous carcinoma (P < 0.001 for DFS; P < 0.001 for OS) or adenocarcinoma (P = 0.034 for DFS; P = 0.035 for OS). In addition, we enrolled 53 patients as an independent set of cases for the further validation of AGS. Multivariate analyses verified AGS was an independent prognostic factor for NSCLC patients (P = 0.020 for DFS; P = 0.018 for OS). CONCLUSIONS: Preoperative AGS is an independent prognostic factor for patients with operable NSCLC.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Albumina Sérica/análise , Soroglobulinas/análise , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
6.
Biomed Pharmacother ; 107: 1434-1446, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30257360

RESUMO

Increasing evidence has highlighted the pivotal roles of deregulated long non-coding RNAs (lncRNAs) in tumourigenesis. However, the biological functions and mechanisms of lncRNAs in human lung adenocarcinoma (LUAD) remain elusive. Small nucleolar RNA host gene 6 (SNHG6), a novel lncRNA, is aberrantly expressed in various cancers. In this study, SNHG6 was upregulated in LUAD tissues, and its upregulation was positively associated with advanced TNM stage, large tumour size and poor overall survival (OS) in LUAD patients. Gain- and loss-of-function experiments confirmed that SNHG6 promoted cell cycle progression, cell proliferation, migration and invasion, and epithelial-mesenchymal transition (EMT) in vitro. Animal experiments demonstrated that SNHG6 knockdown remarkably inhibited xenograft formation in vivo. Moreover, mechanistic experiments identified that SNHG6 functions as a competing endogenous RNA (ceRNA) through competitively sponging miR-26a-5p to regulate E2F7 expression, cell motility and EMT in LUAD cells. In summary, our findings reveal that SNHG6 may act as an oncogenic lncRNA in LUAD carcinogenesis by regulating the miR-26a-5p/E2F7 axis.


Assuntos
Adenocarcinoma de Pulmão/genética , Fator de Transcrição E2F7/genética , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Adenocarcinoma de Pulmão/patologia , Animais , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cell Prolif ; 51(5): e12473, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30094882

RESUMO

OBJECTIVES: FBXW7 acts as a tumour suppressor by targeting at various oncoproteins for ubiquitin-mediated degradation. However, the clinical significance and the involving regulatory mechanisms of FBXW7 manipulation of NSCLC regeneration and therapy response are not clear. MATERIALS AND METHODS: Immunohistochemical staining and qRT-PCR were applied to detect FBXW7 and Snai1 expression in 100 samples of NSCLC and matched tumour-adjacent tissues. FBXW7 manipulation of cancer biological functions were studied by using MTT assay, immunoblotting, flow cytometry, transwells, wound healing assay, and sphere-formation assays. Immunofluorescence and co-immunoprecipitation were used to analyse the possible interaction between Snai1 and FBXW7. RESULTS: We detected the decreased FBXW7 expression in majority of the NSCLC tissues, and lower FBXW7 level was correlated with advanced TNM stage. Furthermore, those patients with decreased FBXW7 expression tend to have both poorer 5-year survival outcomes, and shorter disease-free survival, comparing to those with higher FBXW7 levels. Functionally, we found that FBXW7 enforcement suppressed NSCLC progression by inducing cell growth arrest, increasing chemo-sensitivity and inhibiting Epithelial-mesenchymal Transition (EMT) progress. Results further showed that FBXW7 could interact with Snai1 directly to degrade its expression through ubiquitylating alternation in NSCLC, which could be partially abrogated by restoring Snai1 expression. CONCLUSIONS: FBXW7 conduction of tumour suppression was partly through degrading Snai1 directly for ubiquitylating regulation in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Proteína 7 com Repetições F-Box-WD/metabolismo , Neoplasias Pulmonares/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Ubiquitina/metabolismo , Células A549 , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Intervalo Livre de Doença , Feminino , Células HEK293 , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Cicatrização/fisiologia
8.
Int J Oncol ; 53(4): 1601-1612, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30066905

RESUMO

Tamoxifen (TAM) resistance is a substantial challenge in the treatment of estrogen receptor (ER)-positive breast cancer. Previous studies have revealed an important role of microRNA (miRNA/miR)-26a in TAM resistance in breast cancer. However, the mechanism underlying the regulatory effects of miR-26a on TAM resistance remains to be elucidated. The expression levels of miR-26a in ER-positive breast cancer were detected by reverse transcription-quantitative polymerase chain reaction. E2F transcription factor 7 (E2F7) and MYC proto-oncogene, bHLH transcription factor (MYC) levels were detected by western blotting. The present study demonstrated that miR-26a expression was reduced in ER-positive breast cancer compared with in normal breast tissues, whereas E2F7 expression was significantly elevated. Furthermore, an inverse correlation between miR-26a and E2F7 expression was detected in ER-positive breast cancer. The results indicated that miR-26a directly inhibited E2F7 expression through translational inhibition and indirectly inhibited MYC expression partly via E2F7 repression. E2F7, in turn, decreased miR-26a expression via MYC-induced transcriptional inhibition of miRNAs. Furthermore, transfection with miR-26a mimics increased the expression of its host genes (CTD small phosphatase like and CTD small phosphatase 2), whereas ectopic E2F7 expression abrogated the effects of miR-26a. These findings indicated that miR-26a and E2F7 may form a double-negative feedback loop, resulting in downregulation of miR-26a and upregulation of E2F7 in ER-positive breast cancer. Both miR-26a knockdown and E2F7 overexpression conferred resistance to TAM in MCF-7 cells. Conversely, miR-26a overexpression and E2F7 silencing resensitized MCF-7 resistant cells to TAM. These findings revealed that a feedback loop between miR-26a and E2F7 may promote TAM resistance in ER-positive breast cancer.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F7/genética , MicroRNAs/metabolismo , Tamoxifeno/farmacologia , Adulto , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Regulação para Baixo , Fator de Transcrição E2F7/metabolismo , Retroalimentação Fisiológica , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Estrogênicos/metabolismo , Tamoxifeno/uso terapêutico , Regulação para Cima
9.
Oncol Lett ; 15(2): 2465-2470, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29434959

RESUMO

The method of suturing for incisions is crucial for the comprehensive treatment of clinical patients with breast cancer. Suturing is considered a major part of post-surgical recovery and may serve as a marker for evaluation of surgical outcome. The present study aimed to establish an effective means of suturing for patients who received modified radical surgery that helps to improve the cosmetic outcome of the incision. Enrolled patients were divided into an active and a control group. Ti-Ni memory alloy wire for intradermal suture in the active group and silk for interruption suture in the control group were applied to assess the different prognosis-associated factors. The Vancouver Scar Scale (VSS) was used to evaluate the wound size and the recovery time of the scars. The association between diabetes and the number of days of wound healing was also analyzed. The results indicated that the mean VSS score of the active group was decreased compared with that of the control group (P<0.001). The VSS scores of four main features (vascularity, pigmentation, pliability and height) between the two groups also statistically differed (P<0.001). Furthermore, the mean number of days of wound healing was significantly decreased for the active group compared with that for the control group (P=0.0026) in the patients with diabetes. In addition, the usage of Ti-Ni memory alloy wire was able to decrease the mean number of wound healing days between patients with diabetes and their non-diabetic counterparts (P=0.7009). The present study indicated that intradermal suture offers improved cosmetic outcome for patients undergoing mastectomy with or without axillary surgery. This technique may be useful for preventing scar overgrowth and for facilitating the recovery process in patients with diabetes.

10.
Oncotarget ; 9(3): 4239-4248, 2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29423118

RESUMO

Antibodies against the immune checkpoint proteins PD-1 and PD-L1 are novel therapeutic drugs for the treatment of advanced non-small cell lung cancer (NSCLC). Many clinical trials involving these drugs achieved breakthroughs in patients previously treated for advanced NSCLC. However, the results of these clinical studies are not consistent. In this report, we performed a meta-analysis to assess the efficacy and safety of anti-PD-1/PD-L1 antibodies compared with docetaxel treatment for advanced NSCLC patients from 5 randomized clinical trials. We demonstrated that the patients in anti-PD-1/PD-L1 antibody therapy groups had significantly longer overall survival (OS) (HR = 0.69, 95% CI 0.63-0.75, P < 0.05) and progression-free survival (PFS) (HR = 0.76, 95% CI 0.63-0.92, P < 0.05) than those in chemotherapy groups, especially PD-L1 positive patients. Anti-PD-1/PD-L1 antibodies improved the objective response rate (ORR) compared with docetaxel (OR = 1.64, 95% CI 1.19-2.26, p < 0.05). In addition, the anti-PD-1/PD-L1 antibody therapy had fewer treatment-related adverse events (AEs) (OR = 0.33, 95% CI 0.28-0.39, P < 0.05) than docetaxel, especially the grade ≥3 AEs (OR = 0.18, 95% CI 0.12-0.28, P < 0.001). In conclusion, our study revealed that, compared with docetaxel, anti-PD-1/PD-L1 antibody therapy improved clinical efficacy and safety in previously treated advanced NSCLC patients. This therapy may be a promising treatment for advanced NSCLC patients.

11.
Int J Mol Med ; 41(4): 1967-1975, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29336465

RESUMO

Let-7 microRNAs have been reported to have tumor suppressive functions; however, the effect of Let-7 when used in combination with chemotherapies is uncertain, but may have potential for use in clinical practice. In this study, we used RT-qPCR, western blot analysis, cell proliferation assay, flow cytometry analysis, immunohistochemistry (IHC) staining, luciferase assays, cell sorting analysis and xenografted tumor model to explore the role of Let-7 in the chemotherapy sensitivity of breast cancer stem cells. The findings of the current study indicated that Let­7 enhances the effects of endocrine therapy potentially by regulating the self­renewal of cancer stem cells. Let­7c increased the anticancer functions of tamoxifen and reduced the ratio of cancer stem­like cells (CSCs), sensitizing cells to therapy-induced repression in an estrogen receptor (ER)­dependent manner. Notably, Let­7 decreased the tumor formation ability of estrogen­treated breast CSCs in vivo and suppressed Wnt signaling, which further consolidated the previously hypothesis that Let­7 decreases the self­renewal ability, contributing to reduced tumor formation ability of stem cells. The suppressive effects exerted by Let­7 on stem­like cells involved Let­7c/ER/Wnt signaling, and the functions of Let­7c exerted with tamoxifen were dependent on ER. Taken together, the findings identified a biochemical and functional link between Let­7 and endocrine therapy in breast CSCs, which may facilitate clinical treatment in the future using delivery of suppressive Let-7.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Autorrenovação Celular/efeitos dos fármacos , MicroRNAs/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Tamoxifeno/farmacologia , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos Hormonais/uso terapêutico , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Tamoxifeno/uso terapêutico , Regulação para Cima , Via de Sinalização Wnt/efeitos dos fármacos
12.
Cancer Invest ; 35(10): 639-646, 2017 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-29243989

RESUMO

To determine the most suitable strategy in treating patients with invasive breast cancer from Northwest China. Lower recurrence score (RS) correlated with lower recurrence ratio. Patients having a medium-high 21-gene RS who received adjuvant therapy presented lower recurrence risk. Younger patients having RS results (⩾31) tended to accept adjuvant therapy more often, however, those having intermediate RS results were inclined to wait and did not receive chemotherapy. These results suggested that RS-based precision medicine will allow individualized diagnosis and treatment, resulting in better outcomes and preserved medical resources.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Quimioterapia Adjuvante , China , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Medicina de Precisão , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
13.
Oncotarget ; 8(61): 103261-103273, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262559

RESUMO

Stem-like cells in tumor group featured the major role in the chemotherapy resistance of breast cancer, and the reduction of stem-like cells helped to perish the tumor when receiving chemotherapy. Smaller stem cells number indicated better therapeutic effect in vitro and in clinics, but how did miR-129 and Notch signaling function in breast cancer stem-like cells (BrCSCs) were unclear yet. Through using sphere forming assay and FACS sorting, we found that miR-129 decreased the proportion of stem-like cells in breast cancer cells. Results further indicated that miR-129 degraded the Estrogen Receptor 1 (ESR1) mRNA through a post-translational manner and contributed to the decline of stem-like cells number, preventing tumor regeneration. Cyclin d1 and DICER 1 were proved to promote Let-7 maturation, and in present study, we proved that miR-129 exhibited inhibition on ESR1 and halted the cyclin d1/DICER 1 sustaining of Let-7, which consequently released the Let-7 degradation of NUMB. The restoration of suppressive NUMB by upregulating miR-129 resulted in NOTCH signaling inhibition. In conclusion, we demonstrated the negative regulation of miR-129 on NOTCH signaling activation in BrCSCs' renewal, which was achieved via continuous suppression on cyclin d1/DICER1 sustaining of Let-7 level, and eventually rescued the targeted inhibition of NUMB. The miR-129/ESR1 signaling played pivotal role in controlling DICER1/Let-7/NOTCH cascade via cyclin d1, revealing the novel mechanism of dual Let-7 in non-coding genes network.

14.
Exp Ther Med ; 14(3): 2584-2594, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28962198

RESUMO

Evaluating the clinicopathological features of patients receiving definitive treatment for esophageal cancer may facilitate the identification of patterns and factors associated with post-operative complications, and enable the development of a surveillance strategy for surviving patients at a higher risk of disease recurrence. In the present study, clinical data from 579 patients with esophageal cancer that underwent radical resection of esophagus were collected. These patients were admitted to two medical centers in Northwest China, and information regarding the presence or absence of basic chronic diseases and post-operative results were retrospectively analyzed. The level of selected stem cell markers, including aldehyde dehydrogenase 1, CD133, integrin subunit α 6, integrin subunit ß 4 and T-cell factor-4, were determined in esophageal cancer tissue samples in order to determine whether these markers may be useful predictors of disease prognosis and recurrence. Post-operative complications in patients receiving radical resection of the esophagus included respiratory system complications, cardiovascular abnormalities and esophageal anastomotic fistulae. Diabetes, basic respiratory disease and lower pre-surgical serum albumin levels were observed to be individual risk factors associated with post-operative complications, including respiratory system complications of acute respiratory failure and pulmonary infection, cardiovascular abnormalities of atrial fibrillation and arrhythmia, as well as the development of esophageal anastomotic fistulae. Diagnosis of esophageal cancer at later stage was significantly correlated with anastomotic fistula. Molecular detection of stem cell markers for prognosis prediction was achieved by immunohistochemical and immunofluorescence staining assays. The results demonstrated that the presence of stem-like cells in cancer tissues was associated with poor disease prognosis and a high recurrence ratio. In conclusion, the results of the current study suggested that post-operative complications were more likely to occur in patients with diabetes, basic respiratory disease or lower serum albumin levels prior to surgery. Therefore, sufficient intensive peri-operative care, rigorous operative risk assessments, and the selection of the patients with early or mid-stage esophageal cancer, may decrease the risk of post-surgical complications in patients receiving radical resection of the esophagus. In addition, a high ratio of esophageal cancer stem-like cells was associated with cancer recurrence. These results suggest that an intensive surveillance strategy should be implemented in order to facilitate early detection of disease recurrence and improve the clinical management of these patients post-surgery.

15.
Oncol Rep ; 38(2): 1190-1198, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28656290

RESUMO

miR-367 is one of the most abundant miRNAs in human embryonic stem cells (hESCs) and is mainly involved in maintaining the pluripotency of stem cells. However, its role in cancer development remains poorly understood. In the present study, we explored the function and mechanism of the endogenous miR-367 in non-small cell lung cancer (NSCLC). In the present study, we demonstrated that the level of miR-367 in NSCLC was significantly higher than that in adjacent normal tissues, and its upregulation was positively correlated with tumor size, tumor differentiation and tumor-node-metastasis (TNM) stage. miR-367 was an indicator of a poorer prognosis in NSCLC patients. Furthermore, overexpression of miR-367 significantly inhibited apoptosis and enhanced proliferation by promoting cell cycle transition from G1 to S phase. In contrast, knockdown of miR-367 markedly reversed the cellular events observed with miR-367 overexpression. Moreover, we identified that F-box and WD repeat domain-containing 7 (FBXW7) is a novel target of miR-367. It reverses the oncogenic effects of miR-367 by downregulating its substrates, c-Myc and c-Jun, in NSCLC cells. Finally, studies in vivo revealed that knockdown of miR-367 inhibited the growth of xenografts in the nude mice by increasing the expression of FBXW7. In summary, our findings indicate that miR-367 exerts tumor-promoting effect by negatively regulating FBXW7 in NSCLC, and it could become a potential therapeutic target for NSCLC intervention.


Assuntos
Adenocarcinoma/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/secundário , Proteína 7 com Repetições F-Box-WD/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Apoptose , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Adesão Celular , Movimento Celular , Proliferação de Células , Proteína 7 com Repetições F-Box-WD/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Exp Clin Cancer Res ; 35(1): 158, 2016 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-27737687

RESUMO

BACKGROUND: LCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown. METHODS: Cellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-kB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1&2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel. RESULTS: The expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for both cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1&2 and released RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects. CONCLUSION: Thus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Tiazóis/administração & dosagem , Ubiquitina-Proteína Ligases/metabolismo , Adulto , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Paclitaxel/farmacologia , Prognóstico , Proteólise , Tiazóis/farmacologia , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Oncol ; 49(4): 1289-96, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27498621

RESUMO

X-linked inhibitor of apoptosis protein (XIAP) and second mitochondrial-derived activator of caspase (Smac) are two important prognostic biomarkers for cancer. They are negatively correlated in many types of cancer. However, their relationship is still unknown in lung cancer. In the present study, we found that there was a negative correlation between Smac and XIAP at the level of protein but not mRNA in NSCLC patients. However, XIAP overexpression had no effect on degrading endogenous Smac in lung cancer cell lines. Therefore, we constructed plasmids with full length of Smac (fSmac) and mature Smac (mSmac) which located in cytoplasm instead of original mitochondrial location, and was confirmed by immunofluorescence. Subsequently, we found that mSmac rather than fSmac was degraded by XIAP and inhibited cell viability. CHX chase assay and ubiquitin assay were performed to illustrate XIAP degraded mSmac through ubiquitin pathway. Overexpression of XIAP partially reverted apoptotic induction and cell viability inhibition by mSmac, which was due to inhibiting caspase-3 activation. In nude mouse xenograft experiments, mSmac inhibited Ki-67 expression and slowed down lung cancer growth, while XIAP partially reversed the effect of mSmac by degrading it. In conclusion, XIAP inhibits mature Smac-induced apoptosis by degrading it through ubiquitination in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Apoptose , Proteínas Reguladoras de Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/genética , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ubiquitinação
18.
Pathol Res Pract ; 212(10): 893-898, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27499151

RESUMO

PURPOSE: To investigate the correlation among OTUD7B and NIK expression and the clinicopathological characteristics in NSCLC patients. METHODS: One hundred and twenty patients were involved in this study. We detected OTUD7B and NIK expression by immunohistochemistry and analyzed their correlation with clinicopathological data. RESULTS: The expression of OTUD7B and NIK were negatively correlated in NSCLC tumor samples (rs=-0.421, P<0.001). The higher expression of OTUD7B was associated with smaller tumor size(P=0.018), less lymph node metastasis (P=0.012) and earlier TNM stage(P=0.039), while the higher expression of NIK was only related to more lymph node metastasis(P=0.031) and later TNM stage(P=0.011). MMP-9 was negatively correlated with OTUD7B and positively correlated with NIK. In addition, the high expression of OTUD7B was associated with good prognosis of NSCLC patients (log-rank=6.714, P=0.0096), and a high OTUD7B/low NIK index can predict an even better prognosis (log-rank=11.794, P=0.0006). Moreover, the multivariate Cox regression analysis showed that OTUD7B rather than NIK is an independent marker of overall survival in NSCLC patients(HR=1.602, 95% CI 1.009-2.544, P=0.046). CONCLUSIONS: OTUD7B and NIK may play important roles in the development of lung cancer. The combination of OTUD7B and NIK expression may be a good index for predicting the prognosis of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Endopeptidases/metabolismo , Neoplasias Pulmonares/metabolismo , Metástase Linfática/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Idoso , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
19.
Tumour Biol ; 37(10): 13509-13520, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27465556

RESUMO

Fibronectin is involved in orchestrating many diverse cellular behaviors, including adhesion, invasion, differentiation, and proliferation and recently has also been shown to participate in the development of chemoresistance. In this study, we found that fibronectin expression was inversely correlated with clinical responses to docetaxel treatment in non-small cell lung cancer patients. Subsequently, we showed that fibronectin pretreatment could enhance cell viability and reduce apoptosis in docetaxel-treated lung cancer cells because fibronectin induced phosphorylated Src and caspase-8, rendering the later inactive, thus inhibiting docetaxel-induced apoptosis. The inhibition of apoptosis by fibronectin was found to be enhanced by Src overexpression and reversed by Src knockdown in lung cancer cells. Further investigation revealed that a downregulation of phospho-Src via treatment with a Src kinase inhibitor could also abolish fibronectin activity and recover docetaxel-induced apoptosis. Molecular studies revealed that this reversion was due to decreased phospho-Src levels rather than a reduction in total Src expression. Inhibition of phospho-Src reduced phospho-caspase-8 and promoted caspase-8 activity, restoring apoptosis following docetaxel and fibronectin co-treatment. Finally, xenografts experiments demonstrated that fibronectin promoted lung cancer cell proliferation during docetaxel treatment in vivo. Our findings indicate that fibronectin promotes Src and caspase-8 phosphorylation in lung cancer cells, which decreases caspase-8 activation and protects tumor cells from docetaxel-induced apoptosis. Therefore, the fibronectin/Src/caspase-8 pathway may play a crucial role in docetaxel resistance in lung cancer.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspase 8/metabolismo , Fibronectinas/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Taxoides/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Docetaxel , Feminino , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Gradação de Tumores , Estadiamento de Neoplasias , Fosforilação , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Oncol Lett ; 11(4): 2635-2643, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27073531

RESUMO

The E-cadherin gene (CDH1) is associated with poor prognosis and metastasis in patients with breast cancer, and methylation of its promoter is correlated with decreased gene expression. However, there is currently no direct evidence that CDH1 promoter methylation indicates poor prognosis in patients with breast cancer. In the present study, methylation-specific polymerase chain reaction (PCR) was applied to detect the methylation status of the CDH1 promoter in 137 primary breast cancer, 85 matched normal breast tissue and 13 lung metastasis specimens. Reverse transcription-quantitative PCR was used to assess the relative expression levels of CDH1 mRNA, and correlation analysis between CDH1 methylation status, and gene expression, clinicopathological characteristics and patient survival was performed. Methylation of CDH1 was identified in 40.9% (56/137) of primary breast cancer specimens, 61.5% (8/13) of lung metastasis specimens and none of the matched normal breast specimens. The downregulation of CDH1 mRNA and E-cadherin protein expression were identified to be significantly correlated with CDH1 methylation (P<0.05). In addition, CDH1 methylation was significantly associated with lymph node metastasis and estrogen receptor status of patients (P<0.05). In univariate analyses, patients with CDH1 methylation exhibited poor overall survival (OS) and disease-free survival (DFS; P<0.05). Furthermore, multivariate analyses revealed that CDH1 methylation was an independent prognostic factor predicting poor OS (HR, 1.737; 95% CI, 0.957-3.766; P=0.041) and DFS (HR, 2.018; 95% CI, 2.057-3.845; P=0.033) in patients with breast cancer. Therefore, the present study suggests that CDH1 promoter methylation may be correlated with breast carcinogenesis and indicates poor prognosis in patients with breast cancer.

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