RESUMO
BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide. However, limited effective biomarkers are associated with the tumorigenesis and prognosis of CRC. METHODS: The present study identified potential signatures from The Cancer Genome Atlas (TCGA) database and further validated the identified biomarkers in CRC tissues by immunohistochemistry (IHC). RESULTS: The expression of insulin-like growth factor 1 receptor (IGF-1R) and Livin gene was significantly upregulated in CRC samples compared to the adjacent normal samples in the TCGA dataset. IHC indicated that IGF-1R and Livin protein levels are increased in CRC and adenoma tissues compared to normal tissues. Notably, the IGF-1R protein levels differed significantly between adenoma and CRC. The elevated IGF-1R and Livin expression was associated with CRC clinicopathological features, including age, gender, histological subtype, individual cancer stages, nodal metastasis, and TP53-mutant in TCGA. Additionally, the IGF-1R promoter methylation level was closely related to CRC. Consistent with the TCGA study, IHC indicated that overexpressed IGF-1R and Livin proteins were independent risk factors for stage and metastasis. A marked correlation was established between IGF-1R and Livin expression in CRC, while the survival map showed no significant correlation with CRC. Kaplan-Meier survival curves showed that CRC patients with high IGF-1R or Livin expression had a prolonged overall disease-free survival than those with low expression in TCGA. CONCLUSION: IGF-1R and Livin are associated with CRC tumorigenesis and might be valuable for novel biomarker identification and targeted therapeutic strategy development.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas de Neoplasias/metabolismo , Receptor IGF Tipo 1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese/patologia , Neoplasias Colorretais/patologia , Humanos , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose/análise , Proteínas de Neoplasias/análise , Estadiamento de Neoplasias , Prognóstico , Receptor IGF Tipo 1/análise , Receptor IGF Tipo 1/genéticaRESUMO
OBJECTIVE: The aim of this study was to explore the expression of Livin in benign and malignant parotid gland tumors. We also investigate the role of Livin in the occurrence and progression of parotid gland tumors. PATIENTS AND METHODS: Livin expression in 30 cases of normal parotid gland tissues, 40 cases of benign parotid gland tumors and 60 cases of malignant parotid gland tumors was detected by immunohistochemistry. The correlation between Livin expression and pathological characteristics of patients with parotid gland tumors was analyzed. The differentially expressed Livin in normal parotid gland tissues and malignant parotid gland tumors was determined by Western blot and quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), respectively. RESULTS: Livin expression was unable to be detected in normal parotid gland tissues. The positive rate of Livin expression in benign and malignant parotid gland tumors was 17.50% and 71.67%, respectively (p<0.05). Livin expression was correlated to malignant level, clinical stage and tumor diameter in 60 cases of malignant parotid gland tumors (p<0.05). However, the positive rate of Livin expression was not correlated to lymph node metastasis, age and sex of patients with parotid gland tumors (p>0.05). CONCLUSIONS: Livin expression is closely related to the pathological progression of parotid gland tumors, which may serve as a hallmark in diagnosis, treatment and prognosis of patients with parotid gland tumors.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas de Neoplasias/metabolismo , Glândula Parótida/patologia , Neoplasias Parotídeas/diagnóstico , Proteínas Adaptadoras de Transdução de Sinal/análise , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose/análise , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Estadiamento de Neoplasias , Glândula Parótida/cirurgia , Neoplasias Parotídeas/patologia , Neoplasias Parotídeas/cirurgia , Prognóstico , Fatores Sexuais , Adulto JovemRESUMO
Gallbladder cancer (GBC) is a demanding fatal disease with no ideal treatment for inoperable patients. Recent reports have determined TNF-α associated lymphatic metastasis in GBC, while its resistance to TNF-α-killing remains largely unexplored. In this assay, we first found cellular inhibitor of apoptosis (cIAP1) overexpressed in GBC tissues and the roles in promoting the proliferation and migration of GBC in vitro as its homology cIAP2 does. Then how GBC cell survives TNF-α toxicity and TNF-α-induced apoptosis first prevail as follows. The reduction in cIAP1 does not give rise to apoptosis even with the stimulation of TNF-α. Importantly, the loss of cIAP1 enhanced TNF-α/cycloheximide-induced apoptosis in higher activation statuses of Caspase-8, Caspase-3 without the induction of Complex â ¡. In response to TNF-α, the reduction in cIAP1 caused the suppression in nuclear factor-κB (NF-κB) pathway and inhibition of transcription of cell death regulator cellular FLICE-like Inhibitory Protein (c-FLIP) instead. To conclude, cIAP1 is an oncological protein abundant in GBC tissues, which enhances proliferation and immigration and blocks TNF-α from apoptosis through NF-κB pathway in vitro.
Assuntos
Neoplasias da Vesícula Biliar/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Apoptose , Movimento Celular , Proliferação de Células , Neoplasias da Vesícula Biliar/patologia , Humanos , Proteínas Inibidoras de Apoptose/análise , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The poor prognosis of ovarian cancer (it is the leading cause of death from gynecological cancers) is mainly due to the acquisition of resistance to carboplatin. Among the possible resistance pathways, resistance to apoptosis and especially the overexpression of inhibitor of apoptosis proteins (IAP) cIAP1 and X-linked IAP (XIAP), have been implicated. DEBIO 1143, a SMAC (second mitochondria-derived activator of caspase) mimetic, belongs to a new class of targeted agents currently being evaluated in clinical trials, which activate apoptotic cell death and block pro-survival signaling in cancer cells. Here, we demonstrate that DEBIO 1143 in vitro inhibits the cell viability of two carboplatin-sensitive cell lines (IGROV-1 and A2780S) as well as three carboplatin-resistant cell lines (A2780R, SKOV-3 and EFO-21). Of note, DEBIO 1143 is able to reverse resistance to carboplatin by inducing cell death either by apoptosis or necroptosis depending on the cell lines. To identify a biomarker able to predict the sensitivity of the cell lines to DEBIO 1143 treatment we analyzed the expression of the DEBIO 1143 targets cIAP1 and XIAP, and one of their downstream targets, caspase 9. These proteins did not constitute a marker of DEBIO 1143 sensitivity/resistance. Importantly, we confirmed these findings in vivo in SKOV-3 xenograft models where DEBIO 1143 highly potentiated carboplatin treatment.
Assuntos
Antineoplásicos/farmacologia , Azocinas/farmacologia , Compostos Benzidrílicos/farmacologia , Carboplatina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Azocinas/administração & dosagem , Compostos Benzidrílicos/administração & dosagem , Carboplatina/administração & dosagem , Caspase 9/análise , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Proteínas Inibidoras de Apoptose/análise , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Resultado do Tratamento , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/análiseRESUMO
Abstract Purpose: To evaluate histopathological and ultrastructural changes and expression of proteins related to apoptosis CASPASE 3 and XIAP after experimental induction of temporary focal cerebral ischemia (90 minutes) due to obstruction of the middle cerebral artery in alcoholism model. Methods: Forty adult Wistar rats were used, subdivided into 5 experimental groups: control group (C); Sham group (S); Ischemic group (I); Alcoholic group (A); and Ischemic and Alcoholized group (I+A): animals submitted to the same treatment of group A and after four weeks were submitted to focal cerebral ischemia during 90 minutes, followed by reperfusion of 48 hours. Were processed for histopathological analysis and immunohistochemistry (for the protein expression of CASPASE -3 and XIAP). Results: Greater histopathological changes were observed in the animals of groups I and I+A in the three areas analyzed. The neuronal loss was higher in the medial striatum region of the animals of groups I and I + A. The protein expression of CASPASE -3 was higher than that of XIAP in the groups I and I + A for both proteins. Conclusion: The expression of XIAP was slightly higher where the histopathological changes and expression of CASPASE -3 was less evident.
Assuntos
Animais , Masculino , Ataque Isquêmico Transitório/patologia , Alcoolismo/patologia , Proteínas Inibidoras de Apoptose/análise , Caspase 3/análise , Fatores de Tempo , Imuno-Histoquímica , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Distribuição Aleatória , Ataque Isquêmico Transitório/metabolismo , Ratos Wistar , Apoptose , Artéria Cerebral Média , Microscopia Eletrônica de Transmissão , Alcoolismo/metabolismo , Edema , Eletromiografia/métodos , Mitocôndrias/patologiaRESUMO
Survivin, which is highly expressed in the majority of tumors, but not in most normal adult tissues, has been identified to have significant clinical applications. In the present study, using survivinspecific monoclonal antibodies (mAbs), we aimed to establish methods for detecting the expression of survivin in cancer cell lines, serum samples, urine samples and cancer tissues from patients with bladder cancer (BCa) and renal cell carcinoma (RCC), and to evaluate the efficacy of survivin as a tumor marker in the surveillance of BCa and RCC. First, mAbs were labeled with horseradish peroxidase (HRP), and a sandwich enzymelinked immunosorbent assay (ELISA) with mAbs and HRPconjugated mAbs was developed to detect survivin expression in serum and urine samples from BCa and RCC patients, with samples from healthy controls (HCs) used for comparison. The HRPconjugated mAbs were also used to detect survivin expression in cancer cell lines by western blotting. Survivin expression in cancer tissues from BCa patients was also evaluated by immunohistochemistry. The results showed that the sandwich ELISA was successfully established, and significantly higher expression of survivin was subsequently detected in BCa and RCC patients as compared with HCs in both urinary and serum samples (P<0.05), and was more pronounced in urine. The HRPmAbs could recognize survivin in cancer cell lines. Western blotting and immunohistochemistry results confirmed survivin expression in the 5637 BCa cell line, as well as BCa tissues. In addition, the expressions of survivin in BCa tissues, urine and serum were consistent in our study. In conclusion, the sandwich ELISA successfully established in the present study was of high sensitivity and specificity in the detection of survivin expression. The results also indicated that survivin is a potential tumor marker for the surveillance of BCa and RCC.
Assuntos
Anticorpos Monoclonais/metabolismo , Carcinoma de Células Renais/metabolismo , Proteínas Inibidoras de Apoptose/análise , Neoplasias Renais/metabolismo , Regulação para Cima , Neoplasias da Bexiga Urinária/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/urina , Linhagem Celular Tumoral , Detecção Precoce de Câncer , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose/sangue , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/urina , Neoplasias Renais/sangue , Neoplasias Renais/urina , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Sensibilidade e Especificidade , Survivina , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/urinaRESUMO
AIM: To evaluate the usefulness of Ki-67 index and survivin as predictive prognostic factors for rectal cancer treated with preoperative chemoradiotherapy. PATIENTS AND METHODS: The Ki-67 index and survivin expression were examined in patients with stage II/III rectal cancer (n=46) by immunohistochemistry. Patients were divided into a high-group and a low-group for the Ki-67 index, and positive and negative groups for survivin expression. Overall and disease-free survival were compared between the groups, and the correlation between Ki-67 index and survivin expression was assessed. RESULTS: The 5-year disease-free survival rate of the group with high Ki-67 index was significantly lower than that of the group with low Ki-67 index (53% and 88%, p=0.03), as was the 5-year overall survival rate (68% and 100%, p=0.03). Findings for survivin were not significant. CONCLUSION: Ki-67 index and survivin may be useful biomarkers for rectal cancer with preoperative CRT.
Assuntos
Proteínas Inibidoras de Apoptose/análise , Antígeno Ki-67/análise , Neoplasias Retais/terapia , Idoso , Biomarcadores Tumorais/análise , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Período Pré-Operatório , Prognóstico , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , SurvivinaRESUMO
Background: microRNA-23b (miR-23b) is a multiple functional miRNA. We hypothesize that miR-23b plays a role in the pathogenesis of sepsis. Our study investigated the effect of miR-23b on sepsis-induced immunosuppression. Methods: Mice were treated with miR-23b inhibitors by tail vein injection 2 days after cecal ligation puncture (CLP)-induced sepsis. Apoptosis in spleens and apoptotic signals were investigated, and survival was monitored. T-cell immunoreactivities were examined during late sepsis. Nuclear factor κB (NF-κB)-inducing kinase (NIK), tumor necrosis factor (TNF)-receptor associated factor 1 (TRAF1), and X-linked inhibitor of apoptosis protein (XIAP), the putative targets of miR-23b, were identified by a dual-luciferase reporter assay. Results: miR-23b expression is upregulated and sustained during sepsis. The activation of the TLR4/TLR9/p38 MAPK/STAT3 signal pathway contributes to the production of miR-23b in CLP-induced sepsis. miR-23b inhibitor decreased the number of spleen cells positive by terminal deoxynucleotidyl transferase dUTP nick-end labeling and improved survival. miR-23b inhibitor restored the immunoreactivity by alleviating the development of T-cell exhaustion and producing smaller amounts of immunosuppressive interleukin 10 and interleukin 4 during late sepsis. We demonstrated that miR-23b mediated immunosuppression during late sepsis by inhibiting the noncanonical NF-κB signal and promoting the proapoptotic signal pathway by targeting NIK, TRAF1, and XIAP. Conclusions: Inhibition of miR-23b reduces late-sepsis-induced immunosuppression and improves survival. miR-23b might be a target for immunosuppression.
Assuntos
Tolerância Imunológica , Proteínas Inibidoras de Apoptose/metabolismo , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sepse/patologia , Fator 1 Associado a Receptor de TNF/metabolismo , Animais , Apoptose , Fusão Gênica Artificial , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Genes Reporter , Proteínas Inibidoras de Apoptose/análise , Luciferases/análise , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/análise , Baço/patologia , Análise de Sobrevida , Linfócitos T/imunologia , Fator 1 Associado a Receptor de TNF/análise , Quinase Induzida por NF-kappaBRESUMO
Non-dysplastic Barrett's oesophagus (NDBE) occurs as a consequence of an inflammatory response triggered through prolonged gastro-oesophageal reflux and it may precede the development of oesophageal adenocarcinoma. NF-κB activation as a result of the inflammatory response has been shown in NDBE, but the possible mechanism involved in the process is unknown. The aim of this study was to assess, using immunohistochemistry, Survivin and Bcl3 expression as potential biomarkers for NF-κB activation along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Survivin is an NF-κB-inducible anti-apoptotic protein, and Bcl3 is a negative regulator of NF-κB. There was progressive upregulation of Survivin expression along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Bcl3 expression was upregulated in non-dysplastic Barrett's oesophagus, low-grade, high-grade dysplasia and oesophageal adenocarcinoma when compared to squamous group. The study shows the differential expression of Bcl3 between the squamous and Barrett's stage, suggesting that Bcl3 could be a surrogate marker for early event involving constitutive NF-κB activation. In addition, the study suggests that NF-κB activation may infer resistance to apoptosis through the expression of anti-apoptotic genes such as Survivin, which showed progressive increase in expression throughout the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. This ability to avoid apoptosis may underlie the persistence and malignant predisposition of Barrett's metaplasia.
Assuntos
Adenocarcinoma/química , Esôfago de Barrett/metabolismo , Biomarcadores Tumorais/análise , Transformação Celular Neoplásica/química , Neoplasias Esofágicas/química , Esôfago/química , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose/análise , NF-kappa B/análise , Proteínas Proto-Oncogênicas/análise , Fatores de Transcrição/análise , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Proteína 3 do Linfoma de Células B , Esôfago de Barrett/patologia , Biópsia , Transformação Celular Neoplásica/patologia , Neoplasias Esofágicas/patologia , Esôfago/patologia , Feminino , Humanos , Masculino , Metaplasia , Pessoa de Meia-Idade , Transdução de Sinais , Survivina , Adulto JovemRESUMO
Survivin, an inhibitor of the apoptosis protein family, is a potent tumor marker for diagnosis and prognosis. The enzyme-linked immunosorbent assay (ELISA) is one of the methods that has been used for detection of survivin. However, ELISA has several disadvantages caused by the use of conventional antibodies, and we have therefore been trying to develop a novel ELISA system using camelid single-domain antibodies (VHHs) as advantageous replacements. Here we report a supplemental approach to improve the VHH-polyclonal antibody sandwich ELISA for survivin detection. Iodoacetyl-functionalized pullulan was synthesized, and its thiol reactivity was characterized by a model reaction with l-cysteine. The thiophilic pullulan was applied to an immunoassay asan additive upon coating of standard assay plates with an anti-survivin VHH fusion protein with C-terminal cysteine. The results showed that the mole ratio of the additive to VHH had a significant effect on the consequent response. Mole ratios of 0.07, 0.7, and 7 led to 90% lower, 15% higher, and 69% lower responses, respectively, than the response of a positive control in which no additive was used. The background levels observed in any additive conditions were as low as that of a negative control lacking both VHH and the additive. These results indicate the applicability of the thiol-reactive pullulan as a response enhancer to VHH-based ELISA.
Assuntos
Anticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Glucanos/química , Proteínas Inibidoras de Apoptose/análise , Anticorpos de Domínio Único/imunologia , Animais , Anticorpos/química , Cisteína/química , Humanos , Ácido Iodoacético/química , Anticorpos de Domínio Único/química , SurvivinaRESUMO
AIMS: Survivin-a member of the family of inhibitor of apoptosis proteins that control cell division, apoptosis and metastasis-is overexpressed in virtually all human cancers, including laryngeal squamous cell carcinoma (LSCC). Recent findings also correlate survivin expression with the regulation of angiogenesis. The novel main aim of this study was a preliminary investigation into the potential role of survivin expression in LSCC neoangiogenesis, as determined by endoglin-assessed microvascular density (MVD). METHODS: Immunohistochemical expression of nuclear survivin and endoglin-assessed MVD were ascertained by image analysis in 75 consecutive LSCCs. RESULTS: Statistical analysis disclosed a strong direct correlation between nuclear survivin expression and MVD. Patients whose nuclear survivin expression was ≥6.0% had a significantly higher LSCC recurrence rate, and a significantly shorter disease-free survival (DFS) than those with a nuclear survivin expression <6.0%. The LSCC recurrence rate was also higher and the DFS shorter in patients with endoglin-assessed MVD ≥6.89%. The OR for recurrence was 2.79 in patients with LSCC with a nuclear survivin expression ≥6.0%, and 12.31 in those with an MVD≥6.89%. CONCLUSIONS: Survivin-targeting strategies to enhance tumour cell response to apoptosis and inhibit tumour growth should receive more attention with a view to developing agents for use in multimodality advanced LSCC treatment, or combined with conventional chemotherapy. Given the present preliminary evidence in LSCC, survivin targeting should also be further investigated for anti-angiogenic purposes, to reduce tumour blood flow and induce cancer necrosis.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/química , Núcleo Celular/química , Endoglina/análise , Neoplasias de Cabeça e Pescoço/química , Proteínas Inibidoras de Apoptose/análise , Neoplasias Laríngeas/química , Microvasos/química , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Núcleo Celular/patologia , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/cirurgia , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Razão de Chances , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço , Survivina , Fatores de TempoRESUMO
PURPOSE: Survivin is thought to play an important role in carcinogenesis and is found to be associated with poor clinical outcome in various malignancies. Gene -31 G/C polymorphism has been identified as a risk factor for the development of several types of tumors. The purpose of this study was to investigate the association between survivin gene promoter -31C/G polymorphism and urothelial carcinoma (UC) risk in Serbian population and to compare the different expressions of survivin in UC of different disease stages, histological grades and tumor location in the upper or lower urinary tract. METHODS: DNA from 94 patients with primary UC and from 82 healthy subjects was subjected to PCR restriction fragment length polymorphism analysis (PCR-RFLP) to identify individual genotypes. UC samples were subjected to immunohistochemical analysis to assess survivin expression in these lesions. RESULTS: It was observed that the frequency of G/G genotype was greater in patients with UC (58.7%) than in controls (32%). Compared with study subjects carrying the C/G or C/C genotypes, significantly increased UC risk was found for individuals carrying the G/G genotype. Those carrying the G/G genotype had a significantly increased UC risk compared with those with C/G or C/C genotypes. Patients with UC carrying the G/G genotype had a greater prevalence of muscle-invading (stage T2-T4), high-grade (G2) tumor and immunohistochemicaly overexpressed survivin compared with those carrying the C/G or C/C genotypes. CONCLUSIONS: G/G genotype of the -31C/G polymorphism might be a risk factor for UC development.
Assuntos
Predisposição Genética para Doença , Proteínas Inibidoras de Apoptose/genética , Polimorfismo Genético , Neoplasias Urológicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Proteínas Inibidoras de Apoptose/análise , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Survivina , Neoplasias Urológicas/patologiaRESUMO
Distinguishing WHO grade II astrocytomas from grade III is a difficult task. This study looks into the potential prognostic use of mitotic activity and the proliferation markers Ki67/MiB-1 (Ki67), survivin and DNA topoisomerase IIα (TIIα) in 59 WHO grade II diffuse astrocytomas (DA) and 33 WHO grade III anaplastic astrocytomas (AA), IDH1 R132H-mutated and not otherwise specified (NOS) by means of immunohistochemistry. All proliferation markers showed higher expression in AA compared with DA. Only Ki67 had significantly greater expression in astrocytomas, NOS vs. astrocytomas, IDH1-mutated. Uni-/multivariable COX-regression analyses showed that greater expression of both survivin and TIIα were associated with poorer survival when stratified for IDH1-mutation status and, additionally, achieved hazard rates surpassing clinically established prognostic factors such as age and WHO performance status. Ki67 achieved only statistical significance in univariable analyses, whereas mitoses did not reveal any relation to survival. IDH1-mutated astrocytomas had significantly better survival than astrocytomas, NOS. Among IDH1-mutated astrocytomas no significant difference in survival was shown between DA and AA. Our findings suggest a potential usefulness of proliferation markers in the prognostic setting of astrocytomas independent of IDH1-mutation status, and survivin and TIIα are potential candidates in that regard.
Assuntos
Antígenos de Neoplasias/biossíntese , Astrocitoma/patologia , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/patologia , DNA Topoisomerases Tipo II/biossíntese , Proteínas de Ligação a DNA/biossíntese , Proteínas Inibidoras de Apoptose/biossíntese , Adulto , Idoso , Antígenos de Neoplasias/análise , Astrocitoma/genética , Astrocitoma/mortalidade , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , DNA Topoisomerases Tipo II/análise , Proteínas de Ligação a DNA/análise , Feminino , Humanos , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose/análise , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Survivina , Adulto JovemRESUMO
AIM: To investigate whether bile survivin and carbohydrate antigen 199 (CA199) can be helpful in distinguishing cholangiocarcinoma (malignant obstructive jaundice) from benign obstructive jaundice. METHODS: Receiver operating characteristic curve was used to evaluate the feasibility of bile survivin and CA199 in differentiating cholangiocarcinoma from benign obstructive jaundice. RESULTS: The area under the curve for survivin and CA199 in bile and serum were 0.780 (p < 0.001), 0.6 (p = 0.084), 0.746 (p < 0.001) and 0.542 (p = 0.464), respectively. Combination of bile survivin and CA199 could improve the diagnostic capability. CONCLUSION: Bile survivin and CA199 are significantly increased in patients with cholangiocarcinoma and may be useful biomarkers in differentiating distinguishing cholangiocarcinoma from benign obstructive jaundice.
Assuntos
Antígenos Glicosídicos Associados a Tumores/sangue , Neoplasias dos Ductos Biliares/diagnóstico , Bile/metabolismo , Colangiocarcinoma/diagnóstico , Proteínas Inibidoras de Apoptose/análise , Icterícia Obstrutiva/diagnóstico , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Diagnóstico Diferencial , Feminino , Humanos , Proteínas Inibidoras de Apoptose/sangue , Icterícia Obstrutiva/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC , SurvivinaRESUMO
INTRODUCTION: Actinic cheilitis (AC) is a lip intraepithelial neoplasia, whose cells present alterations similar to those presented by invasive squamous cell carcinomas (SCCs). OBJECTIVE: To conduct clinical and laboratory evaluation by histopathology and immunohistochemistry of the efficacy of actinic cheilitis treatment using photodynamic therapy (PDT) with methyl aminolevulinate (MAL) and noncoherent red light. MATERIALS AND METHODS: Patients with actinic cheilitis detected by histopathological examination were submitted to two sessions of photodynamic therapy with a two-week interval between them. They were examined immediately after the sessions, four, six, and twelve weeks after beginning treatment when a new biopsy was carried out. Clinical histopathological and immunohistochemical parameters were evaluated before and after treatment. RESULTS: Of the 23 patients who underwent biopsy, 16 completed two photodynamic therapy sessions and the material of one patient was insufficient for immunohistochemistry. Complete clinical response was achieved in 62.5% (10 of 16 patients) and 37.5% still remained with clinical evidence of AC. In spite of this, no case of cure by histopathological analysis was found. There was no significant statistical change among the values of Ki-67, survivin, and p53 observed before and after treatment. CONCLUSION: Photodynamic therapy, as carried out in this trial, was not an efficacious therapeutic option for treating patients with actinic cheilitis included in this sample.
Assuntos
Ácido Aminolevulínico/análogos & derivados , Queilite/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácido Aminolevulínico/uso terapêutico , Queilite/metabolismo , Queilite/patologia , Cor , Feminino , Humanos , Proteínas Inibidoras de Apoptose/análise , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Fotoquimioterapia/efeitos adversos , Survivina , Resultado do Tratamento , Proteína Supressora de Tumor p53/análiseRESUMO
OBJECTIVE: To assess the association of survivin expression with clinicopathological features and biochemical recurrence (BCR) after radical prostatectomy (RP) in a large multi-institutional cohort. METHODS: Survivin expression was evaluated by immunohistochemistry on a tissue microarray of RP cores from 3 117 patients. Survivin expression was considered altered when at least 10% of the tumour cells stained positive. The association of altered survivin expression with BCR was evaluated using Cox proportional hazards regression models. RESULTS: Survivin expression was altered in 1 330 patients (42.6%). Altered expression was associated with higher Gleason score on RP (P = 0.001), extracapsular extension (P = 0.019), seminal vesicle invasion (P < 0.001) and lymph node metastases (P = 0.009). The median (interquartile range) follow-up was 38 (21-66) months. Patients with altered survivin expression had a shorter BCR-free survival time than those with normal expression (5-year BCR-free survival estimates: 74.7 vs 79.0%; P = 0.008). Altered survivin expression did not retain its prognostic value, however, after adjustment for the effect of established clinicopathological factors (P = 0.73). Subgroup analyses also showed no independent prognostic value of survivin. CONCLUSIONS: Survivin expression is commonly altered in patients undergoing RP. Altered survivin expression is associated with the clinicopathological features of biologically and clinically aggressive PCa. Survivin expression was associated with BCR only in univariable analysis, limiting its value in daily clinical decision-making.
Assuntos
Proteínas Inibidoras de Apoptose/biossíntese , Recidiva Local de Neoplasia/epidemiologia , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Idoso , Humanos , Proteínas Inibidoras de Apoptose/análise , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Prognóstico , Antígeno Prostático Específico/sangue , Prostatectomia/métodos , Estudos Retrospectivos , SurvivinaRESUMO
We examined the survivin expression pattern by immunohistochemistry in 43 fibroadenomas and 153 ductal carcinomas of the breast. The subcellular localization of survivin and the intensity of immunoreaction were assessed. We analyzed the differences of survivin expression between fibroadenomas and carcinomas. We also correlated the survivin expression pattern in carcinomas with other clinicomorphological parameters such as the age of patients, the grade and size of primary tumor as well as the lymph node metastasis. Overall, survivin was detected in 107/153 carcinomas (69.9%) and in 26/43 fibroadenomas (60.5%). Statistical analysis confirmed significant correlations between the assessed parameters in fibroadenomas and carcinomas. Grade of carcinomas was significantly related to survivin expression in both subcellular localization and the intensity of immunoreaction. Tumor grade 3 was associated with nuclear positivity and combined nuclear and cytoplasmic localization. Carcinomas larger than 20 mm showed nuclear and combined localization in 81% of cases and higher intensity of survivin immunoreaction was also notably related to larger carcinomas. Statistically significant differences were also observed between subcellular survivin localization and intensity of immunoreaction. Our result suggest that nuclear accumulation of survivin is associated with proliferative fenotype and survivin was shown to be a worse prognostic marker in breast ductal carcinoma.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Carcinoma Ductal de Mama/química , Carcinoma Intraductal não Infiltrante/química , Fibroadenoma/química , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Carcinoma Intraductal não Infiltrante/secundário , Núcleo Celular/química , Núcleo Celular/patologia , Proliferação de Células , Feminino , Fibroadenoma/patologia , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Gradação de Tumores , Survivina , Carga TumoralRESUMO
Objective: To investigate the effect of silencing DJ-1 on xenografted human laryngeal squamous cell carcinoma (LSCC) Hep-2 cells in nude mice. Methods: Xenograft model of human LSCC was established by subcutaneous transplantation of Hep-2 cells in 24 nude mice. The LSCC-bearing nude mice were randomly divided into 3 groups (n=8 in each):DJ-1 siRNA low dose group and DJ-1 siRNA high dose group were injected in tumors with 20 µg of DJ-1 siRNA or 40 µg of DJ-1 siRNA in 50 µL, respectively; control group was injected with 5% glucose solution in 50 µL, twice a week for 3 weeks. The weight and size of tumors were measured before injection. The animals were sacrificed 48 h after the final treatment, and the tumors were harvested and weighed. The apoptosis and proliferation of tumor cells were determined; the expressions of Caspase-3 and Ki-67 in tumor specimens were detected with immunohistochemistry. The expression of DJ-1, PTEN, survivin mRNA and protein in tumor tissues were detected by RT-PCR and Western blotting, respectively. Results: Tumor weight in low dose group[(0.66±0.15)g] and high dose group[(0.48±0.11)g] were significantly lower than that in control group[(0.83±0.16)g, all P<0.05]. The inhibition rates of low dose group and high dose group were (20.48±0.18)% and (42.16±0.13)%, respectively. Immunohistochemistry showed that the expression of Caspase-3 was increased and Ki-67 was reduced in tumor specimens, compared with the control group (all P<0.05). RT-PCR and Western blot results showed that in low dose group and high dose group the mRNA and protein expression of DJ-1 and survivin significantly decreased (all P<0.05), while PTEN mRNA and protein content increased (all P<0.05). Conclusion: High dose DJ-1 siRNA can inhibit the tumor growth in human LSCC xenograft nude mouse model, which indicates that down-regulating DJ-1 and survivin, and up-regulating PTEN expression may lead to blockage of PI3K-PKB/Akt signaling pathway and promoting tumor cell apoptosis.
Assuntos
Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/fisiopatologia , Linhagem Celular Tumoral/química , Linhagem Celular Tumoral/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/fisiopatologia , Neoplasias Laríngeas/química , Neoplasias Laríngeas/fisiopatologia , Proteína Desglicase DJ-1/farmacologia , Interferência de RNA/fisiologia , RNA Mensageiro/farmacologia , RNA Interferente Pequeno/fisiologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma de Células Escamosas/genética , Caspase 3/análise , Caspase 3/efeitos dos fármacos , Linhagem Celular Tumoral/fisiologia , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Neoplasias de Cabeça e Pescoço/genética , Xenoenxertos/efeitos dos fármacos , Xenoenxertos/fisiologia , Humanos , Proteínas Inibidoras de Apoptose/análise , Proteínas Inibidoras de Apoptose/efeitos dos fármacos , Antígeno Ki-67/análise , Antígeno Ki-67/efeitos dos fármacos , Neoplasias Laríngeas/genética , Camundongos Nus , PTEN Fosfo-Hidrolase/análise , PTEN Fosfo-Hidrolase/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
INTRODUCTION: The aim of this study was to detect the survivin, carcinoembryonic antigen (CEA) and ErbB2 in the saliva, serum and local tumor-exfoliated cells of oral squamous cell carcinoma (OSCC) patients, for providing reliable tumor markers for the early detection of oral malignant cancer. MATERIALS AND METHODS: The saliva, serum, and local tumor-exfoliated cell samples of 26 OSCC patients without chemotherapy and 10 non-cancer patients were collected in Department of Oral and Maxillofacial Surgery, School of Stomatology, Peking University. The contents of survivin, CEA and ErbB2 using were detected usingenzyme-linked immunosorbent assay. RESULTS: The survivin and CEA levels in saliva and local tumor-exfoliated cells of OSCC patients were significantly higher than those in the non-cancer patients (P < 0.05), but there was no significant difference in the content of the above factors in the serum sample between two groups. There was no significant difference in the ErbB2 content in the saliva, serum or local tumor-exfoliated cells between two groups. CONCLUSION: Survivin and CEA levels are significantly increased in the saliva and local tumor-exfoliated cells in OSCC patients, and they can be used as reliable markers for the early detection of oral malignant cancer.
Assuntos
Biomarcadores Tumorais/análise , Antígeno Carcinoembrionário/análise , Carcinoma de Células Escamosas/química , Neoplasias de Cabeça e Pescoço/química , Proteínas Inibidoras de Apoptose/análise , Neoplasias Bucais/química , Receptor ErbB-2/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Antígeno Carcinoembrionário/sangue , Antígeno Carcinoembrionário/metabolismo , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/sangue , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/sangue , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Receptor ErbB-2/sangue , Receptor ErbB-2/metabolismo , Saliva/química , Saliva/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , SurvivinaRESUMO
High-grade papillary urothelial carcinoma with subepithelial connective tissue invasion (T1HG) is an aggressive disease at high risk of progression after transurethral resection/Bacillus Calmette-Guerin standardized therapy. The European Organization for Research and Treatment of Cancer has identified T1HG bladder carcinoma that is single and ≤3 cm in the largest dimension at first diagnosis as a category in which the prognosis cannot be further stratified based on conventional criteria. This category may benefit from biomarker analysis as a valuable tool to determine the patient's outcome. To further the issue of biomarkers in predicting aggressiveness in single T1HG bladder carcinoma ≤3 cm in greatest dimension at first diagnosis, we have conducted a validation study of the biomarker risk score set previously reported by our group. The study set included immunohistochemical detection of galectin-3, CD44, E-cadherin (E-CAD), CD138, p16, survivin, HYAL-1, and topoisomerase-IIα in 92 randomly selected specimens at participating institutions. Topoisomerase-IIα expression was identified as a predictor of disease-free survival. p16, survivin, and E-CAD expression predicted progression-free survival, but p16 and E-CAD also predicted overall survival. The current study validates a panel of immunohistochemical markers with the potential of being implemented in practice and supports the use of biomarkers in predicting aggressiveness in patients with first diagnosis of single T1HG bladder carcinoma ≤3 cm in greatest dimension and therefore in identifying patients who need closer surveillance or earlier aggressive treatment.