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1.
Cancer Cell ; 6(5): 459-69, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15542430

RESUMO

The receptor tyrosine kinase HER2 enhances tumor metastasis; however, its role in homing to metastatic organs is poorly understood. The chemokine receptor CXCR4 has recently been shown to mediate the movement of malignant cancer cells to specific organs. Here, we show that HER2 enhances the expression of CXCR4, which is required for HER2-mediated invasion in vitro and lung metastasis in vivo. HER2 also inhibits ligand-induced CXCR4 degradation. Finally, a significant correlation between HER2 and CXCR4 expression was observed in human breast tumor tissues, and CXCR4 expression correlated with a poor overall survival rate in patients with breast cancer. These results provide a plausible mechanism for HER2-mediated breast tumor metastasis and establish a functional link between HER2 and CXCR4 signaling pathways.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptor ErbB-2/fisiologia , Receptores CXCR4/metabolismo , Regulação para Cima , Animais , Humanos , Ligantes , Neoplasias Pulmonares/secundário , Camundongos , Células NIH 3T3 , Metástase Neoplásica , Transfecção , Células Tumorais Cultivadas
2.
Nat Cell Biol ; 6(10): 931-40, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15448698

RESUMO

The phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of the epithelial-mesenchymal transition (EMT) that occurs during embryonic development. Snail, a zinc-finger transcription factor, triggers this process by repressing E-cadherin expression; however, the mechanisms that regulate Snail remain elusive. Here we find that Snail is highly unstable, with a short half-life about 25 min. We show that GSK-3beta binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein. Phosphorylation of the first motif regulates its beta-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization. A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT. Furthermore, inhibition of GSK-3beta results in the upregulation of Snail and downregulation of E-cadherin in vivo. Thus, Snail and GSK-3beta together function as a molecular switch for many signalling pathways that lead to EMT.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Mesoderma/metabolismo , Fatores de Transcrição/metabolismo , Motivos de Aminoácidos , Sítios de Ligação , Neoplasias da Mama/patologia , Caderinas/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/química , Sequência Consenso , Cisteína Endopeptidases/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Inibidores Enzimáticos/farmacologia , Células Epiteliais/citologia , Glicogênio Sintase Quinase 3 beta , Humanos , Leupeptinas/farmacologia , Lítio/farmacologia , Mesoderma/citologia , Complexos Multienzimáticos/metabolismo , Mutação , Fosforilação , Complexo de Endopeptidases do Proteassoma , Ligação Proteica , Fatores de Transcrição da Família Snail , Especificidade por Substrato , Fatores de Transcrição/química , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética , Dedos de Zinco
3.
Cureus ; 13(12): e20302, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35028207

RESUMO

Introduction Interbody spacers are necessary for achieving disc height restoration when surgical intervention is used for the treatment of severe degenerative disc disease. Minimally invasive lateral lumbar interbody fusion (MIS LLIF) is a popular surgical approach that historically uses large static interbody spacers through a lateral approach. However, static spacers have been associated with iatrogenic distraction and excessive impaction forces, which may increase the risk of subsidence and loss of lordosis, compromising stability. Expandable interbody spacers with or without adjustable lordosis may help address these concerns by maximizing segmental lordosis and aiding in sagittal balance correction. This study describes the clinical and radiographic outcomes of patients treated with expandable interbody spacers with or without adjustable lordosis, for MIS LLIF. Materials and methods This is retrospective, single-surgeon Institutional Review Board-exempt chart review was of 103 consecutive patients who had undergone MIS LLIF at one to two contiguous level(s) utilizing expandable interbody spacers with or without adjustable lordosis (66/103 patients had adjustable lordosis spacers). Collection of clinical and radiographic functional outcomes occurred at preoperative and postoperative time points through 24 months. Results One-hundred and three consecutive patients were evaluated-average age, 58.2 ± 12.1 years; 42.1% (45/107) were female. There were 78.6% (81/103) one-level cases and 21.4% (22/103) two-level cases for a total of 125 levels; 44.8% (56/125) were performed at L4-5 and 34.4% (43/125) at L3-4. The average estimated blood loss was 24.6 ± 12.3cc. Mean operative time was 61.0 ± 19.1 min, and mean fluoroscopic time was 28.2 ± 14.6 sec. Visual Analog Scale (VAS) back and leg pain scores decreased significantly by an average of 7.1 ± 1.0 points at 24 months (p<0.001). Oswestry Disability Index (ODI) scores significantly decreased by a mean of 67.4 ± 8.9 points at 24 months (p<0.001). Lumbar lordosis significantly improved by a mean of 3.1 ± 8.8° at 24 months (p=0.001). Anterior, middle, and posterior disc height significantly increased at 24 months by averages of 4.7 ± 3.1, 4.0 ± 3.0, and 2.1 ± 2.2mm, respectively (p<0.001). Neuroforaminal height had significantly increased at 24 months by a mean of 3.0 ± 3.6mm (p<0.001). Segmental lordosis significantly improved by 3.7 ± 2.9° at 24 months (p<0.001). There were 51 patients with abnormal preoperative Pelvic Incidence-Lumbar Lordosis (PI-LL) measurements that significantly improved by 9.1 ± 4.9° (p<0.001) and 52 patients with normal preoperative PI-LL measurements that improved by 0.2 ± 4.6° (p=0.748) at 24 months. One-hundred percent fusion occurred at all levels, and no findings of radiolucency were observed. One case of subsidence (1/125, 0.8%) was reported at 24 months. No implanted-related complications were reported, with 0% pseudoarthrosis and no secondary surgery required at the operative levels. Conclusion Indirect decompression and sagittal correction were achieved and maintained through a 24-month follow-up. Functional clinical outcomes significantly improved based on decreased VAS pain and ODI scores at 24 months. This study resulted in positive clinical and radiographic outcomes for patients who underwent MIS LLIF with expandable interbody spacers with or without adjustable lordosis.

4.
Magn Reson Imaging ; 65: 129-135, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31644925

RESUMO

PURPOSE: To investigate the correlation between the FA parameters and Ki-67 labeling index, and their diagnostic performance in grading supratentorial non-enhancing gliomas and neuronal-glial tumors (GNGT). METHODS: This institutional review board-approved, Health Insurance Portability and Accountability (HIPAA) compliant retrospective study enrolled 35 patients, including 19 with low grade GNGT and 16 with high grade GNGT. The mean FA, maximal FA and mean maximal FA values derived from diffusion tensor imaging were measured. The correlation between the FA parameters and the Ki-67 labeling index was assessed by Spearman rank test. The receiver operating characteristic curve analysis and multivariate logistic regression analysis were performed to detect the optimal imaging parameters in grading GNGT. RESULTS: The three FA parameters of low grade GNGT were significantly lower than the high grade GNGT (p < 0.001). The mean FA, maximal FA and mean maximal FA had significant positive correlation with Ki-67 labeling index (p = 0.001, p < 0.001, p < 0.001 respectively). The maximal FA showed a higher sensitivity and specificity in grading of non-enhancing GNGT with specificity of 78.9%, sensitivity of 100.0%, respectively. CONCLUSIONS: The FA parameters correlated with Ki-67 labeling index, and were useful surrogates in preoperative grading supratentorial non-enhancing GNGT.


Assuntos
Anisotropia , Neoplasias Encefálicas/diagnóstico por imagem , Imagem de Tensor de Difusão , Glioma/diagnóstico por imagem , Adulto , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Feminino , Glioma/patologia , Humanos , Antígeno Ki-67 , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Neurônios/patologia , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade
5.
World Neurosurg ; 110: e627-e635, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29162528

RESUMO

OBJECTIVE: Reoperation and readmission are often avoidable, costly, and difficult to predict. We sought to identify risk factors for readmission and reoperation after spine surgery and to use these factors to develop a scoring system predictive of readmission and reoperation. METHODS: The National Surgical Quality Improvement Project database for years 2012 to 2014 was reviewed for patients undergoing spinal surgery, and 68 perioperative characteristics were analyzed. RESULTS: A total of 111,892 patients who underwent spinal surgery were identified. The rate of reoperation was 3.1%, the rate of readmission was 5.2%, and the occurrence of either was 6.6%. Multivariate analysis found 20 perioperative factors significantly associated with both readmission and reoperation. Preoperative and operative factors found significant included age >60 years, African-American race, recent weight loss, chronic steroid use, on dialysis, blood transfusion required, American Society of Anesthesiologists classification ≥3, contaminated wound, >10% probability of experiencing morbidity, and operative time >3 hours. Postoperative associations identified included urinary tract infection, stroke, dehiscence, pulmonary embolism, sepsis, septic shock, deep and superficial surgical site infection, reintubation, and failure to wean from ventilator. An unweighted and weighted risk score were generated that yielded receiver operating characteristic curves with areas under the curve of 0.707 (95% confidence interval [CI]: 0.701-0.713) and 0.743 (95% CI: 0.736-0.749) 0.708 (95% CI: 0.702-0.715), respectively. CONCLUSIONS: Patients with an unweighted score ≥7 had a more than 20-fold increased risk of reoperation or readmission and a more than 1000-fold increased risk of mortality than did patients with a score of 0.


Assuntos
Readmissão do Paciente , Reoperação , Coluna Vertebral/cirurgia , Área Sob a Curva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Análise Multivariada , Melhoria de Qualidade , Curva ROC , Sistema de Registros , Fatores de Risco
6.
Cancer Res ; 65(8): 3257-63, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15833858

RESUMO

HER2 overexpression, a known prognostic factor in many human cancers, can activate phosphatidylinositol-3 kinase (PI-3K)/Akt pathways and plays an important role in mediating cell survival and tumor development. Hypoxia-inducible factors (HIFs) promote angiogenesis and energy metabolism and thereby enhance tumor growth and metastasis. HIFs, composed of alpha and beta subunits, are activated in most human cancers, including those that overexpress HER2. Previous reports have suggested that increased PI-3K/Akt or decreased PTEN activity may activate the HIF pathway in various tumors, but the detailed mechanism is still not completely understood. Here we reported an interaction between the HIF and PI-3K/Akt pathways in HER2-overexpressing cancer cells. Our results indicate that HER2 overexpression, which results in constitutively active Akt, turns on HIF-1alpha independently of hypoxia, and this activation is weaker than that under hypoxic condition. Further investigation showed that Akt is required for the hypoxia-independent HIF activity. The PI-3K/Akt pathway did not affect the HIF-1alpha binding with its E3 ligase von Hippel-Lindau but enhanced the binding affinity between the HIF-1 alpha and beta subunits. Furthermore, we found that Akt interacts with HIF-1beta and regulates HIF activity. Our results indicated that HER2 can induce HIF activation via the activation of Akt suggesting that activation of HER2/Akt pathway may promote angiogenesis independent of hypoxia, which may have important implications for the oncogenic activity of HER2 and Akt.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptor ErbB-2/biossíntese , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição/metabolismo , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Camundongos , Células NIH 3T3 , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt , Receptor ErbB-2/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Fatores de Transcrição/genética , Transcrição Gênica , Transfecção , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau
7.
Cancer Res ; 63(22): 7630-3, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14633680

RESUMO

Bik was initially identified as a BH3-domain-only protein that interacts with E1B 19K. Although systemically administered wild-type Bik significantly inhibited tumor growth and metastasis in an orthotopic nude mouse model, the proapoptotic potency of Bik can be modulated by posttranslational phosphorylation. Here, we found that Bik mutants, in which threonine 33 and/or serine 35 were changed to aspartic acid to mimic the phosphorylation at these two residues, enhanced their binding affinity with the antiapoptotic proteins Bcl-X(L) and Bcl-2 and were more potent than wild-type Bik in inducing apoptosis and inhibiting cell proliferation in various human cancer cells. Bik mutants also suppressed tumorigenicity and tumor-taking rate in a mouse ex vivo model. Moreover, Bik mutant-liposome complexes inhibited tumor growth and prolonged life span more effectively than the wild-type Bik-liposome complex in an in vivo orthotopic animal model. Thus, our results demonstrate that Bik mutant genes, more potent than wild-type Bik, induce cell death and suggest that their inhibition on the growth of various cancers should be explored further.


Assuntos
Terapia Genética/métodos , Proteínas de Membrana , Neoplasias/terapia , Proteínas/genética , Animais , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Proteínas Mitocondriais , Mutagênese Sítio-Dirigida , Neoplasias/genética , Neoplasias/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X
8.
Oncogene ; 23(21): 3883-7, 2004 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-15021910

RESUMO

Constitutively active HER2/neu activates nuclear factor kappa-B (NF-kappaB) in cells and induces their resistance to apoptotic stimuli such as tumor necrosis factor-alpha (TNF-alpha). Here, we show that integrin-linked kinase (ILK), the crucial signal transducer in the integrin pathway, is involved in HER2/neu-mediated activation of NF-kappaB. Expression of HER2/neu increases ILK activity. Blocking ILK activity with a kinase-deficient mutant ILK (ILK-KD) inhibits NF-kappaB activation and sensitizes HER2/neu-transformed cells to TNF-alpha-induced apoptosis. Stable expression of ILK-KD in HER2/neu-transformed cells suppressed Akt phosphorylation and the expression of IkappaB kinase alpha and beta (IKKalpha and beta) at both the protein and mRNA levels, preventing IkappaB-alpha degradation and NF-kappaB activation. Furthermore, HER2/neu stimulated the transcriptional activity of the putative IKKbeta promoter through ILK and Akt. Our results demonstrate that upregulation of IKKalpha and IKKbeta by the ILK/Akt pathway is required for the HER2/neu-mediated NF-kappaB antiapoptotic pathway.


Assuntos
Apoptose , Regulação da Expressão Gênica , NF-kappa B/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Receptor ErbB-2/fisiologia , Animais , Quinase I-kappa B , Camundongos , Células NIH 3T3 , RNA Mensageiro/análise , Regulação para Cima
9.
J Clin Neurosci ; 22(7): 1091-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25957783

RESUMO

We present a 69-year-old woman who presented with chronic headaches and was found to have a pituitary mass on MRI, which was biopsied and said to be lymphocytic hypophysitis. The woman was placed on prednisone and followed with routine eye examinations. Two years later, the lesion gradually increased in size and the woman developed a decrease in peripheral vision in the right eye. An MRI showed abutment of the right optic nerve by the mass. A repeat endoscopic transsphenoidal biopsy/resection of the pituitary lesion was performed. Histopathological analysis of the specimen was consistent with diagnosis of xanthomatous hypophysitis (XH). XH is an inflammatory disorder of the pituitary gland characterized by an infiltration of lipid-laden histiocytes, also known as xanthoma cells. The mass was biopsied and a diagnosis of lymphocytic hypophysitis was made. The woman reported improved visual acuity and peripheral vision postoperatively. One year after the second resection, her visual symptoms worsened. Repeat MRI revealed expansion of the residual pituitary tissue. She was referred to the radiation oncology department for external beam radiation therapy and was placed on a maintenance dose of steroids. Since undergoing radiation therapy, her vision has improved slightly and her 3month MRI revealed stable lesion size. This woman illustrates a rare pituitary pathology presented with a literature review of published patients describing xanthomatous hypophysitis. A discussion of the clinical presentation, epidemiology, etiology, diagnosis, histology and treatment is provided.


Assuntos
Neuro-Hipófise/patologia , Neoplasias Hipofisárias/complicações , Xantomatose/complicações , Idoso , Anti-Inflamatórios/uso terapêutico , Biópsia , Feminino , Histiócitos/patologia , Humanos , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia , Procedimentos Neurocirúrgicos , Neuro-Hipófise/cirurgia , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Complicações Pós-Operatórias/terapia , Prednisona/uso terapêutico , Reoperação , Resultado do Tratamento , Transtornos da Visão/etiologia , Xantomatose/patologia , Xantomatose/cirurgia
10.
Cancer Gene Ther ; 11(11): 740-7, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15359286

RESUMO

Survivin is expressed in many cancers but not in normal adult tissues and is transcriptionally regulated. To test the feasibility of using the survivin promoter to induce cancer-specific transgene expression in lung cancer gene therapy, a vector expressing a luciferase gene driven by the survivin promoter was constructed and evaluated in vitro and in vivo. We found that the survivin promoter was generally more highly activated in cancer cell lines than in normal and immortalized normal cell lines. When delivered intravenously by DNA:liposome complexes, the survivin promoter was more than 200 times more cancer specific than the cytomegalovirus promoter in vivo. To identify lung cancer patients who may benefit from gene therapy with the survivin promoter, we measured survivin protein expression in surgical specimens of 75 non-small-cell lung cancers and 10 normal lung tissues by immunohistochemical staining and found that survivin is expressed in most of the non-small-cell lung cancers tested (81%, 61 of 75) but none of the normal lung tissues. The survivin promoter also induced transgene expression of a mutant Bik in cancer cells, which suppressed the growth of cancer cells in vitro and in vivo. These results indicate that the survivin promoter is a cancer-specific promoter for various cancers and that it may be useful in cancer gene therapy.


Assuntos
Terapia Genética , Proteínas Associadas aos Microtúbulos/genética , Regiões Promotoras Genéticas , Sequência de Bases , Primers do DNA , Humanos , Proteínas Inibidoras de Apoptose , Proteínas de Neoplasias , Plasmídeos , Survivina , Transfecção , Transgenes
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