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Cancer Sci ; 110(9): 2941-2959, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31343810


A sensitive and specific diagnosis biomarker, in principle scalable to most cancer types, is needed to reduce the prevalent cancer mortality. Meanwhile, the investigation of diagnosis determinants of a biomarker will facilitate the interpretation of its screening results in clinic. Here we design a large-scale (1558 enrollments), multicenter (multiple hospitals), and cross-validation (two datasets) clinic study to validate plasma Hsp90α quantified by ELISA as a pan-cancer biomarker. ROC curve shows the optimum diagnostic cutoff is 69.19 ng/mL in discriminating various cancer patients from all controls (AUC 0.895, sensitivity 81.33% and specificity 81.65% in test cohort; AUC 0.893, sensitivity 81.72% and specificity 81.03% in validation cohort). Similar results are noted in detecting early-stage cancer patients. Plasma Hsp90α maintains also broad-spectrum for cancer subtypes, especially with 91.78% sensitivity and 91.96% specificity in patients with AFP-limited liver cancer. In addition, we demonstrate levels of plasma Hsp90α are determined by ADAM10 expression, which will affect Hsp90α content in exosomes. Furthermore, Western blotting and PRM-based quantitative proteomics identify that partial false ELISA-negative patients secret high levels of plasma Hsp90α. Mechanism analysis reveal that TGFß-PKCγ gene signature defines a distinct pool of hyperphosphorylated Hsp90α at Theronine residue. In clinic, a mechanistically relevant population of false ELISA-negative patients express also higher levels of PKCγ. In sum, plasma Hsp90α is a novel pan-cancer diagnosis biomarker, and cancer diagnosis with plasma Hsp90α is particularly effective in those patients with high expression of ADAM10, but may be insufficient to detect the patients with low ADAM10 and those with hyperphosphorylated Hsp90α.

Biomarcadores Tumorais/sangue , Proteínas de Choque Térmico HSP90/sangue , Neoplasias/diagnóstico , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Adolescente , Adulto , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Criança , Pré-Escolar , Conjuntos de Dados como Assunto , Ensaio de Imunoadsorção Enzimática , Exossomos/metabolismo , Reações Falso-Negativas , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Fosforilação , Estudos Prospectivos , Curva ROC , Treonina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
Neoplasia ; 21(4): 413-427, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30925417


Tumor lymphangiogenesis has been previously documented to predict regional lymph node metastasis and promote the spread to distant organs. However, the underlying mechanism initiating tumor lymphangiogenesis remains unclear. Here we described a novel role of tumor cell-derived Lysyl Oxidase-like protein 2 (LOXL2) in promoting lymphangiogenesis and lymph node metastasis in breast cancer. Immunohistochemistry (IHC) analysis of samples from breast cancer patients showed that the expression of LOXL2 was positively correlated with lymphatic vessel density and breast cancer malignancy. In animal studies, LOXL2-overexpressing breast cancer cells significantly increased lymphangiogenesis and lymph node metastasis, whereas knockdown of LOXL2 suppressed both processes. In order to study the mechanisms of lymphangiogenesis progression, we performed further in vitro investigations and the data revealed that LOXL2 significantly enhanced lymphatic endothelial cells (LECs) invasion and tube formation through directly activation of the Akt-Snail and Erk pathways. Moreover, LOXL2 also stimulated fibroblasts to secrete high level of pro- lymphangiogenic factors VEGF-C and SDF-1α. Taken together, our study elucidates a novel function of tumor cell secreted LOXL2 in lymphangiogenesis and lymph node metastasis, demonstrating that LOXL2 serves as a promising target for anti-lymphangiogenesis and anti-metastasis therapies for breast cancer.

Aminoácido Oxirredutases/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linfangiogênese/genética , Neovascularização Patológica/genética , Aminoácido Oxirredutases/metabolismo , Animais , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Camundongos , Neovascularização Patológica/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo
Environ Microbiol Rep ; 7(1): 128-38, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25223900


The discovery of denitrifying anaerobic methane oxidation with nitrite as electron acceptor mediated by 'Candidatus Methylomirabilis oxyfera' connected the biogeochemical carbon and nitrogen cycle in a new way. However, it is important to have a comprehensive understanding about the distribution of M. oxyfera-like bacteria in the terrestrial realm, especially the wetland ecosystems that are known as the largest natural source of atmospheric methane. Here, our molecular evidence demonstrated that a wide geographical distribution of M. oxyfera-like bacteria at oxic/anoxic interfaces of various wetlands (n = 91) over the Chinese territory. Intriguingly, the M. oxyfera-like bacteria were detected in some extreme environments, indicating that M. oxyfera-like bacteria occupied a wide range of habitats. Quantitative polymerase chain reaction estimated that the abundance of M. oxyfera-like bacteria ranged from 2.2 × 10(3) to 2.3 × 10(7) copies g(-1) dry soil, and up to around 0.62% of the total number of bacteria. Moreover, the M. oxyfera-like bacteria showed high biodiversity in wetland ecosystems based on the analysis of 462 pmoA and 287 16S rRNA gene sequences. The current study revealed the widespread distribution and biogeography of M. oxyfera-like bacteria in the terrestrial system.

Ecossistema , Methylococcaceae/isolamento & purificação , Microbiologia do Solo , Anaerobiose , Biodiversidade , China , Desnitrificação , Metano/metabolismo , Methylococcaceae/classificação , Methylococcaceae/genética , Methylococcaceae/metabolismo , Dados de Sequência Molecular , Ciclo do Nitrogênio , Filogenia , Áreas Alagadas