Discovery of Retinoblastoma-Associated Binding Protein 46 as a Novel Prognostic Marker for Distant Metastasis in Nonsmall Cell Lung Cancer by Combined Analysis of Cancer Cell Secretome and Pleural Effusion Proteome

Wang, Chih‐Liang; Wang, Chun-I; Liao, Pao‐Chi; Chen, Chi-De; Li, Ying; Chuang, Wen-Yu; Tsai, Ying‐Huang; Chen, Hua‐Chien; Chang, Yu‐Sun; Yu, Jau‐Song; Wu, Chih‐Ching

doi:10.1021/pr900160h

Cited by 64 publications

(54 citation statements)

References 76 publications

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“…Formalin-fixed and paraffinembedded tissues were examined by IHC according to previously described procedures. (10) The Grp58 antibody (Atlas) was used at 1:2000 dilution. The second antibody was horseradish peroxidase-conjugated anti-rabbit antibody (Santa Cruz Biotechnology, Inc.).…”

Section: Methodsmentioning

confidence: 99%

Glucose‐regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer

Liao

Huang

et al. 2011

Cancer Science

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Human papilloma virus infection is critical but not sufficient to cause cervical cancer. Molecular markers of cervical carcinogenesis are essential. The aim of this study was to identify aberrantly expressed proteins in cervical cancer and determine their clinical significance. A two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomic strategy was used for screening candidate proteins. Immunoblotting and immunohistochemical (IHC) analyses were performed to confirm the results of 2-DE, and the clinical significance was estimated. Glucose-regulated protein 58 (Grp58) was overexpressed in 73% of cancers. The IHC staining showed that the Grp58 histoscore was significantly higher in patients with adenocarcinoma (AD) compared with squamous cell carcinoma (P < 0.05). Grp58 staining was intense in AD with a penetration depth greater than half of the cervical stroma (P = 0.033). High Grp58 expression was associated with low overall survival and recurrence-free survival (RFS) rates (P = 0.007 and P = 0.013, respectively). In multivariate analysis, high Grp58 expression (P = 0.042) and lymph node metastasis (P = 0.026) were determined as independent prognostic factors for RFS. Patients exhibiting both high Grp58 expression and lymph node metastasis displayed poorer outcomes than the other patient groups. In functional studies, knockdown of Grp58 in HeLa cells led to decreased cell invasiveness and inhibition of lung metastasis in a xenograft mouse model. In conclusion, Grp58 serves as a potent prognostic factor of cervical AD. Estimation of the Grp58 index in conjunction with the lymph node metastasis status might aid in predicting the prognosis of cervical AD. (Cancer Sci 2011; 102: 2255-2263 C ervical cancer is one of the most common cancers among women worldwide. Approximately 500 000 diagnoses of cervical cancer are made each year, leading to 274 000 deaths, although the incidence and death rate have declined markedly in the past three decades because of effective screening.(1) Human papillomaviruses (HPV) are the causative agents of over 99% of cervical cancers containing viral sequences. Infection by highrisk HPV types is necessary but not sufficient for progression to cancer. Most HPV infections are transient without clinical manifestation and are cleared naturally; <1% of women become HPV carriers and remain at high risk of developing cervical cancer.(2)The mechanisms underlying the progression and regression of lesions caused by HPV infection are unknown, and further investigation of the molecular alterations in cervical cancer is needed.Glucose-regulated protein 58 (Grp58) is a glycoprotein-specific thiol-oxidoreductase belonging to the disulfide isomerase family of proteins. Grp58 is a multifunctional protein.(3) Recent studies suggest that Grp58 plays a role in cancer, although related information is limited. Hirano et al.(4) demonstrated that enhanced expression of Grp58 was associated with oncogenic transformation in normal rat kidney cells. Grp58 overexpression modulates STAT3 signaling in cancer...

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Section: Methodsmentioning

confidence: 99%

Glucose‐regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer

Liao

Huang

et al. 2011

Cancer Science

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“…Formalin-fixed and paraffin-embedded tissues were examined with immunohistochemistry (IHC) using primary antibody listed in Supplementary Table S2 and the avidin-biotin complex method according to previously described procedures (20). The staining intensity was graded as absent (0), weak (1þ), medium (2þ), or strong (3þ).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Interleukin-32 Increases Human Gastric Cancer Cell Invasion Associated with Tumor Progression and Metastasis

Tsai

Wang

Tsai

et al. 2014

Clinical Cancer Research

101

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Purpose: The proinflammatory cytokine interleukin-32 (IL-32) is a novel tumor marker highly expressed in various human carcinomas, including gastric cancer. However, its effects on prognosis of patients with gastric cancer and cancer metastasis are virtually unknown at present. The main aim of this study was to explore the clinical significance of IL-32 in gastric cancer and further elucidate the molecular mechanisms underlying IL-32-mediated migration and invasion.Experimental Design: Gastric cancer cells with ectopic expression or silencing of IL-32 were examined to identify downstream molecules and establish their effects on cell motility, invasion, and lung metastasis in vivo.Results: IL-32 was significantly upregulated in gastric cancer and positively correlated with aggressiveness of cancer and poor prognosis. Ectopic expression of IL-32 induced elongated morphology and increased cell migration and invasion via induction of IL-8, VEGF, matrix metalloproteinase 2 (MMP2), and MMP9 expression via phosphor-AKT/phospho-glycogen synthase kinase 3b/active b-catenin as well as hypoxiainducible factor 1a (HIF-1a) signaling pathways. Conversely, depletion of IL-32 in gastric cancer cells reversed these effects and decreased lung colonization in vivo. Examination of gene expression datasets in oncomine and staining of gastric cancer specimens demonstrated the clinical significance of IL-32 and its downstream molecules by providing information on their coexpression patterns.Conclusions: IL-32 contributes to gastric cancer progression by increasing the metastatic potential resulting from AKT, b-catenin, and HIF-1a activation. Our results clearly suggest that IL-32 is an important mediator for gastric cancer metastasis and independent prognostic predictor of gastric cancer. Clin Cancer Res; 20(9); 2276-88. Ó2014 AACR.

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“…All cells were cultured at 37°C with a humidified atmosphere of 95% air/5% CO 2 . Conditioned media (CM) from the various cancer cell lines were collected and processed as previously described (16).…”

Section: Patient Population and Clinical Specimens-this Study Was Appmentioning

confidence: 99%

In-depth Proteomic Analysis of Six Types of Exudative Pleural Effusions for Nonsmall Cell Lung Cancer Biomarker Discovery

Liu

Chen

Wang³

et al. 2015

Molecular & Cellular Proteomics

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Pleural effusion (PE), a tumor-proximal body fluid, may be a promising source for biomarker discovery in human cancers. Because a variety of pathological conditions can lead to PE, characterization of the relative PE proteomic profiles from different types of PEs would accelerate discovery of potential PE biomarkers specifically used to diagnose pulmonary disorders. Using quantitative proteomic approaches, we identified 772 nonredundant proteins from six types of exudative PEs, including three malignant PEs (MPE, from lung, breast, and gastric cancers), one lung cancer paramalignant PE, and two benign diseases (tuberculosis and pneumonia). Spectral counting was utilized to semiquantify PE protein levels. Principal component analysis, hierarchical clustering, and Gene Ontology of cellular process analyses revealed differential levels and functional profiling of proteins in each type of PE. We identified 30 candidate proteins with twofold higher levels (q<0.05) in lung cancer MPEs than in the two benign PEs. Three potential markers, MET, DPP4, and PTPRF, were further verified by ELISA using 345 PE samples. The protein levels of these potential biomarkers were significantly higher in lung cancer MPE than in benign diseases or lung cancer paramalignant PE. The area under the receiver-operator characteristic curve for three combined biomarkers in discriminating lung cancer MPE from benign diseases was 0.903. We also observed that the PE protein levels were more clearly discriminated in effusions in which the cytological examination was positive and that they would be useful in rescuing the false negative of cytological examination in diagnosis of nonsmall cell lung cancer-MPE. Western blotting analysis further demonstrated that MET overexpression in lung cancer cells would contribute to the elevation of soluble MET in MPE. Our results collectively demonstrate the utility of label-free quantitative proteomic approaches in establishing differential PE proteomes and provide a new database of proteins that can be used to facilitate identification of pulmonary disorder-related biomarkers. Molecular & Cellular Proteomics

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Discovery of Retinoblastoma-Associated Binding Protein 46 as a Novel Prognostic Marker for Distant Metastasis in Nonsmall Cell Lung Cancer by Combined Analysis of Cancer Cell Secretome and Pleural Effusion Proteome

Cited by 64 publications

References 76 publications

Glucose‐regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer

Glucose‐regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer

Interleukin-32 Increases Human Gastric Cancer Cell Invasion Associated with Tumor Progression and Metastasis

In-depth Proteomic Analysis of Six Types of Exudative Pleural Effusions for Nonsmall Cell Lung Cancer Biomarker Discovery

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