The Clinicopathological and Prognostic Impact of 14-3-3 Protein Isoforms Expression in Human Cholangiocarcinoma by Immunohistochemistry

Wu, Qiao; Liu, Changzheng; Luan, Tao; Yu, Lan; Liu, Wei; Chen, Songsen; He, Xianghuo

doi:10.7314/apjcp.2012.13.4.1253

Cited by 18 publications

(17 citation statements)

References 28 publications

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“…High levels of other 14-3-3 isoforms have been associated with more severe disease or worse outcomes in many patient groups, including, but not limited to, carcinoma [30-33], Creutzfeldt-Jakob disease [34], Alzheimer’s disease [35], multiple sclerosis [36], infarction [37] and HIV [38]. Analysis of serum 14-3-3η expression in relation to joint damage and progression revealed significantly higher levels of 14-3-3η in patients who already had radiographic evidence of damage at study baseline, as well as in those who developed progression by the end of the follow-up period.…”

Section: Discussionmentioning

confidence: 99%

14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage

et al. 2014

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IntroductionThe aim of this study was to investigate whether 14-3-3η, a specific isoform of a family of proteins regulating processes such as cellular signalling, activates cell-signalling pathways and induces factors known to contribute to the pathophysiology of rheumatoid arthritis (RA). We also investigated whether 14-3-3η is associated with more severe disease in both early and established RA.MethodsWe investigated the effect of 14-3-3η on the activation of RA-relevant signalling cascades and induction of proinflammatory mediators that contribute to the joint damage process. 14-3-3η titres from 33 patients with early RA (mean RA duration = 1.8 months) and from 40 patients with established RA were measured in serum drawn at the 3-year time point of the Behandel Strategieën study. The relationship between 14-3-3η titres and standard clinical variables was investigated by correlation analysis. The association with radiographic damage and radiographic progression over at least a 2-year period was investigated using univariate and multivariate regression analyses.Results14-3-3η activated selected members of the mitogen-activated protein kinase (MAPK) family, mainly extracellular regulated kinase 1/2 and c-Jun kinase, but not p38MAPK. Activation by 14-3-3η, using levels spanning the concentration range found in RA patient serum, resulted in the induction of inflammatory transcripts such as interleukin 1 (IL-1) and IL-6 and factors linked to the joint damage process, such as receptor activator of nuclear factor κB ligand and matrix metalloproteinase 1. Serum 14-3-3η correlated significantly with rheumatoid factor (RF) (r = 0.43) and anticitrullinated protein antibodies (ACPAs) (r = 0.31) in the early RA cohort, but not with C-reactive protein (CRP) or the Disease Activity Score in 28 joints in either cohort. Serum 14-3-3η concentrations were significantly higher in patients with radiographically assessed joint damage and in those who had radiographic progression. By multivariate analysis, we show that 14-3-3η complemented markers such as CRP, RF and ACPA in informing RA radiographic status and/or progression.ConclusionsExtracellular 14-3-3η activates key signalling cascades and induces factors associated with the pathogenesis of RA at concentrations found in patients with RA, and its expression is higher in patients with radiographic damage and RA progression.

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Section: Discussionmentioning

confidence: 99%

14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage

et al. 2014

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“…In this regard, the LR for moderate to high disease categorization based on CDAI increased from 20.5 to 37.6 when 14-3-3η was added to CRP. Although in this study we specifically evaluated 14-3-3η in RA, in other diseases it has been reported that elevated expression of other 14-3-3 isoforms is associated with more severe disease or worse outcomes, including but not limited to cancer and Creutzfeldt-Jakob disease [ 18 – 26 ].…”

Section: Discussionmentioning

confidence: 99%

Serum 14-3-3η level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab

Hirata¹,

Marotta²,

Gui³

et al. 2015

Arthritis Res Ther

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IntroductionTreat-to-target strategies to achieve low disease activity or clinical remission are key in the treatment of rheumatoid arthritis (RA). 14-3-3η is a joint-derived biomarker that is expressed at significantly higher levels in patients with RA than in healthy subjects, other autoimmune diseases, or viral and bacterial arthritides. In this study, we sought to investigate the utility of pretreatment levels of 14-3-3η and serial measurement of 14-3-3η to inform therapeutic outcomes.MethodsSerum 14-3-3η levels were measured in 149 Japanese patients with RA before the initiation of therapy and at 1-year follow-up. Patients were treated with either methotrexate (MTX), adalimumab (ADA), tocilizumab (TCZ), or tofacitinib (TOF). 14-3-3η positivity was defined as ≥0.19 ng/ml and at two times and four times this cutoff. In contingency analysis, we determined the association of 14-3-3η with disease severity. Wilcoxon matched-pairs test was used to evaluate the significance of pre- to post-treatment changes. Mann–Whitney U test was performed for differences between treatment response groups. Fisher’s exact test was used to assess associations of 14-3-3η with a good response defined by European League Against Rheumatism criteria as well as remission defined by the Disease activity Score in 28 joints with erythrocyte sedimentation rate (DAS28-ESR) and the Clinical Disease Activity Index score.Results14-3-3η-positive patients had more severe disease before the initiation of treatment. When combined with C-reactive protein (CRP), 14-3-3η positivity added significantly and incrementally to the identification of patients with high disease activity. 14-3-3η levels were significantly decreased at 1 year and were modifiable across all classes of therapeutics. Patients who reverted to negative 14-3-3η levels had better clinical response than patients who remained positive at 1 year or became positive. Pretreatment 14-3-3η levels informed 1-year DAS28-ESR remission in the TCZ-treated group, in contrast to the ADA, MTX, or TOF groups, while no differences in pretreatment 14-3-3η expression based on clinical response.Conclusions14-3-3η is a modifiable marker in identifying patients with RA in a high disease state. Patients who achieve a negative 14-3-3η status following 1-year of treatment do better clinically with pretreatment 14-3-3η informing response to TCZ.

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“…In CCA specimens, 14-3-3ζ was up-regulated compared to the peritumoral counterpart, and its expression level directly correlated with advanced tumor stage and lymphatic metastasis. Moreover, 14-3-3ζ was reported as an independent negative prognostic factor for overall survival 134–136 . In CCA cells, 14-3-3ζ silencing dramatically impaired motility and invasiveness, while substantially revoking EMT phenotypic traits, even when induced by TGF-β 135,136 .…”

Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 99%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

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The Clinicopathological and Prognostic Impact of 14-3-3 Protein Isoforms Expression in Human Cholangiocarcinoma by Immunohistochemistry

Cited by 18 publications

References 28 publications

14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage

14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage

Serum 14-3-3η level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

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