14-3-3σ is a tumor suppressor gene induced by p53 in response to DNA damage and reportedly associated with resistance to chemotherapy. The aim of this study was to investigate whether 14-3-3σ expression is also associated with resistance to neoadjuvant chemotherapy consisting of paclitaxel followed by 5-FU/epirubicin/cyclophosphamide (P-FEC) in human breast cancer patients. A total of 123 primary breast cancer patients treated with neoadjuvant chemotherapy (P-FEC) were included in this study. Immunohistochemistry of 14-3-3σ and p53 as well as direct sequencing of TP53 were performed using the tumor biopsy samples obtained prior to neoadjuvant chemotherapy. Thirty-eight of the tumors (31%) were positive for 14-3-3σ. There was no significant association between 14-3-3σ expression and TP53 mutation or p53 expression. However, 14-3-3σ expression showed a significantly (P=0.009) negative association with pathological complete response (pCR) to P-FEC, and multivariate analysis demonstrated that only 14-3-3σ (P=0.015) and estrogen receptor (P=0.021) were significantly and independently associated with pCR. The combination of 14-3-3σ expression and TP53 mutation status had an additive negative effect on pCR, i.e., pCR rates were 45.5% for 14-3-3σ negative/TP53 mutant tumors, 24.6% for 14-3-3σ negative/TP53 wild tumors, 23.1% for 14-3-3σ positive/TP53 mutant tumors, and 0% for 14-3-3σ positive/TP53 wild tumors. These results demonstrate that 14-3-3σ expression is significantly associated with resistance to P-FEC and this association is independent of other biological markers. The combination of 14-3-3σ expression and TP53 mutation status has an additively negative effect on the response to P-FEC.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate whether 14-3-3eta, a specific isoform of a family of proteins regulating processes such as cellular signaling, activates cell-signaling pathways and induces factors known to contribute to the pathophysiology of rheumatoid arthritis (RA). We also investigated whether 14-3-3eta is associated with more severe disease in both early and established RA.
We investigated the effect of 14-3-3eta on the activation of RA-relevant signaling cascades and induction of pro-inflammatory mediators that contribute to the joint damage process. 14-3-3eta titres were measured in serum from 33 patients with early RA (mean duration 1.8 months) and 40 patients with established RA from the 3-year time point of the Behandel Strategieen (BeSt) cohort. The relationship between 14-3-3eta titres and standard clinical variables was investigated by correlation analysis. The association with radiographic damage and radiographic progression over at least two years was investigated using univariate and multivariate regression analyses.
14-3-3eta activated selective members of the mitogen-activated protein kinase (MAPK) family, mainly extracellular regulated kinase (ERK) 1/2 and c-jun kinase (JNK) but not p38MAPK. Activation by 14-3-3eta, using levels spanning the concentration range found in RA patient serum, resulted in the induction of inflammatory transcripts such as IL-1 and IL-6 and factors linked to the joint damage process, such as receptor activator of nuclear factor kappa-B ligand (RANKL) and matrix metalloproteinase-1 (MMP-1). Serum 14-3-3eta correlated significantly with rheumatoid factor (RF) (r=0.43) and anti-citrullinated protein antibodies, (ACPA) (r=0.31) in only the early RA cohort but not with C-reactive protein (CRP) or Disease Activity Score 28 in either cohort. Serum 14-3-3eta concentrations were significantly higher in patients with radiographically assessed joint damage and in those who had radiographic progression. Through multivariate analysis, 14-3-3eta was shown to complement markers such as CRP, RF, and ACPA in informing radiographic status and/or progression.
Extracellular 14-3-3eta activates key signaling 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 who demonstrate progression.
[Show abstract][Hide abstract] ABSTRACT: 14-3-3 proteins participate in various cellular processes, including apoptosis, proliferation and malignant transformation. 14-3-3σ, a member of the 14-3-3 protein family, is important in several types of cancer; however, little is known about the clinical significance and biological roles of 14-3-3σ in gastric cancer. The present study analyzed the expression pattern of 14-3-3σ in gastric cancer and investigated its correlation with the prognosis of gastric cancer patients. Furthermore, the association of 14-3-3σ with Ki-67, Bcl-2 and Bax was evaluated. 14-3-3σ was expressed at higher level in gastric cancer tissue compared with healthy gastric tissue, and 14-3-3σ expression was significantly correlated with tumor size and tumor node metastasis stage (P<0.05). To the best of our knowledge, the present study data are the first to suggest that 14-3-3σ expression has been significantly associated with poor prognosis in gastric cancer. Additionally, 14-3-3σ overexpression was positively correlated with Ki-67 and Bcl-2 expression levels. Thus, 14-3-3σ is a potential prognostic marker for gastric cancer patients, and may be involved in regulating the apoptosis and proliferation of gastric cancer cells.
Maddalena Barba, Laura Pizzuti, Isabella Sperduti, Clara Natoli, Teresa Gamucci, Domenico Sergi, Luigi Di Lauro, Luca Moscetti, Fiorentino Izzo, Massimo Rinaldi, [...], Angela Vaccaro, Laura Iezzi, Antonino Grassadonia, Andrea Michelotti, Letizia Perracchio, Edoardo Pescarmona, Franco Di Filippo, Antonio Giordano, Marcello Maugeri-Saccà, Patrizia Vici
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