12 research outputs found
The Prognostic Value of 14-3-3 Isoforms in Vulvar Squamous Cell Carcinoma Cases: 14-3-3β and ε Are Independent Prognostic Factors for These Tumors
BACKGROUND: The 14-3-3 family is comprised of highly conserved proteins that are functionally important in the maintenance of homeostasis. Their involvement with the cell cycle, their association with proto-oncogenes and oncogenes, and their abnormal expression in various tumors has linked this family of proteins to the etiology of human cancer. Mounting evidence now indicates that 14-3-3σ is a cancer suppressor gene but the roles of the other 14-3-3 isoforms and their interactions in tumorigenesis have not yet been elucidated. In our current study, we examined the expression of 14-3-3β, γ, ε, ζ, η and τ in a large series of vulvar squamous cell carcinomas to evaluate any clinical significance. METHODS: Tumor biopsies from 298 vulvar carcinomas were examined by immunohistochemistry for the expression of 14-3-3β, γ, ε, ζ, η and τ. Statistical analyses were employed to validate any associations between the expression of any 14-3-3 isoform and clinicopathologic variables for this disease. RESULTS: High cytoplasmic levels of 14-3-3β, γ, ζ, ε and η were observed in 79%, 58%, 50%, 86% and 54% of the vulvar carcinomas analyzed, respectively, whereas a low nuclear expression of 14-3-3τ was present in 80% of these cases. The elevated cytoplasmic expression of 14-3-3β, γ, ε, ζ and η was further found to be associated with advanced disease and aggressive features of these cancers. The overexpression of cytoplasmic 14-3-3β and ε significantly correlated with a poor disease-specific survival by univariate analysis (P = 0.007 and P = 0.04, respectively). The independent prognostic significance of these factors was confirmed by multivariate analysis (P = 0.007 and P = 0.009, respectively). CONCLUSIONS: We reveal for the first time that the 14-3-3β, γ, ε, ζ, η and τ isoforms may be involved in the progression of vulvar carcinomas. Furthermore, our analyses show that high cytoplasmic levels of 14-3-3β and ε independently correlate with poor disease-specific survival
Expression and regulation of type 2A protein phosphatases and alpha4 signalling in cardiac health and hypertrophy
Abstract Cardiac physiology and hypertrophy are regulated
by the phosphorylation status of many proteins, which
is partly controlled by a poorly defined type 2A protein
phosphatase-alpha4 intracellular signalling axis. Quantitative
PCR analysis revealed that mRNA levels of the type
2A catalytic subunits were differentially expressed in H9c2
cardiomyocytes (PP2ACb[PP2ACa[PP4C[PP6C),
NRVM (PP2ACb[PP2ACa = PP4C = PP6C), and
adult rat ventricular myocytes (PP2ACa[
PP2ACb[PP6C[PP4C). Western analysis confirmed
that all type 2A catalytic subunits were expressed in H9c2
cardiomyocytes; however, PP4C protein was absent in
adult myocytes and only detectable following 26S proteasome
inhibition. Short-term knockdown of alpha4 protein
expression attenuated expression of all type 2A catalytic
subunits. Pressure overload-induced left ventricular (LV)
hypertrophy was associated with an increase in both
PP2AC and alpha4 protein expression. Although PP6C
expression was unchanged, expression of PP6C regulatory
subunits (1) Sit4-associated protein 1 (SAP1) and (2)
ankyrin repeat domain (ANKRD) 28 and 44 proteins was
elevated, whereas SAP2 expression was reduced in
hypertrophied LV tissue. Co-immunoprecipitation studies
demonstrated that the interaction between alpha4 and
PP2AC or PP6C subunits was either unchanged or reduced
in hypertrophied LV tissue, respectively. Phosphorylation
status of phospholemman (Ser63 and Ser68) was significantly
increased by knockdown of PP2ACa, PP2ACb, or
PP4C protein expression. DNA damage assessed by histone
H2A.X phosphorylation (cH2A.X) in hypertrophied tissue
remained unchanged. However, exposure of cardiomyocytes
to H2O2 increased levels of cH2A.X which was
unaffected by knockdown of PP6C expression, but was
abolished by the short-term knockdown of alpha4 expression.
This study illustrates the significance and altered
activity of the type 2A protein phosphatase-alpha4 complex
in healthy and hypertrophied myocardium
Prognostic value of comorbidity for auto-SCT eligibility and outcome in relapsed or refractory aggressive non-Hodgkin's lymphoma
Salvage reinduction therapy followed by high-dose chemotherapy (HDCT) and auto-SCT is the treatment of choice for fit patients with refractory or relapsed aggressive non-Hodgkin's lymphoma (NHL). We assessed the prognostic value of comorbidity at the time of relapse to predict receipt of auto-SCT and outcome. We analyzed 156 consecutive NHL patients, referred to our center between 1999 and 2007 for salvage reinduction therapy, followed by HDCT and auto-SCT. Comorbidity according to the hematopoietic SCT comorbidity index was scored at relapse and directly before HDCT and auto-SCT. Primary end points were actual receipt of auto-SCT and survival. At relapse, comorbidity scores of 0, 1-2 and >/=3 were found among 64 (41%), 62 (40%) and 30 (19%) patients, respectively. Ultimately, 95 patients received auto-SCT. Higher comorbidity scores at relapse were associated with significantly less chance of receiving auto-SCT and with inferior OS, independently from secondary age-adjusted International Prognostic Index (sAAIPI) scores. For transplanted patients, OS rates at 5 years were 62, 30 and 17% for relapse comorbidity scores of 0, 1-2 and >/=3, respectively. In patients with relapsed NHL, comorbidity at relapse is associated with receipt of auto-SCT and subsequent survival independently from the sAAIPI.Bone Marrow Transplantation advance online publication, 23 August 2010; doi:10.1038/bmt.2010.188