14 research outputs found
Novel transcript profiling of diffuse alveolar damage induced by hyperoxia exposure in mice: Normalization by glyceraldehyde 3-phosphate dehydrogenase
Under mechanical ventilation with high-inspired oxygen concentration, diffuse
alveolar damage (DAD) was found to take place in some patients. To clarify the
molecular pathophysiology of this condition we investigated the time course of gene
expression changes induced by hyperoxia exposure in mouse lung using real-time
quantitative polymerase chain reaction (real-time qPCR). Our results normalized by
glyceraldehyde 3-phosphate dehydrogenase showed that mRNA levels of cysteine rich
protein 61 (CYR61) and connective tissue growth factor (CTGF) were significantly
up-regulated, while those of surfactant-associated protein C (SFTPC), cytochrome
P450, 2F2 (CYP2F2), Claudin 1, (CLDN1), membrane-associated zonula occludens
protein-1 (ZO-1), lysozyme (LYZS), and P lysozyme structural (LZP-S) were
significantly down-regulated. Increasing level of mRNAs, each encoding CYR61 and
CTGF, suggests a serious risk of fibrosing alveolitis. Decrease in levels of mRNAs for
SFTPC, CYP2F2, CLDN1, ZO-1, LYZS, and LZP-S suggests alveolar dysfunction
and disruption of the immune system. Moreover we confirmed apoptotic conditions,
such as significant up-regulations of mRNA levels in Myc and Galectin-3. Hyperoxic
condition probably yielded reactive oxygen species (ROS), which resulted in a malignant cycle of ROS production by Myc overexpression
Epstein–Barr virus RNA confers resistance to interferon-α-induced apoptosis in Burkitt’s lymphoma
We investigated whether Epstein–Barr virus (EBV) infection could counteract the antitumor effect of interferon (IFN)-α. EBV-negative subclones isolated from EBV-positive Burkitt’s lymphoma (BL) cell lines Akata, Daudi and Mutu were found to fall into apoptosis after IFN-α treatment. On the other hand, EBV-positive counterparts exhibited striking resistance against IFN-α-induced apoptosis. Transfection of an individual EBV latent gene into EBV-negative BL cells revealed that EBV-encoded poly(A)(–) RNAs (EBERs) were responsible for IFN resistance. EBERs bound double-stranded (ds) RNA-activated protein kinase (PKR), a key mediator of the antiviral effect of IFN-α, and inhibited its phosphorylation. Transfection of dominant-negative PKR, which was catalytically inactive and could block phosphorylation of endogenous PKR, made EBV-negative BL cells resistant to IFN-α-induced apoptosis. Furthermore, EBERs did not bind mutant PKR, which was catalytically active but lacked dsRNA-binding activity, nor did they inhibit its phosphorylation. These results indicate that EBERs confer resistance to IFN-α-induced apoptosis via binding to PKR and inhibition of its phosphorylation. This is the first report that the virus counteracts IFN-induced apoptosis in virus-associated tumors
Estrogen/GPR30 Signaling Contributes to the Malignant Potentials of ER-Negative Cervical Adenocarcinoma via Regulation of Claudin-1 Expression
Cervical adenocarcinomas are believed to lose estrogen response on the basis of no expression of a nuclear estrogen receptor such as ERα in clinical pathology. Here, we demonstrated that cervical adenocarcinoma cells respond to a physiological concentration of estrogen to upregulate claudin-1, a cell surface molecule highly expressed in cervical adenocarcinomas. Knockout of claudin-1 induced apoptosis and significantly inhibited proliferation, migration, and invasion of cervical adenocarcinoma cells and tumorigenicity in vivo. Importantly, all of the cervical adenocarcinoma cell lines examined expressed a membrane-bound type estrogen receptor, G protein–coupled receptor 30 (GPR30/GPER1), but not ERα. Estrogen-dependent induction of claudin-1 expression was mediated by GPR30 via ERK and/or Akt signaling. In surgical specimens, there was a positive correlation between claudin-1 expression and GPR30 expression. Double high expression of claudin-1 and GPR30 predicts poor prognosis in patients with cervical adenocarcinomas. Mechanism-based targeting of estrogen/GPR30 signaling and claudin-1 may be effective for cervical adenocarcinoma therapy
Prognostic significance of the co-expression of EGFR and HER2 in adenocarcinoma of the uterine cervix.
Prognostic factors and therapeutic targets are needed for the patients with cervical adenocarcinoma because they have a poor prognosis. Recently, co-expression of multiple receptor tyrosine kinases (RTKs) has been found to be associated with aggressive biological behavior and poor prognosis of several types of malignancy. To evaluate the significance of the expression of multiple RTKs in uterine cervical cancers, we examined the expression profile of RTKs (EGFR, HER2 and c-Met) and the correlation of their expression with clinicopathological features and prognosis of patients with cervical adenocarcinomas. AIS and adenocarcinoma showed strong expression of a single RTK (EGFR, HER2 or c-Met) on the cell membrane in 41 (77.4%) of 53 cases. Twenty (46%) of the 43 adenocarcinoma cases were positive for double or triple RTKs (P = 0.034). Positivity for EGFR and double positivity for EGFR and HER2 (EGFR+/HER2+/c-Met+ and EGFR+/HER2+/c-Met-) were significantly correlated with lymph node metastasis (P = 0.010 for single and P = 0.013 for double) and UICC stage (P = 0.021 for single and P = 0.007 for double). Positivity for HER2 was significantly correlated with tumor size (P = 0.029). Relapse-free survival (RFS) was significantly shorter in patients who were double positive for EGFR and HER2. Our results suggest that EGFR and HER2 are potential therapeutic targets and that their co-expression is a prognostic factor for cervical adenocarcinoma
Elevated expression of G protein-coupled receptor 30 (GPR30) is associated with poor prognosis in patients with uterine cervical adenocarcinoma
Uterine cervical adenocarcinoma has a worse
prognosis than that of squamous cell carcinoma and
useful diagnostic and prognostic markers are needed.
Estrogen is one of the key regulators of several cancers,
however, the estrogen signaling has not been focused on
in cervical adenocarcinoma. Here, we shows expression
profile of classical estrogen receptor (ER) and a novel
membrane type estrogen receptor, G protein-coupled
receptor 30 (GPR30), in surgical specimens (n=53).
GPR30 was strongly expressed on the cell membrane
and in the cytoplasm in adenocarcinoma in situ (AIS)
and adenocarcinoma, and its expression was especially
strong at the invasion front in most of the cases of
GPR30-positive adenocarcinoma. Nuclear staining of
ER was strong in non-neoplastic glands, whereas it was
almost absent in most of the AIS and adenocarcinoma
cases. There was a weak but statistically significant
negative correlation between immunoreactivity of
GPR30 and that of ER in cervical AIS and
adenocarcinoma lesions (Spearman’s correlation, r=-
0.324, p=0.017). ROC curve analysis revealed that
immunoreactivity of GPR30 successfully distinguished
neoplasms from non-neoplastic glands with high
specificity (100%) and sensitivity (75.5%). GPR30
positivity was significantly correlated with histological
type (p=0.009), tumor diameter (p=0.003), tumor size
(p<0.001), lymphovascular infiltration (p=0.005) and
UICC stage (p<0.001). ER expression was correlated
only with tumor factor (p=0.047). GPR30-high patients
had poor prognosis with a significantly shorter overall
survival (OS) period (p=0.0309). GPR30 expression is a
potential diagnostic and prognostic marker
Analysis of the expression and localization of tight junction transmembrane proteins, claudin-1, -4, -7, occludin and JAM-A, in human cervical adenocarcinoma
Objective. Tight junction proteins have
recently been reported to be useful for distinguishing
between neoplastic and non-neoplastic tissues. In this
study, we evaluated the expression and localization of
tight junction transmembrane proteins in human cervical
adenocarcinoma and adenocarcinoma in situ (AIS), and
we determined whether their expression patterns could
distinguish cervical adenocarcinoma from nonneoplastic cervical glands. Methods. Fifty-five patients
with cervical adenocarcinoma or AIS were included in
this study. Surgical specimens were immunohistochemically stained for claudin (CLDN) -1, -4, -7,
occludin, and JAM-A. Results. Significantly higher
expression levels of CLDNs and JAM-A were found in
cervical AIS and adenocarcinoma than in non-neoplastic
glands. In cervical AIS and adenocarcinoma, localization
of CLDN-1 and JAM-A was extended throughout the
whole cell membranes, whereas they were
predominantly expressed at the most apical cell-cell
junction in non-neoplastic glands. ROC curve analysis
revealed that immunoreactivities of CLDN-1 or JAM-A
successfully distinguished neoplasms from nonneoplastic cervical glands with high specificity (CLDN1, 79.1%; JAM-A, 79.1%) and high sensitivity (CLDN1, 84.1%; JAM-A, 95.5%). Conclusions. As expected,
there were immunohistochemical differences between
cervical adenocarcinoma and non-neoplastic cervical
glands by using antibodies against tight junction
transmembrane proteins. These results suggest that
CLDN-1 and JAM-A are potential biomarkers for
cervical adenocarcinoma
Novel transcript profiling of diffuse alveolar damage induced by hyperoxia exposure in mice: Normalization by glyceraldehyde 3-phosphate dehydrogenase
Immunoreactive intensity of RTKs in cervical adenocarcinomas.
<p>Immunoreactive intensity of RTKs in cervical adenocarcinomas.</p
Expression profiles of receptor tyrosine kinases in cervical adenocarcinoma.
<p>One (10%) of the 10 AIS cases exhibited a multiple simultaneous positive status. In adenocarcinoma, 20 cases (46%, n = 43) exhibited multiple simultaneous positive status. The percentage of cases with positive expression of multiple RTKs was significantly higher in adenocarcinoma than in AIS (Fig 2, chi-square test, p = 0.034).</p
Analyses of correlation between expression of multiple RTKs and clinicopathological features.
<p>Analyses of correlation between expression of multiple RTKs and clinicopathological features.</p