Search tips
Search criteria

Results 1-25 (1338378)

Clipboard (0)

Related Articles

1.  Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer 
AIM: To investigate the expression of mitogen-activated protein kinases (MAPKs) and its upstream protein kinase in human gastric cancer and to evaluate the relationship between protein levels and clinicopathological parameters.
METHODS: Western blot was used to measure the expression of extracellular signal-regulated kinase (ERK)-1, ERK-2, ERK-3, p38 and mitogen or ERK activated protein kinaseMEK-1 proteins in surgically resected gastric carcinoma, adjacent normal mucosa and metastatic lymph nodes from 42 patients. Immunohistochemistry was employed for their localization.
RESULTS: Compared with normal tissues, the protein levels of ERK-1 (integral optical density value 159526±65760 vs 122807±65515, P = 0.001), ERK-2 (168471±95051 vs 120469±72874, P<0.001), ERK-3 (118651±71513 vs 70934±68058, P<0.001), P38 (104776±51650 vs 82930±40392, P = 0.048) and MEK-1 (116486±45725 vs 101434±49387, P = 0.027) were increased in gastric cancer tissues. Overexpression of ERK-3 was correlated to TNM staging [average ratio of integral optic density (IOD)tumor: IODnormal in TNM I, II, III, IV tumors was 1.43±0.34, 5.08±3.74, 4.99±1.08, 1.44±1.02, n = 42, P = 0.023] and serosa invasion (4.31±4.34 vs 2.00±2.03, P = 0.037). In poorly differentiated cancers (n = 33), the protein levels of ERK-1 and ERK-2 in stage III and IV tumors were higher than those in stage I and II tumors (2.64±3.01 vs 1.01±0.33, P = 0.022; 2.05±1.54 vs 1.24±0.40, P = 0.030). Gastric cancer tissues with either lymph node involvement (2.49±2.91 vs 1.03±0.36, P = 0.023; 1.98±1.49 vs 1.24±0.44, P = 0.036) or serosa invasion (2.39±2.82 vs 1.01±0.35, P = 0.022; 1.95±1.44 vs 1.14±0.36, P = 0.015) expressed higher protein levels of ERK-1 and ERK-2. In Borrmann II tumors, expression of ERK-2 and ERK-3 was increased compared with Borrmann III tumors (2.57±1.86 vs 1.23±0.60, P = 0.022; 5.50±5.05 vs 1.83±1.21, P = 0.014). Borrmann IV tumors expressed higher p38 protein levels. No statistically significant difference in expression of MAPKs was found when stratified to tumor size or histological grade (P>0.05). Protein levels of ERK-2, ERK-3 and MEK-1 in metastatic lymph nodes were 2-7 folds higher than those in adjacent normal mucosa. The immunohistochemistry demonstrated that ERK-1, ERK-2, ERK-3, p38 and MEK-1 proteins were mainly localized in cytoplasm. The expression of MEK-1 in gastric cancer cells metastasized to lymph nodes was higher than that of the primary site.
CONCLUSION: MAPKs, particularly ERK subclass are overexpressed in the majority of gastric cancers. Overexpression of ERKs is correlated to TNM staging, serosa invasion, and lymph node involvement. The overexpression of p38 most likely plays a prominent role in certain morphological subtypes of gastric cancers. MEK-1 is also overexpressed in gastric cancer, particularly in metastatic lymph nodes. Upregulation of MAPK signal transduction pathways may play an important role in tumorigenesis and metastatic potential of gastric cancer.
PMCID: PMC4250727  PMID: 15655810
Gastric cancer; Mitogen-activated protein kinase; Extracellular signal-regulated kinase; Signal transduction
2.  The soluble Decoy Receptor 3 is regulated by a PI3K-dependent mechanism and promotes migration and invasion in renal cell carcinoma 
Molecular Cancer  2013;12:120.
Overexpression of Decoy Receptor 3 (DcR3), a soluble member of the tumor necrosis factor receptor superfamily, is a common event in several types of cancer. In renal cell carcinoma (RCC), DcR3 overexpression is associated with lymph node and distant metastasis as well as a poor prognosis. However, the functional role and regulation of DcR3 expression in RCC is so far unknown.
Modulation of DcR3 expression by siRNA and ectopic gene expression, respectively, was performed in ACHN and 769-P RCC cell lines. Functional effects of a modulated DcR3 expression were analyzed with regard to migration, invasion, adhesion, clonogenicity, and proliferation. Furthermore, quantitative RT-PCR and immunoblot analyses were performed to evaluate the expression of downstream mediators of DcR3. In further experiments, luciferase assays, quantitative RT-PCR and immunoblot analyses were applied to study the regulation of DcR3 expression in RCC. Additionally, an ex vivo tissue slice culture technique combined with immunohistochemistry was used to study the regulation of DcR3 expression in human RCC specimens.
Here, we show that DcR3 promotes adhesion, migration and invasiveness of RCC cells. The DcR3-dependent increase in cellular invasiveness is accompanied with an up-regulation of integrin alpha 4, matrixmetalloproteinase 7 and urokinase plasminogen activator (uPA). Further, we identified a signaling pathway regulating DcR3 expression in RCC. Using in vitro experiments as well as an ex vivo RCC tissue slice culture model, we demonstrate that expression of DcR3 is regulated in a PI3K/AKT-dependent manner involving the transcription factor nuclear factor of activated T-cells (NFAT).
Taken together, our results identify DcR3 as a key driver of tumor cell dissemination and suggest DcR3 as a promising target for rational therapy of RCC.
PMCID: PMC3852559  PMID: 24107265
DcR3; Renal cell carcinoma; AKT; NFAT; Metastasis
3.  Significance of decoy receptor 3 in sera of hepatocellular carcinoma patients 
Upsala Journal of Medical Sciences  2010;115(4):232-237.
Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is amplified and over-expressed in various cancers. The objective of the present study was to investigate the concentration of DcR3 in sera of hepatocellular carcinoma (HCC) patients and its clinical significance.
Serum concentrations of DcR3 were measured by enzyme-linked immunosorbent assay (ELISA) in 67 patients with HCC, 8 with liver cirrhosis, 17 with cholecystitis, and in 28 healthy individuals. Immunohistochemistry was employed to access protein expression of DcR3 in the corresponding HCC tissues.
Serum concentrations of DcR3 in patients with HCC or cirrhosis were significantly higher than in healthy individuals (P < 0.01). Moreover, serum concentrations of DcR3 in HCC patients were associated with TNM stage, para-cirrhosis, capsular infiltration, and metastasis or recurrence of disease (P < 0.05). There was a positive correlation between the serum concentration of DcR3 and protein expression in HCC tissues (r = 0.472, P < 0.01).
The high serum concentration of DcR3 might play a certain role in pathogenesis, progress, and metastasis of HCC. Moreover, DcR3 might serve as a valuable molecular indicator in early diagnosis and contribute to predicting the clinical outcome in HCC patients.
PMCID: PMC2971479  PMID: 20977315
Decoy receptor 3 (DcR3); enzyme-linked immunosorbent assay (ELISA); hepatocellular carcinoma (HCC); immunohistochemistry (IHC)
4.  Aberrant expression and function of death receptor-3 and death decoy receptor-3 in human cancer 
Death receptor-3 (DR3) and death decoy receptor-3 (DcR3) are both members of the tumour necrosis factor receptor (TNFR) superfamily. The TNFR superfamily contains eight death domain-containing receptors, including TNFR1 (also called DR1), Fas (also called DR2), DR3, DR4, DR5, DR6, NGFR and EDAR. Upon the binding of these receptors with their corresponding ligands, the death domain recruits various proteins that mediate both the death and proliferation of cells. Receptor function is negatively regulated by decoy receptors (DcR1, DcR2, DcR3 and OPG). DR3/DcR3 are a pair of positive and negative players with which vascular endothelial growth inhibitor (VEGI) interacts. VEGI has been suggested to be a potential tumour suppressor. The inhibitory effects of VEGI on cancer are manifested in three main areas: a direct effect on cancer cells, an anti-angiogenic effect on endothelial cells, and the stimulation of dendritic cell maturation. A recent study indicated that DR3 may be a new receptor for E-selectin, which has been reported to be associated with cancer metastasis. DcR3 is a soluble receptor, highly expressed in various tumours, which lacks an apparent transmembrane segment, prevents cytokine response through ligand binding and neutralization, and is an inhibitor of apoptosis. DcR3 serves as a decoy receptor for FasL, LIGHT and VEGI. The cytokine LIGHT activates various anti-tumour functions and is expected to be a promising candidate for cancer therapy. Certain tumours may escape FasL-dependent immune-cytotoxic attack by expressing DcR3, which blocks FasL function. DR3/DcR3 play profound roles in regulating cell death and proliferation in cancer. The present review briefly discusses DR3/DcR3 and attempts to elucidate the role of these negative and positive players in cancer.
PMCID: PMC3440669  PMID: 22977485
death receptor-3; death decoy receptor-3; cancer
5.  ‘Decoy’ and ‘non-decoy’ functions of DcR3 promote malignant potential in human malignant fibrous histiocytoma cells 
International Journal of Oncology  2013;43(3):703-712.
Decoy receptor 3 (DcR3) is a soluble secreted protein that belongs to the tumor necrosis factor receptor (TNFR) superfamily. DcR3 inhibits the Fas ligand (FasL)/Fas apoptotic pathway by binding to FasL, competitively with Fas receptor. Previous studies have reported that overexpression of DcR3 has been detected in various human malignancies and that DcR3 functions as a ‘decoy’ for FasL to inhibit FasL-induced apoptosis. In addition, recent studies have revealed that DcR3 has ‘non-decoy’ functions to promote tumor cell migration and invasion, suggesting that DcR3 may play important roles in tumor progression by decoy and non-decoy functions. We have previously reported that overexpression of DcR3 was observed in human malignant fibrous histiocytoma (MFH), however, the roles of DcR3 in MFH have not been studied. In the present study, to elucidate the roles of DcR3 in tumor progression of MFH, we examined the effects of DcR3 inhibition on cell apoptosis, migration and invasion in human MFH cells. siRNA knockdown of DcR3 enhanced the FasL-induced apoptotic activity and significantly decreased cell migration and invasion with a decrease in the activation of phosphatidylinositol 3 kinase (PI3K)/Akt and matrix metalloproteinase (MMP)-2. The findings in this study strongly suggest that DcR3 plays important roles in tumor progression of human MFH by decoy as well as non-decoy functions and that DcR3 may serve as a potent therapeutic target for human MFH.
PMCID: PMC3787885  PMID: 23817777
DcR3; apoptosis; migration; invasion; matrix metalloproteinase
6.  Decoy Receptor 3 Is a Prognostic Factor in Renal Cell Cancer12 
Neoplasia (New York, N.Y.)  2008;10(10):1049-1056.
Decoy receptor 3 (DcR3) is a soluble protein that binds to and inactivates the death ligand CD95L. Here, we studied a possible association between DcR3 expression and prognosis in patients with renal cell carcinomas (RCCs).
A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples was generated. Decoy receptor 3 expression in tumors of 560 patients was examined by immunohistochemistry. The effect of DcR3 expression on disease-specific survival and progression-free survival was assessed using univariate analysis and multivariate Cox regression analysis. Decoy receptor 3 serum levels were determined by ELISA.
High DcR3 expression was associated with high-grade (P = .005) and high-stage (P = .048) RCCs. The incidence of distant metastasis (P = .03) and lymph node metastasis (P = .002) was significantly higher in the group with high DcR3 expression. Decoy receptor 3 expression correlated negatively with disease-specific survival (P < .001) and progression-free survival (P < .001) in univariate analyses. A multivariate Cox regression analysis retained DcR3 expression as an independent prognostic factor that outperformed the Karnofsky performance status. In patients with high-stage RCCs expressing DcR3, the 2-year survival probability was 25%, whereas in patients with DcR3-negative tumors, the survival probability was 65% (P < .001). Moreover, DcR3 serum levels were significantly higher in patients with high-stage localized disease (P = .007) and metastatic disease (P = .001).
DcR3 expression is an independent prognostic factor of RCC progression and mortality. Therefore, the assessment of DcR3 expression levels offers valuable prognostic information that could be used to select patients for adjuvant therapy studies.
PMCID: PMC2546583  PMID: 18813347
7.  Decoy receptor 3 (DcR3) overexpression predicts the prognosis and pN2 in pancreatic head carcinoma 
This study was carried out to examine decoy receptor 3 (DcR3) expression and investigate its clinical and prognostic significance in patients with pancreatic head carcinoma.
Tissue samples were obtained from 50 patients with pancreatic head carcinoma. DcR3 protein expression in tissues and sera was assessed by immunohistochemistry and ELISA. Correlations between DcR3 and clinicopathologic features and prognoses were analyzed statistically.
Serum DcR3 levels were significantly elevated in patients with pancreatic head carcinoma compared with patients with cystadenoma and healthy individuals (P < 0.01 and P < 0.01, respectively). DcR3 overexpression correlated with lymph node metastases and TNM stages (P < 0.05 and P < 0.05, respectively). Median overall survival for the high DcR3 group was 16.3 months, compared to 21.6 months for the low DcR3 group (P < 0.05). In the low DcR3 group, no significant difference was found in the overall survival between patients who underwent standard pancreatoduodenectomy (SPD) and those who had radical pancreatoduodenectomy (RPD) (P > 0.05). In the high DcR3 group, the median overall survival rates were 16.8 months in the RPD group and 13.5 months in the SPD group (P < 0.05).
We found that DcR3 was overexpressed in pancreatic head carcinoma. The patients with high DcR3 levels had higher pN2 stages than those with low DcR3 levels. Detecting serum DcR3 level preoperatively might be an additional approach for evaluating pN2 stage and guiding the range of lymphadenectomy.
PMCID: PMC3946126  PMID: 24597666
DcR3; Lymphadenectomy; Pancreatic head carcinoma; Prognosis
8.  DcR3 and survivin are highly expressed in colorectal carcinoma and closely correlated to its clinicopathologic parameters 
Objective: To investigate the expression of death decoy receptor 3 (DcR3) and survivin in colorectal carcinoma. Methods: Tumor and normal tissues were taken from a total of 100 colorectal carcinoma patients during surgery, and the expression of DcR3 and survivin was examined by immunohistochemistry, Western blotting, and reverse transcription-polymerase chain reaction (RT-PCR) analyses. Results: RT-PCR showed that the expression levels of DcR3 mRNA (0.846±0.242, P<0.01) and survivin mRNA (0.7835±0.2392, P<0.01) in colorectal cancer tissues were significantly higher than those in adjacent normal tissues. Western blotting showed that the expression levels of DcR3 protein (0.795±0.261, P<0.01) and survivin protein (0.6765±0.1351, P<0.01) in tumor tissues were significantly higher than those in non-cancer tissues. The immunohistochemical streptavidin-peroxidase (SP) method showed that the positive expression rates of DcR3 and survivin were 67.0% and 58.0% in colorectal cancer tissues, and 18.0% and 3.0% in non-cancerous colorectal tissues (P<0.05), respectively. The positive correlations of DcR3 (P<0.01) and survivin (P<0.01) to the differentiation of colorectal carcinoma cells, lymph node metastasis, and pathological stage were observed. The expression of DcR3 and survivin was found to be positively correlated to clinicopathologic parameters of colorectal carcinoma. Conclusion: The overexpressed DcR3 and survivin in colorectal cancer may contribute to the development of the cancer. The monitoring of these two proteins may be useful for the diagnosis, differentiation, metastasis, and determination of stages of colorectal carcinoma.
PMCID: PMC2738837  PMID: 19735100
Death decoy receptor 3 (DcR3); Survivin; Colorectal carcinoma
9.  Death decoy receptor overexpression and increased malignancy risk in colorectal cancer 
AIM: To evaluate human epidermal growth factor receptor 2 (HER2) and death decoy receptor (DcR3) as colorectal cancer prognostic indicators.
METHODS: Colorectal carcinoma specimens from 300 patients were analyzed by immunohistochemistry to detect the staining patterns of HER2 and DcR3. Classification of HER2 staining was carried out using the United States Food and Drug Administration semi-quantitative scoring system, with scores of 0 or 1+ indicating a tumor-negative (normal expression) status and scores of 2+ and 3+ indicating a tumor-positive (overexpression) status. Classification of DcR3 was carried out by quantitating the percentage of positive cells within the stained section, with < 10% indicating a tumor-negative status and ≥ 10% indicating a tumor-positive status. Correlation of the HER2 and DcR3 staining status with clinicopathological parameters [age, sex, tumor size, differentiation, and the tumor, node, metastasis (pTNM) classification] and survival was statistically assessed.
RESULTS: Tumor-positive status for HER2 and DcR3 was found in 18.33% and 58.33% of the 300 colorectal carcinoma specimens, respectively. HER2 tumor-positive status showed a significant correlation with tumor size (P = 0.003) but not with other clinicopathological parameters. DcR3 tumor-positive status showed a significant correlation with tumor differentiation (P < 0.001), pTNM stage (P < 0.001), and lymph node metastasis (P < 0.001). However, correlation coefficient analysis did not indicate that a statistically significant correlation exists between tumor-positive status for the HER2 and DcR3 overexpression (P = 0.236). Patients with specimens classified as DcR3-overexpressing had a significantly worse overall survival (OS) rate than those without DcR3 overexpression (median OS: 42.11 vs 61.21 mo; HR = 50.27, 95%CI: 44.90-55.64, P < 0.001). HER2 overexpression had no significant impact on median OS (35.10 mo vs 45.25 mo; HR = 44.40, 95%CI: 39.32-49.48, P = 0.344). However, patients with specimens classified as both HER2- and DcR3-overexpressing had a significantly poorer median OS than those with only HER2 overexpression (31.80 mo vs 52.20 mo; HR = 35.10, 95%CI: 22.04-48.16, P = 0.006).
CONCLUSION: HER2 overexpression is not an independent prognostic marker of colorectal cancer, but DcR3 overexpression is highly correlated with lymph node metastasis and poor OS.
PMCID: PMC3989983  PMID: 24764685
Colorectal carcinoma; Human epidermal growth factor receptor 2; Death decoy receptor; Immunohistochemistry; Prognosis
10.  Overexpression of DcR3 and Its Significance on Tumor Cell Differentiation and Proliferation in Glioma 
The Scientific World Journal  2014;2014:605236.
Background. Overexpression of decoy receptor 3 (DcR3) have been reported in various classes of malignancies. However, its expression and clinicopathological contribution in gliomas has not been fully elucidated. Objective. To explore the expression and clinical significance of DcR3 protein in relation to tumor cell differentiation and proliferation in glioma cell lines and tissues. Methods. One hundred and twenty-five samples of glioma patients and 18 cases of normal brain tissues were recruited. The expression of DcR3 protein was detected using immunohistochemistry. Tumor differentiation was assessed by histologic characters and the status of glial fibrillary acidic protein (GFAP). Tumor cell labeling indexes (LIs) of Ki-67 and PCNA were also obtained. The relationship between the DcR3 level and clinicopathological features was investigated, including tumor differentiation, LIs, and survival. Meanwhile, the expression of DcR3 protein was also measured in the supernatants of 8 glioma cell lines and glioma cells freshly prepared from 8 human glioblastoma specimens by using western blot. Results. The level of DcR3 protein in gliomas was significantly higher than that in normal brain tissues (P < 0.01). DcR3 expression showed positive correlations with tumor pathological grade (r = 0.621, P < 0.01) and negative with GFAP expression (r = −0.489, P < 0.01). Furthermore, there were positive correlations between DcR3 expression and Ki-67, PCNA LIs (r = 0.529, P < 0.01; r = 0.556, P < 0.01). The survival in the DcR3 negative group was 50 ± 1.79 months, longer than that of the DcR3 positive group (48.36 ± 2.90), however, without significance (P = 0.149). Different levels of DcR3 could also be detected in the culturing supernatants of all the 8 glioma cell lines and glioma cells freshly obtained from 8 human glioblastoma specimens. Conclusions. The overexpression of DcR3 might play a crucial role in the tumorigenesis, differentiation, and proliferation of glioma.
PMCID: PMC3972858  PMID: 24741354
11.  Gefitinib-Induced Killing of NSCLC Cell Lines Expressing Mutant EGFR Requires BIM and Can Be Enhanced by BH3 Mimetics 
PLoS Medicine  2007;4(10):e316.
The epidermal growth factor receptor (EGFR) plays a critical role in the control of cellular proliferation, differentiation, and survival. Abnormalities in EGF-EGFR signaling, such as mutations that render the EGFR hyperactive or cause overexpression of the wild-type receptor, have been found in a broad range of cancers, including carcinomas of the lung, breast, and colon. EGFR inhibitors such as gefitinib have proven successful in the treatment of certain cancers, particularly non-small cell lung cancers (NSCLCs) harboring activating mutations within the EGFR gene, but the molecular mechanisms leading to tumor regression remain unknown. Therefore, we wished to delineate these mechanisms.
Methods and Findings
We performed biochemical and genetic studies to investigate the mechanisms by which inhibitors of EGFR tyrosine kinase activity, such as gefitinib, inhibit the growth of human NSCLCs. We found that gefitinib triggered intrinsic (also called “mitochondrial”) apoptosis signaling, involving the activation of BAX and mitochondrial release of cytochrome c, ultimately unleashing the caspase cascade. Gefitinib caused a rapid increase in the level of the proapoptotic BH3-only protein BIM (also called BCL2-like 11) through both transcriptional and post-translational mechanisms. Experiments with pharmacological inhibitors indicated that blockade of MEK–ERK1/2 (mitogen-activated protein kinase kinase–extracellular signal-regulated protein kinase 1/2) signaling, but not blockade of PI3K (phosphatidylinositol 3-kinase), JNK (c-Jun N-terminal kinase or mitogen-activated protein kinase 8), or AKT (protein kinase B), was critical for BIM activation. Using RNA interference, we demonstrated that BIM is essential for gefitinib-induced killing of NSCLC cells. Moreover, we found that gefitinib-induced apoptosis is enhanced by addition of the BH3 mimetic ABT-737.
Inhibitors of the EGFR tyrosine kinase have proven useful in the therapy of certain cancers, in particular NSCLCs possessing activating mutations in the EGFR kinase domain, but the mechanisms of tumor cell killing are still unclear. In this paper, we demonstrate that activation of the proapoptotic BH3-only protein BIM is essential for tumor cell killing and that shutdown of the EGFR–MEK–ERK signaling cascade is critical for BIM activation. Moreover, we demonstrate that addition of a BH3 mimetic significantly enhances killing of NSCLC cells by the EGFR tyrosine kinase inhibitor gefitinib. It appears likely that this approach represents a paradigm shared by many, and perhaps all, oncogenic tyrosine kinases and suggests a powerful new strategy for cancer therapy.
Andreas Strasser and colleagues demonstrate that activation of the proapoptotic BH3-only protein BIM is essential for tumor cell killing and that shutdown of the EGFR−MEK−ERK signaling cascade is critical for BIM activation.
Editors' Summary
Normally, cell division (which produces new cells) and cell death are finely balanced to keep the human body in good working order. But sometimes cells acquire changes (mutations) in their genetic material that allow them to divide uncontrollably to form cancers—life-threatening, disorganized masses of cells. One protein with a critical role in cell division that is often mutated in tumors is the epidermal growth factor receptor (EGFR). In normal cells, protein messengers bind to EGFR and activate its tyrosine kinase. This enzyme then adds phosphate groups to tyrosine (an amino acid) in proteins that form part of signaling cascades (for example, the MEK–ERK signaling cascade) that tell the cell to divide. In cancers that have mutations in EGFR, signaling is overactive so the cancer cells divide much more than they should. Some non-small cell lung cancers (NSCLC, the commonest type of lung cancer), for example, have activating mutations within the EGFR tyrosine kinase. Treatment with EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib induces the cells in these tumors to stop growing and die. This cell death causes tumor shrinkage (regression) and increases the life expectancy of patients with this type of NSCLC.
Why Was This Study Done?
Unfortunately, treatment with TKIs rarely cures NSCLC, so it would be useful to find a way to augment the effect that TKIs have on cancer cells. To do this, the molecular mechanisms that cause cancer-cell death and tumor regression in response to these drugs need to be fully understood. In this study, the researchers have used a combination of biochemical and genetic approaches to investigate how gefitinib kills NSCLC cells with mutated EGFR.
What Did the Researchers Do and Find?
The researchers first measured the sensitivity of NSCLC cell lines (tumor cells that grow indefinitely in dishes) to gefitinib-induced apoptosis. Gefitinib caused extensive apoptosis in two cell lines expressing mutant EGFR but not in one expressing normal EGFR. Next, they investigated the mechanism of gefitinib-induced apoptosis in the most sensitive cell line (H3255). Apoptosis is activated via two major pathways. Hallmarks of the “intrinsic” pathway include activation of a protein called BAX and cytochrome c release from subcellular compartments known as mitochondria. Gefitinib treatment induced both these events in H3255 cells. BAX (a proapoptotic member of the BCL-2 family of proteins) is activated when proapoptotic BH3-only BCL-2 proteins (for example, BIM; “BH3-only” describes the structure of these proteins) bind to antiapoptotic BCL2 proteins. Gefitinib treatment rapidly increased BIM activity in H3255 and HCC827 cells (but not in gefitinib-resistant cells) by increasing the production of BIM protein and the removal of phosphate groups from it, which increases BIM activity. Pharmacological blockade of the MEK–ERK signaling cascade, but not of other EGFR signaling cascades, also caused the accumulation of BIM. By contrast, blocking BIM expression using a technique called RNA interference reduced gefitinib-induced apoptosis. Finally, a combination of gefitinib and a BH3-mimicking compound called ABT-737 (which, like BIM, binds to antiapoptotic BCL-2 proteins) caused more apoptosis than gefitinib alone.
What Do These Findings Mean?
These findings (and those reported by Gong et al. and Costa et al.) indicate that activation of the proapoptotic BH3-only protein BIM is essential for gefitinib-induced killing of NSCLC cells that carry EGFR tyrosine kinase mutations. They also show that inhibition of the EGFR–MEK–ERK signaling cascade by gefitinib is essential for BIM activation. Because these findings come from studies on NSCLC cell lines, they need confirming in freshly isolated tumor cells and in tumors growing in people. However, the demonstration that a compound that mimics BH3 action enhances gefitinib-induced killing of NSCLC cells suggests that combinations of TKIs and drugs that affect the intrinsic pathway of apoptosis activation might provide a powerful strategy for treating cancers in which tyrosine kinase mutations drive tumor growth.
Additional Information.
Please access these Web sites via the online version of this summary at
A perspective by Ingo Mellinghoff discusses this article and two related research articles
Wikipedia pages on epidermal growth factor receptor, apoptosis, and BCL2 proteins (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
CancerQuest provides information on all aspects of cancer from Emory University (in several languages)
US National Cancer Institute information for patients and professionals on lung cancer (in English and Spanish)
Information for patients from Cancer Research UK on lung cancer including information on treatment with TKIs
Information for patients from Cancerbackup on erlotinib and gefitinib
PMCID: PMC2043013  PMID: 17973573
12.  Prognostic value of RKIP and p-ERK in gastric cancer 
The mitogen-activated protein kinase (MAPK) signaling pathway participates in several steps of tumour development and is considered a prominent therapeutic target for the design of chemotherapeutic agents. We evaluated the expressions of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MEK), an upstream regulator of ERK, and Raf kinase inhibitor protein (RKIP), and investigated correlations of these expressions with clinicopathological features and outcomes in gastric cancer.
Tumour samples were obtained from 105 patients with gastric adenocarcinomas who underwent radical gastrectomy. The expressions of phosphorylated ERK (p-ERK), phosphorylated MEK (p-MEK), and RKIP were analysed by immunohistochemical staining.
Expression of RKIP, p-MEK, and p-ERK was found in 69 (66%), 54 (51%), and 64 (61%) of all tumours, respectively. RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and Union for International Cancer Control (UICC) stage (p = 0.007). RKIP expression was associated with significantly longer relapse-free survival (RFS) (p = 0.0033), whereas p-MEK was not (p = 0.79). Patients with p-ERK expression had slightly, but not significantly shorter RFS than those without such expression (p = 0.054). Patients with positive p-ERK and negative RKIP expression had significantly shorter RFS than the other patients (p < 0.001). The combination of RKIP and p-ERK expression was an independent prognostic factor (hazard ratio, 2.4; 95% confidence interval, 1.3 - 4.6; p = 0.008).
Our results demonstrated that loss of RKIP was associated with tumour progression and poor survival. Negative RKIP expression combined with positive p-ERK expression was an independent predictor of poor outcomes in patients with gastric cancer.
PMCID: PMC3351370  PMID: 22463874
13.  Significance of elevated ERK expression and its positive correlation with EGFR in Kazakh patients with esophageal squamous cell carcinoma 
Extracellular signal-regulated kinases (ERKs) are activated by the MAPK pathway. ERKs are downstream effectors of the epidermal growth factor receptor (EGFR), which belongs to the receptor tyrosine kinases family. Studies on the activation of the EGFR-ERK pathway in Kazakh patients with esophageal squamous cell carcinoma (ESCC) have not been reported. Using immunohistochemical staining on tissue microarrays, we investigated the protein expression of EGFR and ERK in 90 ethnic Kazakh patients with ESCC and 48 adjacent normal esophageal tissues (NETs). EGFR and ERK1 expression was localized in the cytoplasm, whereas ERK2 expression was localized in the nucleus. Both were more highly expression in the ESCC tissues than in the NETs, and the difference was considered significant (P = 0.003, 0.002, and 0.005, respectively). ERK1 and EGFR expression was positively correlated with lymph nodes metastasis (P = 0.011 and 0.013, respectively). ERK1 staining was also significantly associated with tumor-node-metastases stage of ESCC (P = 0.044). ERK2 staining was significantly associated with Histological grade (P = 0.012). Furthermore, ERK1 and EGFR expression in the ESCC tissues were positively correlated (r = 0.413, P < 0.001); EGFR was more highly expressed in the ESCC tissues with high ERK1 expression than in the ESCC tissues with low ERK1 expression (4.95 ± 0.57 vs. 3.21 ± 0.35, P = 0.01). This study is thus far the first to demonstrate the correlation between EGFR overexpression and ERK overexpression in Kazakh patients with ESCC. This correlation suggests that the EGFR-ERK signaling pathway participates in ESCC progression and can thus be used as a prognostic marker.
PMCID: PMC4069965  PMID: 24966948
Esophageal squamous cell carcinoma; Kazakh; epidermal growth factor receptor; extracellular signal-regulated kinase
14.  MMP-2 and DcR3 expression in esophageal cancer tissue and correlation with patient survival 
Objective: This study aims to explore the expression of decoy receptor 3 (DcR3) and the matrix metalloproteinase-2 (MMP-2) in esophageal carcinoma and their relationship with patient survival. Methods: The EnVisionTM immunohistochemistry method was used to examine DcR3 and MMP-2 expression in 150 surgical biopsies of esophageal carcinoma. Expression level was compared with clinical indices and with patient survival. Results: In cancer tissues, the positive expression rate of DcR3 and MMP-2 was 54.00% and 54.67% respectively; this was higher than levels in adjacent normal tissue. DcR3 and MMP-2 were positively correlated with carcinoma size, lymphatic metastasis, invasion degree, clinical stage and 3-year survival. DcR3 and MMP-2 were not correlated with gender, age and tumor degree of differentiation. DcR3 and MMP-2 were positively correlated between in the two groups (r = 0.37, P < 0.01). Kaplan-Meier survival curve showed that higher rates of DcR3 and MMP-2 expression correlated with lower survival. Conclusions: Determining DcR3 and MMP-2 expression may be useful for the diagnosis, treatment and prognosis of patients with esophageal carcinoma.
PMCID: PMC3762627  PMID: 24040480
Esophageal cancer; matrix metalloproteinase-2; decoy receptor
15.  High ERK Protein Expression Levels Correlate with Shorter Survival in Triple-Negative Breast Cancer Patients 
The Oncologist  2012;17(6):766-774.
The clinical significance of extracellular signal–related kinase (ERK) was assessed in patients with triple-negative breast cancer versus patients with non–triple negative breast cancer. High ERK-2 levels were correlated with a lower overall survival rate and high phosphorylated mitogen-activated protein kinase levels were correlated with a higher relapse-free survival rate in triple-negative breast cancer patients.
The mitogen-activated protein kinase (MAPK) signaling pathway is known to be activated in triple-negative breast cancer (TNBC). Extracellular signal–related kinase (ERK), a member of the MAPK pathway, promotes cell proliferation, angiogenesis, cell differentiation, and cell survival. To assess the prognostic impact of ERK in TNBC patients, relative quantities of ERK (ERK-2 and pMAPK) and direct targets of the ERK pathway (MAPK/ERK kinase 1, phospho-enriched protein in astrocytes [PEA]-15, phosphorylated (p)PEA-15, tuberous sclerosis protein 2, p70S6 kinase, and p27) were measured using reverse-phase protein arrays in tumor tissue from patients with TNBC (n = 97) and non-TNBC (n = 223). Protein levels in patients with TNBC were correlated with clinical and tumor characteristics and outcome. The median age of patients with TNBC was 55 years (range, 27–86 years). Disease stage was I in 21%, II in 60%, and III in 20% of the patients. In a multivariate analysis, among patients with TNBC, those with ERK-2–overexpressing tumors had a lower overall survival rate than those with low ERK-2–expressing tumors (hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.19–6.41). However, high pMAPK levels were associated with a significantly higher relapse-free survival rate (HR, 0.66; 95% CI, 0.46–0.95). In conclusion, ERK-2 and pMAPK are valuable prognostic markers in TNBC. Further studies are justified to elucidate ERK's role in TNBC tumorigenicity and metastasis.
PMCID: PMC3380875  PMID: 22584435
Triple-negative breast cancer; ERK; Survival; PEA-15; RPPA
16.  ERK1/2 and MEK1/2 Induced by Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Early during Infection of Target Cells Are Essential for Expression of Viral Genes and for Establishment of Infection 
Journal of Virology  2005;79(16):10308-10329.
Kaposi's sarcoma-associated herpesvirus (KSHV) in vitro target cell infection is characterized by the expression of the latency-associated genes ORF 73 (LANA-1), ORF 72, and K13 and by the transient expression of a very limited number of lytic genes such as lytic cycle switch gene ORF 50 (RTA) and the immediate early (IE) lytic K5, K8, and v-IRF2 genes. During the early stages of infection, several overlapping multistep complex events precede the initiation of viral gene expression. KSHV envelope glycoprotein gB induces the FAK-Src-PI3K-RhoGTPase (where FAK is focal adhesion kinase) signaling pathway. As early as 5 min postinfection (p.i.), KSHV induced the extracellular signal-regulated kinase 1 and 2 (ERK1/2) via the PI3K-PKCζ-MEK pathway. In addition, KSHV modulated the transcription of several host genes of primary human dermal microvascular endothelial cells (HMVEC-d) and fibroblast (HFF) cells by 2 h and 4 h p.i. Neutralization of virus entry and infection by PI-3K and other cellular tyrosine kinase inhibitors suggested a critical role for signaling molecules in KSHV infection of target cells. Here we investigated the induction of ERK1/2 by KSHV and KSHV envelope glycoproteins gB and gpK8.1A and the role of induced ERK in viral and host gene expression. Early during infection, significant ERK1/2 induction was observed even with low multiplicity of infection of live and UV-inactivated KSHV in serum-starved cells as well as in the presence of serum. Entry of UV-inactivated virus and the absence of viral gene expression suggested that ERK1/2 induction is mediated by the initial signal cascade induced by KSHV binding and entry. Purified soluble gpK8.1A induced the MEK1/2 dependent ERK1/2 but not ERK5 and p38 mitogen-activated protein kinase (MAPK) in HMVEC-d and HFF. Moderate ERK induction with soluble gB was seen only in HMVEC-d. Preincubation of gpK8.1A with heparin or anti-gpK8.1A antibodies inhibited the ERK induction. U0126, a selective inhibitor for MEK/ERK blocked the gpK8.1A- and KSHV-induced ERK activation. ERK1/2 inhibition did not block viral DNA internalization and had no significant effect on nuclear delivery of KSHV DNA during de novo infection. Analyses of viral gene expression by quantitative real-time reverse transciptase PCR revealed that pretreatment of cells with U0126 for 1 h and during the 2-h infection with KSHV significantly inhibited the expression of ORF 73, ORF 50 (RTA), and the IE-K8 and v-IRF2 genes. However, the expression of lytic IE-K5 gene was not affected significantly. Expression of ORF 73 in BCBL-1 cells was also significantly inhibited by preincubation with U0126. Inhibition of ERK1/2 also inhibited the transcription of some of the vital host genes such as DUSP5 (dual specificity phosphatase 5), ICAM-1 (intercellular adhesion molecule 1), heparin binding epidermal growth factor, and vascular endothelial growth factor that were up-regulated early during KSHV infection. Several MAPK-regulated host transcription factors such as c-Jun, STAT1α, MEF2, c-Myc, ATF-2 and c-Fos were induced early during infection, and ERK inhibition significantly blocked the c-Fos, c-Jun, c-Myc, and STAT1α activation in the infected cells. AP1 transcription factors binding to the RTA promoter in electrophoretic mobility shift assays were readily detected in the infected cell nuclear extracts which were significantly reduced by ERK inhibition. Together, these results suggest that very early during de novo infection, KSHV induces the ERK1/2 to modulate the initiation of viral gene expression and host cell genes, which further supports our hypothesis that beside the conduit for viral DNA delivery into the cytoplasm, KSHV interactions with host cell receptor(s) create an appropriate intracellular environment facilitating infection.
PMCID: PMC1182676  PMID: 16051824
17.  Membrane expression of TRAIL receptors DR4, DR5, DcR1 and DcR2 in the normal endometrium, atypical endometrial hyperplasia and endometrioid adenocarcinoma: a tissue microarray study 
To evaluate the membrane expression of DR4, DR5, DcR1 and DcR2 in the normal endometrium (NE), atypical endometrial hyperplasia (AEH) and endometrioid adenocarcinoma (EAC).
The study comprised 197 patients: 20 NE, 18 AEH and 159 EAC. Tissue microarrays were constructed. Membrane expression of DR4, DR5, DcR1 and DcR2 was examined and presented as total score (TS).
In EAC, the membrane expression of DR4, DR5 and DcR2 was less common compared to NE (p < 0.001; p < 0.001; p = 0.018) and AEH (p < 0.001; p < 0.001; p = 0.004). In EAC the membrane expression of DcR1 did not differ when compared to NE (p = 0.055) and AEH (p = 0.173). A strong correlation was found between the type of endometrial tissue (NE/AEH/EAC) and the TS of DR4 (p < 0.001), DR5 (p < 0.001), DcR1 (p = 0.033) and DcR2 (p < 0.001). In EAC, the TS of DR4, DR5, DcR1 and DcR2 was not related to grading and staging. In EAC, the membrane expression of DR5, but not DR4, DcR1 and DcR2, was related to better disease-free survival (DFS). The overall survival (OS) was not related to membrane TRAIL receptors expression.
The membrane expression of the receptors for TRAIL DR4, DR5, DcR1 and DcR2 is greater in NE than EAC. The level of membrane staining of the receptors in EAC is not dependent on grading and staging. In EAC patients, membrane expression of DR4, DR5, DcR1 and DcR2 are not independent predictors of survival.
PMCID: PMC3778234  PMID: 23584885
Tissue microarray; TRAIL receptors; Normal endometrium; Atypical endometrial hyperplasia; Endometrial adenocarcinoma
18.  Differential Inhibition of TRAIL-Mediated DR5-DISC Formation by Decoy Receptors 1 and 2 
Molecular and Cellular Biology  2006;26(19):7046-7055.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that induces cancer cell death by apoptosis with some selectivity. TRAIL-induced apoptosis is mediated by the transmembrane receptors death receptor 4 (DR4) (also known as TRAIL-R1) and DR5 (TRAIL-R2). TRAIL can also bind decoy receptor 1 (DcR1) (TRAIL-R3) and DcR2 (TRAIL-R4) that fail to induce apoptosis since they lack and have a truncated cytoplasmic death domain, respectively. In addition, DcR1 and DcR2 inhibit DR4- and DR5-mediated, TRAIL-induced apoptosis and we demonstrate here that this occurs through distinct mechanisms. While DcR1 prevents the assembly of the death-inducing signaling complex (DISC) by titrating TRAIL within lipid rafts, DcR2 is corecruited with DR5 within the DISC, where it inhibits initiator caspase activation. In addition, DcR2 prevents DR4 recruitment within the DR5 DISC. The specificity of DcR1- and DcR2-mediated TRAIL inhibition reveals an additional level of complexity for the regulation of TRAIL signaling.
PMCID: PMC1592888  PMID: 16980609
19.  Significance of increased expression of decoy receptor 3 in chronic liver disease 
Digestive and Liver Disease  2009;41(8):591-598.
Considerable evidence has indicated that apoptosis plays an important role in hepatocyte death in chronic liver disease. However, the cellular and molecular mechanisms underlying liver regeneration in the disease are largely unknown. Plausibly, certain molecules expressed to counteract apoptosis might provide survival advantage of certain liver cells. Therefore, we investigated a possible expression of decoy receptor 3 (DcR3) of the tumor necrosis factor (TNF) receptor family in chronic liver diseases since DcR3 is known to inhibit apoptosis mediated by pro-apoptotic TNF family ligands including FasL.
A series of liver biopsies from patients with different stages of fibrosis were subjected to immunohistochemistry and in situ hybridization.
Both DcR3 protein and mRNA were mainly expressed in biliary epithelial cells and infiltrating lymphocytes in the diseased livers. Most noticeably, intense DcR3 expression was observed in newly developing biliary ductules in regenerative nodules as well as dysplastic nodules of cirrhotic livers. In addition, DcR3 secretion in hepatocellular carcinoma (HCC) cells in culture was via the activation of mitogen-activated protein kinases.
DcR3 was specifically expressed in chronic liver diseases and HCC cells, and DcR3 might facilitate the survival of liver cells by exerting its anti-apoptotic activity during the progression of liver cirrhosis and hepatocarcinogenesis.
PMCID: PMC3305787  PMID: 19195939
Apoptosis; FasL; cirrhosis; HCC; HPC
20.  Epstein-Barr Virus Transcription Activator Rta Upregulates Decoy Receptor 3 Expression by Binding to Its Promoter▿  
Journal of Virology  2007;81(9):4837-4847.
Decoy receptor 3 (DcR3) is a soluble decoy receptor belonging to the tumor necrosis factor receptor superfamily that is overexpressed in various malignant tumor types. DcR3 has been implicated in tumor cell survival by inhibiting apoptosis and by interfering with immune surveillance. A previous study showed that DcR3 expression is associated with Epstein-Barr virus (EBV)-positive lymphomas but rarely with non-EBV-positive B-cell lymphomas, suggesting that the presence of EBV may affect DcR3 expression. Here, we demonstrated enhanced DcR3 expression upon EBV reactivation in P3HR1 cells and in EBV-infected 293 cells. This enhancement, however, could not be detected in 293 cells infected with EBV with BRLF1 deleted. We found that EBV transactivator, Rta, could upregulate DcR3 expression by direct binding to an Rta-responsive element (RRE) located in the DcR3 promoter region and that this RRE is important for Rta-mediated DcR3 expression. Overexpressing CREB-binding protein (CBP) further enhanced Rta-dependent DcR3 expression, suggesting Rta-dependent DcR3 transcription activity is mediated by CBP. Previously, Rta was shown to enhance phosphatidylinositol-3 kinase (PI3-K) activity. However, Rta-transduced PI 3-K activity plays a minor role in DcR3 expression. This is the first report to demonstrate that Rta upregulates a cellular gene by direct binding to an RRE.
PMCID: PMC1900157  PMID: 17301127
21.  Decoy Strategies: The Structure of TL1A:DcR3 complex 
Decoy Receptor 3 (DcR3), a secreted member of the Tumor Necrosis Factor (TNF) receptor superfamily, neutralizes three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands engages unique signaling receptors which direct distinct and critical immune responses. We report the crystal structures of the unliganded DcR3 ectodomain and its complex with TL1A, as well as complementary mutagenesis and biochemical studies. These analyses demonstrate that DcR3 interacts with invariant backbone and side chain atoms in the membrane-proximal half of TL1A which supports recognition of its three distinct TNF ligands. Additional features serve as anti-determinants that preclude interaction with other members of the TNF superfamily. This mode of interaction is unique among characterized TNF:TNFR family members and provides a mechanistic basis for the broadened specificity required to support the decoy function of DcR3, as well as for the rational manipulation of specificity and affinity of DcR3 and its ligands.
PMCID: PMC3065972  PMID: 21300286
22.  Synbindin in Extracellular Signal-Regulated Protein Kinase Spatial Regulation and Gastric Cancer Aggressiveness 
The molecular mechanisms that control the aggressiveness of gastric cancer (GC) remain poorly defined. Here we show that synbindin contributes to the aggressiveness of GC by activating extracellular signal-regulated protein kinase (ERK) signaling on the Golgi apparatus.
Expression of synbindin was examined in normal gastric mucosa (n = 44), intestinal metaplastic gastric mucosa (n = 66), and GC tissues (n=52), and the biological effects of synbindin on tumor growth and ERK signaling were detected in cultured cells, nude mice, and human tissue samples. The interaction between synbindin and mitogen-activated protein kinase kinase (MEK1)/ERK was determined by immunofluorescence and fluorescence resonance energy transfer assays. The transactivation of synbindin by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was detected using luciferase reporter assay and chromatin immunoprecipitation.
High expression of synbindin was associated with larger tumor size (120.8 vs 44.8cm3; P = .01), advanced tumor node metastasis (TNM) stage (P = .003), and shorter patient survival (hazard ratio = 1.51; 95% confidence interval [CI] = 1.01 to 2.27; P = .046). Synbindin promotes cell proliferation and invasion by activating ERK2 on the Golgi apparatus, and synbindin is directly transactivated by NF-κB. Synbindin expression level was statistically significantly higher in human GCs with activated ERK2 than those with low ERK2 activity (intensity score of 11.5, 95% CI = 10.4 to 12.4 vs intensity score of 4.6, 95% CI 3.9 to 5.3; P < .001). Targeting synbindin in xenograft tumors decreased ERK2 phosphorylation and statistically significantly reduced tumor volume (451.2mm3, 95% CI = 328.3 to 574.1 vs 726.1mm3, 95% CI = 544.2 to 908.2; P = .01).
Synbindin contributes to malignant phenotypes of GC by activating ERK on the Golgi, and synbindin is a potential biomarker and therapeutic target for GC.
PMCID: PMC4042874  PMID: 24104608
23.  DcR3 binds to ovarian cancer via heparan sulfate proteoglycans and modulates tumor cells response to platinum with corresponding alteration in the expression of BRCA1 
BMC Cancer  2012;12:176.
Overcoming platinum resistance is a major obstacle in the treatment of Epithelial Ovarian Cancer (EOC). In our previous work Decoy Receptor 3 (DcR3) was found to be related to platinum resistance. The major objective of this work was to define the cellular interaction of DcR3 with EOC and to explore its effects on platinum responsiveness.
We studied cell lines and primary cultures for the expression of and the cells ability to bind DcR3. Cells were cultured with DcR3 and then exposed to platinum. Cell viability was determined by MTT assay. Finally, the cells molecular response to DcR3 was studied using real time RT-PCR based differential expression arrays, standard RT-PCR, and Western blot.
High DcR3 in the peritoneal cavity of women with EOC is associated with significantly shorter time to first recurrence after platinum based therapy (p = 0.02). None-malignant cells contribute DcR3 in the peritoneal cavity. The cell lines studied do not secrete DcR3; however they all bind exogenous DcR3 to their surface implying that they can be effected by DcR3 from other sources. DcR3s protein binding partners are minimally expressed or negative, however, all cells expressed the DcR3 binding Heparan Sulfate Proteoglycans (HSPGs) Syndecans-2, and CD44v3. DcR3 binding was inhibited by heparin and heparinase. After DcR3 exposure both SKOV-3 and OVCAR-3 became more resistant to platinum with 15% more cells surviving at high doses. On the contrary CaOV3 became more sensitive to platinum with 20–25% more cell death. PCR array analysis showed increase expression of BRCA1 mRNA in SKOV-3 and OVCAR-3 and decreased BRCA1 expression in CaOV-3 after exposure to DcR3. This was confirmed by gene specific real time PCR and Western blot analysis.
Non-malignant cells contribute to the high levels of DcR3 in ovarian cancer. DcR3 binds readily to EOC cells via HSPGs and alter their responsiveness to platinum chemotherapy. The paradoxical responses seen were related to the expression pattern of HSPGs available on the cells surface to interact with. Although the mechanism behind this is not completely known alterations in DNA repair pathways including the expression of BRCA1 appear to be involved.
PMCID: PMC3462721  PMID: 22583667
24.  OCT1 is a determinant of synbindin-related ERK signalling with independent prognostic significance in gastric cancer 
Gut  2014;64(1):37-48.
Octamer transcription factor 1 (OCT1) was found to be expressed in intestinal metaplasia and gastric cancer (GC), but the exact roles of OCT1 in GC remain unclear. The objective of this study was to determine the functional and prognostic implications of OCT1 in GC.
Expression of OCT1 was examined in paired normal and cancerous gastric tissues and the prognostic significance of OCT1 was analysed by univariate and multivariate survival analyses. The functions of OCT1 on synbindin expression and extracellular signal-regulated kinase (ERK) phosphorylation were studied in vitro and in xenograft mouse models.
The OCT1 gene is recurrently amplified and upregulated in GC. OCT1 overexpression and amplification are associated with poor survival in patients with GC and the prognostic significance was confirmed by independent patient cohorts. Combining OCT1 overexpression with American Joint Committee on Cancer staging improved the prediction of survival in patients with GC. High expression of OCT1 associates with activation of the ERK mitogen-activated protein kinase signalling pathway in GC tissues. OCT1 functions by transactivating synbindin, which binds to ERK DEF domain and facilitates ERK phosphorylation by MEK. OCT1-synbindin signalling results in the activation of ERK substrates ELK1 and RSK, leading to increased cell proliferation and invasion. Immunofluorescent study of human GC tissue samples revealed strong association between OCT1 protein level and synbindin expression/ERK phosphorylation. Upregulation of OCT1 in mouse xenograft models induced synbindin expression and ERK activation, leading to accelerated tumour growth in vivo.
OCT1 is a driver of synbindin-mediated ERK signalling and a promising marker for the prognosis and molecular subtyping of GC.
PMCID: PMC4283676  PMID: 24717932
Gastric Cancer; Cancer Genetics; Signal Transduction; Cell Proliferation; Cell Migration
25.  Repression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not its receptors during oral cancer progression 
BMC Cancer  2007;7:108.
TRAIL plays an important role in host immunosurveillance against tumor progression, as it induces apoptosis of tumor cells but not normal cells, and thus has great therapeutic potential for cancer treatment. TRAIL binds to two cell-death-inducing (DR4 and DR5) and two decoy (DcR1, and DcR2) receptors. Here, we compare the expression levels of TRAIL and its receptors in normal oral mucosa (NOM), oral premalignancies (OPM), and primary and metastatic oral squamous cell carcinomas (OSCC) in order to characterize the changes in their expression patterns during OSCC initiation and progression.
DNA microarray, immunoblotting and immunohistochemical analyses were used to examine the expression levels of TRAIL and its receptors in oral epithelial cell lines and in archival tissues of NOM, OPM, primary and metastatic OSCC. Apoptotic rates of tumor cells and tumor-infiltrating lymphocytes (TIL) in OSCC specimens were determined by cleaved caspase 3 immunohistochemistry.
Normal oral epithelia constitutively expressed TRAIL, but expression was progressively lost in OPM and OSCC. Reduction in DcR2 expression levels was noted frequently in OPM and OSCC compared to respective patient-matched uninvolved oral mucosa. OSCC frequently expressed DR4, DR5 and DcR1 but less frequently DcR2. Expression levels of DR4, DR5 and DcR1 receptors were not significantly altered in OPM, primary OSCC and metastatic OSCC compared to patient-matched normal oral mucosa. Expression of proapoptotic TRAIL-receptors DR4 and DR5 in OSCC seemed to depend, at least in part, on whether or not these receptors were expressed in their parental oral epithelia. High DR5 expression in primary OSCC correlated significantly with larger tumor size. There was no significant association between TRAIL-R expression and OSSC histology grade, nodal status or apoptosis rates of tumor cells and TIL.
Loss of TRAIL expression is an early event during oral carcinogenesis and may be involved in dysregulation of apoptosis and contribute to the molecular carcinogenesis of OSCC. Differential expressions of TRAIL receptors in OSCC do not appear to play a crucial role in their apoptotic rate or metastatic progression.
PMCID: PMC1924860  PMID: 17592646

Results 1-25 (1338378)