Increased Expression of Specific Thioredoxin Family Proteins; A Pilot Immunohistochemical Study on Human Hepatocellular Carcinoma

Cunnea, Paula; Fernandes, AP; Capitanio, Arrigo; Eken, Servet; Spyrou, Giannis; Björnstedt, Mikael

doi:10.1177/039463200702000103

Cited by 16 publications

(12 citation statements)

References 23 publications

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“…The up-regulation of TRX as well as the down-regulation of GSTA1 emerging from DIGE experiment and validated by Western blot analysis can reflect a disregulation of the cellular redox status which is balanced by the endogeneous thiols buffer system mainly from glutathione and TRX sources (19). Remarkably, high expression of TRX as evaluated by immunohistochemistry in HCC biopsies was recently reported (20). Moreover, higher serum levels of TRX were found in patients with HCC as compared with patients with chronic hepatitis or liver cirrhosis (21).…”

Section: Discussionmentioning

confidence: 91%

Differential proteomic analysis of hepatocellular carcinoma

Corona¹,

Lorenzo²,

Elia³

et al. 2009

Int J Oncol

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Abstract. The principal aim of the present study consisted in the identification of the disregulated proteins associated with the development of hepatocellular carcinoma (HCC). The differences in protein expression between hepatocellular carcinoma (HCC) and the corresponding non-HCC liver tissues were investigated in a cohort of 20 patients using twodimensional fluorescence difference in gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS). The upand down-regulated protein spots that exhibited 1.5-fold difference signal intensity with statistical significance (p<0.05, t-test, confidence intervals 95%) were excised from the gel and identified by peptide mass fingerprinting using matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Thirty-six protein spots corresponding to 29 different disregulated proteins, belonging to heterogeneous metabolic pathways, have been identified. Down-regulated proteins (n=23) were found superior in number than the up-regulated proteins (n=6). Detoxification, carbohydrate metabolism and amino acid biotrasformation represented the main disregulated pathways in HCC. Upregulation of aldo-keto reductase 1C2, thioredoxin and transketolase, involved in metabolic and regulatory cellular processes including proliferation, differentiation and carcinogenesis were remarkable. These proteins could represent useful biomarkers to provide new insights into global pathophysiologic changes of HCC and for the development of new pharmacological approaches to HCC therapy.

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Section: Discussionmentioning

confidence: 91%

Differential proteomic analysis of hepatocellular carcinoma

Corona¹,

Lorenzo²,

Elia³

et al. 2009

Int J Oncol

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“…Trx-1 acts as an antioxidant, growth-promoting, antiapo ptotic and inflammationmodulating protein that provides reduc- ing equivalents and a transcriptional regulator (23). Trx-1 expression was reported to be increased in several human cancers, including lung (24,25), liver (26), pancreatic (27), colorectal (28,29) and gastric carcinoma (30). Increased trx-1 levels are associated with increased proliferation of tumor cells, inhibition of apoptosis, aggressive tumor growth and decreased patient survival (23).…”

Section: Discussionmentioning

confidence: 99%

Targeting S100P Inhibits Colon Cancer Growth and Metastasis by Lentivirus-Mediated RNA Interference and Proteomic Analysis

Jiang

Lai

Zhang

et al. 2011

Mol Med

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S100P was recently found to be overexpressed in a variety of cancers and is considered a potential target for cancer therapy, but the functional role or mechanism of action of S100P in colon cancer is not fully understood. In the present study, we knocked down the gene expression of S100P in colon cancer cells using lentivirus-mediated RNA interference. This step resulted in significant inhibition of cancer cell growth, migration and invasion in vitro and tumor growth and liver metastasis in vivo. Moreover, S100P downstream target proteins were identified by proteomic analysis in colon cancer DLD-1 cells with deletion of S100P. Knockdown of S100P led to downregulation of thioredoxin 1 and β-tubulin and upregulation of Rho guanosine diphosphate (GDP) dissociation inhibitor α (RhoGDIA), all potential therapeutic targets in cancer. Taken together, these findings suggest that S100P plays an important role in colon tumorigenesis and metastasis, and the comprehensive and comparative analyses of proteins associated with S100P could contribute to understanding the downstream signal cascade of S100P, leading to tumorigenesis and metastasis.

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“…The lysates were subjected to SDS-PAGE, transferred onto nitrocellulose membrane, and probed with the following antibodies: anti-eIF2␣ and phosphorylated eIF2␣ (Cell Signaling); anti-PERK, anti-phosphorylated PERK, anti-CADD34, CHOP/GADD153, and ATF4 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA); anti-BiP/GRP78 (Transduction Laboratories); and anti-actin-␤ (Sigma). The ERdj5 antibody used in this study was produced as described previously (23). In summary, two peptides sequences of 14 amino acids were selected from within the ERdj5 human sequence (positions 102-116 (APVKYHG-DRSKESLVC and 640 -654, FYERAKRNFQEEQIN) for peptide synthesis and immunization.…”

Section: Methodsmentioning

confidence: 99%

“…ERdj5 has recently been reported to have reductase activity, cleave the disulfide bonds of misfolded proteins, and accelerate their ERassociated degradation through its physical and functional associations with EDEM (ER degradation-enhancing mannosidase-like protein) and BiP (22). As in the case of the heat shock proteins Hsp70, Hsp27, and BiP as well as in the other members of the thioredoxin system that are overexpressed in many cancers, ERdj5 exhibits elevated expression levels in tumor tissue from human hepatocellular carcinoma (HCC) patients, suggesting a role for this protein in the ER stress response in tumors (23)(24)(25)(26). The aim of this study was to examine whether ERdj5, through regulating the UPR, could alter cancer cell resistance to ER stress.…”

mentioning

confidence: 99%

ERdj5 Sensitizes Neuroblastoma Cells to Endoplasmic Reticulum Stress-induced Apoptosis

Thomas

Spyrou

2009

Journal of Biological Chemistry

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Down-regulation of the unfolded protein response (UPR) can be therapeutically valuable in cancer treatment, and endoplasmic reticulum (ER)-resident chaperone proteins may thus be targets for developing novel chemotherapeutic strategies. ERdj5 is a novel ER chaperone that regulates the ER-associated degradation of misfolded proteins through its associations with EDEM and the ER stress sensor BiP. To investigate whether ERdj5 can regulate ER stress signaling pathways, we exposed neuroblastoma cells overexpressing ERdj5 to ER stress inducers. ERdj5 promoted apoptosis in tunicamycin, thapsigargin, and bortezomib-treated cells. To provide further evidence that ERdj5 induces ER stress-regulated apoptosis, we targeted Bcl-2 to ER of ERdj5-overexpressing cells. Targeting the Bcl-2 to ER prevented the apoptosis induced by ER stress inducers but not by non-ER stress apoptotic stimuli, suggesting induction of ER stress-regulated apoptosis by ERdj5. ERdj5 enhanced apoptosis by abolishing the ER stress-induced phosphorylation of eukaryotic translation initiation factor 2␣ (eIF2␣) and the subsequent translational repression. ERdj5 was found to inhibit the eIF2␣ phosphorylation under ER stress through inactivating the pancreatic endoplasmic reticulum kinase. The compromised integrated stress response observed in ERdj5-overexpressing ERstressed cells due to repressed eIF2␣ phosphorylation correlated with impaired neuroblastoma cell resistance under ER stress. These results demonstrate that ERdj5 decreases neuroblastoma cell survival by down-regulating the UPR, raising the possibility that this protein could be a target for anti-tumor approaches.Accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER), 2 a condition that produces ER stress, induces an intracellular signaling cascade named the unfolded protein response (UPR) (1, 2). The UPR relieves ER stress by inducing protein folding and degradation pathways and inhibiting protein synthesis (1). Upon ER stress, dissociation of the ER chaperone GRP78/BiP from the pancreatic endoplasmic reticulum kinase (PERK) activates PERK. Once activated, PERK phosphorylates the translation initiation factor eIF2␣, leading to inhibition of general protein translation (3). In addition to attenuating global protein synthesis, eIF2␣ phosphorylation promotes a stress-induced gene expression program. During the integrated stress response (ISR), specific mRNAs escape the translational repression, and the synthesis of transcription factors, such as ATF4, activates genes (CHOP and BiP) that promote stress resistance and cell survival (4 -6). ATF4 controls also the expression of GADD34, a subunit of the PP1-holophosphatase complex that dephosphorylates eIF2␣ promoting recovery from the translational inhibition during the UPR (7). Activation of the UPR can result in restoration of ER homeostasis; however, both persistent ER stress and failure of the adaptive response initiate ER-dependent apoptotic cascades (8).Although the UPR protects the cells from normal variations that occu...

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Increased Expression of Specific Thioredoxin Family Proteins; A Pilot Immunohistochemical Study on Human Hepatocellular Carcinoma

Cited by 16 publications

References 23 publications

Differential proteomic analysis of hepatocellular carcinoma

Differential proteomic analysis of hepatocellular carcinoma

Targeting S100P Inhibits Colon Cancer Growth and Metastasis by Lentivirus-Mediated RNA Interference and Proteomic Analysis

ERdj5 Sensitizes Neuroblastoma Cells to Endoplasmic Reticulum Stress-induced Apoptosis

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