Signaling Pathway Blog

αB-Crystallin (Cryab), a member of the mammalian small heat shock protein (sHsp) superfamily, functions as a cytoprotective molecular chaperone by preventing stress-induced aggregation of denatured proteins and keeping aggregation-prone proteins in reservoirs of nonnative, refoldable intermediates within large, soluble, multimeric structures.2 The expression of Cryab in a temporally and spatially controlled fashion during development has led to the speculation that this sHsp may have important roles in the regulation of cellular physiology and growth.3 Indeed, ectopic expression

of Cryab in diverse cell types has been demonstrated to confer protection against a broad range of apoptotic stimuli, including tumor necrosis factor alpha (TNF-α), TNF-related Saracatinib order apoptosis-inducing ligand,4 oxidative stress,5 and exposure to anticancer drugs,6 while silencing Cryab expression by RNA interference (RNAi) sensitizes cells to apoptosis.7 Elevated expression of Cryab has been linked to cancer pathology.8 For example, Cryab overexpression has been clinically detected in a variety of human malignancies and is associated with poor prognosis for several different types of tumors, including renal, breast, hepatoma,

selleck chemicals and lung cancer.9-12 However, the mechanism remains unclear. Given the significant role of Cryab in tumor progression of human cancers, further investigation into the role and mechanism of Cryab in HCC is needed. Most HCC deaths are due to metastasis, a multistep process that mediates the spread of tumor cells from primary tumors to distant sites.13 Although the molecular and genetic events BCKDHA underlying tumor metastasis are still not well understood, intense investigation into this process has led to the notion that molecules involved in epithelial-mesenchymal transition (EMT)

are critical in tumor invasion and metastasis.14 On the other hand, recent studies have shown that a multikinase inhibitor, sorafenib, can inhibit serine/threonine kinases (c-RAF, and mutant and wildtype BRAF) and be used as a “gold” treatment for advanced HCC patients.15 However, the efficiency of sorafenib remains unstable. An investigation to discriminate patients with sorafenib treatment into discrete prognostic groups is lacking. Here, functional and genetic screens demonstrated that Cryab overexpression fosters tumor progression in HCC by inducing EMT by way of activation of extracellular-regulated protein kinase (ERK) signaling, which is subsequently shown to mediate this EMT and sorafenib resistance. Overexpression of αB-Crystallin in HCC cells induces EMT progression through an ERK1/2/Fra-1/slug signaling pathway. Remarkably, these studies demonstrated that Cryab complexes with and elevates 14-3-3ζ protein, leading to up-regulation of ERK1/2 activity. Moreover, high levels of Cryab are associated with impaired sorafenib response with respect to overall survival (OS).

We further found that

estrogen receptor alpha (ERα) could up-regulate PTPRO expression as a transcription factor. Moreover, an in vitro study showed that cell proliferation was inhibited and apoptosis was promoted in PTPRO-transduced HCC cell lines, whereas an in vivo study represented that tumor number and size was increased in ptpro−/− mice. As a result of its tumor-suppressive position, PTPRO was proved to down-regulate signal transducers and activators of transcription (STAT3) activity dependent on Janus kinase 2 (JAK2) and phosphoinositide 3-kinase (PI3K) dephosphorylation. Conclusions: PTPRO expression results in pathological deficiency and gender bias in HCC, which could be attributed to ERα regulation. The suppressive role of PTPRO in HCC could be ascribed Talazoparib datasheet to STAT3 inactivation. (HEPATOLOGY 2013)

Protein tyrosine phosphatase receptor type O (PTPRO), one of the receptor types of phosphotyrosine phosphatases (PTP), was initially discovered in human renal glomerulus.1 It contains six isoforms; the full-length type is expressed in kidney, brain, lung, liver, and breast, whereas the truncated types are expressed in macrophages and B lymphocytes.2 PTPRO is a transmembrane protein; its intracellular region contains a PTP domain that catalyzes the dephosphorylation of tyrosine peptides. This critical function of PTPs is involved in numerous intracellular signaling events that selleck serve various biological behaviors, such as cell proliferation, differentiation, apoptosis, and so forth.3, 4 Recently, an accumulation of evidence has enriched the understanding of cancer biology, and it has been observed that PTPRO exhibits important

aspects concerning tumor suppression. Initially, it was discovered that overexpression of PTPRO enhances apoptosis of the terminally differentiated leukemic cell line, U937, in the presence of 12-O-tetradecanoylphorbol-13-acetate.5 Subsequently, the PTPRO level was shown to be statistically weakened; the promoter region of the gene, ptpro, is frequently methylated in human chronic leukemia, lung cancer, breast cancer, hepatocellular carcinoma (HCC), and so forth.6-10 In support of the role of PTPRO as a tumor suppressor, it was 3-oxoacyl-(acyl-carrier-protein) reductase demonstrated that PTPRO could inhibit cell proliferation in lung cancer cell line A549.8 Additionally, it has been revealed that PTPRO expression can be suppressed by estrogen receptor β (ERβ) in breast cancer. Using an in vitro study, it was demonstrated that ERβ, conjugated with 17β-estradiol (E2), functions at the AP-1 (activator protein 1) site located in the promoter region of ptpro, giving rise to the separation of c-jun and c-fos from AP-1 and leading to the inhibition of ptpro transcription.9 Human HCC, one of the most malignant cancers in the world, is closely associated with a history of chronic hepatitis caused by hepatitis B or C virus (HBV or HCV).11, 12 The global incidence of clinical HCC exhibits a striking gender disparity and occurs much more frequently in male patients.

After determination of total protein by the Lowry assay, 10% polyacrylamide gels were equiloaded with samples, electrophoresed at 90 V, electrotransferred to PVDF membranes, and probed with primary mouse monoclonal antibodies for HMGB-1 or glutathione (Abcam, Cambridge, UK). Secondary goat antimouse horseradish peroxidase (HRP) was used (1:4,000). Blots were developed by ECL (Thermo Scientific, Asheville, NC). Total GSH from whole liver homogenates was measured using the Glutathione Assay Kit

(Cayman Chemicals, Ann Arbor, MI) according to the manufacturer’s protocol. For PCR assays, RNA was isolated from pancreas using a Qiagen RNEasy isolation kit (Qiagen, Germantown, MD). http://www.selleckchem.com/products/VX-809.html qPCR was performed using a standardized preconfigured PCR array (SA Biosciences, Frederick, MD) on the Stratagene MX3000P

(Promega, Madison, WI) according to the respective manufacturers’ protocols. (See Additional Supporting Methods.) To evaluate a possible role for DC in either exacerbating or protecting against APAP toxicity, we employed CD11c.DTR mice in which transient DC depletion can be effected (Supporting Fig. 1). Mice were depleted of DC or mock-depleted and then challenged with APAP. At 12 hours mice were sacrificed and the extent of liver injury determined by histopathology. Mice treated with APAP and depleted of DC (APAP-DC) had markedly more extensive INK 128 clinical trial centrilobular necrosis compared with controls (Fig. 1A,B). Consistent with these findings, serum liver enzymes were highly elevated in APAP-DC mice (Fig. 1C). Similarly, NPC production of inflammatory mediators after APAP challenge, including MCP-1 and IL-6, were higher in mice depleted of DC (Fig. 1D). DC depletion alone, in the absence of APAP challenge, had no effect (Fig. 1A-D). Similarly, effects of APAP were similar in both CD11c.DTR and WT mice, in the absence of Phosphoprotein phosphatase DC depletion (not shown). Notably, APAP metabolism appeared unchanged in APAP-DC mice compared with APAP treatment

alone based on tissue glutathione assay and glutathione adduct formation (Supporting Fig. 2A,B). To determine if there was higher systemic toxicity in APAP-challenged mice after DC depletion, we measured serum levels of inflammatory mediators. We found that serum MCP-1, IL-6, and TNF-α were elevated in APAP-DC mice (Fig. 1E,F). However, as expected, organ damage was limited to the liver, as the lungs, kidneys, pancreas, and intestine were histologically normal (Supporting Fig. 3). To determine whether DC depletion resulted in higher APAP-mediated mortality, mice were treated with APAP and depleted of DC or mock-depleted and then observed for up to 2 weeks. Remarkably, approximately half of APAP-DC mice died within 48 hours of challenge, whereas death was rare in control animals (Fig. 2). There was no further mortality observed in APAP-DC mice after 48 hours from the time of APAP challenge.

S7). However, SND1 inhibition (either by pdTp or by siRNA) did not affect increased Matrigel invasion activity conferred by AEG-1 (data not shown), indicating that SND1 primarily plays a role in regulating cell growth and proliferation. The observation that inhibition of SND1 can significantly inhibit cell growth and viability prompted us to probe deeper into SND1 involvement in HCC. At first we examined the SND1 expression

pattern by immunohistochemistry in tissue microarrays containing 86 primary HCC, 23 metastatic HCC, and 9 normal adjacent liver samples. SND1 expression was detected predominantly selleck inhibitor in the cytoplasm (Fig. 6C). None of the normal liver and HCC samples stained negative for SND1 (Fig. 6C, Table 1). However, compared to normal liver there was a significant increase in SND1 expression in 81 out of 109 HCC patients (≈74%). SND1 expression gradually increased with the stages of the disease based on the Barcelona Liver Clinic

Cancer (BCLC) staging system that showed significant statistical correlation (Table 1). We next checked the consequence of stable overexpression of SND1 see more in Hep3B and stable knockdown of SND1 in QGY-7703 human HCCs in the contexts of cell growth and tumorigenicity. Compared to the control neomycin-resistant cells (Hep3B-Con), Hep3B-SND1-17 clones had significant augmentation in cell growth and proliferation as observed by standard MTT and colony-forming assays (Fig. 7A,B, respectively). On the contrary, the QGY-SND1si-12 clone showed significantly slower cell growth and proliferation compared to QGY-Consi clone stably expressing control scrambled siRNA (Fig. 7A,B). In the in vivo nude mice xenograft assay,

the Hep3B-SND1-17 clone formed significantly larger subcutaneous tumors compared to the Hep3B-Con clone (Fig. 7C-E). As a corollary, the QGY-Consi clone formed significantly larger tumor compared to the QGY-SND1si-12 clone (Fig. 7C-E). Similar findings were observed in additional SND1-overexpressing clones of Hep3B cells and SND1-knockdown clones of QGY-7703 cells (Supporting Information Fig. S8). Nuclear SND1 functions as a transcriptional coactivator and helps in pre-mRNA splicing and AEG-1 also modulates transcription.6, Histone demethylase 7, 14, 19 However, we did not detect colocalization of AEG-1 and SND1 in the nucleus and we documented that AEG-1 interacts with SND1 in the cytoplasm, facilitating RISC activity. Cells lacking fragile X mental retardation protein, another component of RISC, have normal RISC activity,16 further supporting the contribution of AEG-1 in maintaining optimum RISC function. More important, we demonstrate that both AEG-1 and SND1 are overexpressed in HCC compared to normal liver, and human HCC cells exhibit higher RISC activity compared to normal immortal hepatocytes.

At the time of recurrence, four of seven patients showed re-infection by H. pylori. Eradication therapy was successful in these patients, resulting in both bacterial eradication and tumor regression. Three patients who experienced histologic recurrence without H. pylori re-infection were observed Smad inhibitor by a watch and wait strategy and again achieved CR. Conclusions:  None of the patients with H. pylori-positive

stage IE1 gastric MALT lymphoma who experienced tumor recurrence after CR with successful H. pylori eradication showed recurrence at extragastric sites, including lymph nodes without gastric mucosal lesion. These findings click here indicate that endoscopic biopsies without abdominal CT scans are sufficient to detect recurrence in these patients. ”
“Progression of extensive gastric premalignant conditions to cancer might warrant surveillance programms. Recent guidelines suggest a 3-yearly endoscopic follow-up for these patients. Our aim was to determine the cost utility of endoscopic surveillance of patients with extensive gastric premalignant conditions such as extensive atrophy or intestinal metaplasia. A cost-utility economic analysis was performed from a societal perspective in Portugal

using a Markov model to compare two strategies: surveillance versus no surveillance. Clinical data were collected from a systematic review of the literature, costs from STK38 published national data, and community utilities derived from a population study by the EuroQol questionnaire in terms of quality-adjusted life years (QALY). Population started at age 50, for a time horizon of 25 years and an annual discount rate of 3% was used for cost and effectiveness. Primary outcome was the incremental

cost-effectiveness ratio (ICER) of a 3-yearly endoscopic surveillance versus no surveillance for a base case scenario and in deterministic and probabilistic sensitivity analysis. Secondary outcomes were ICER of 5- and 10-yearly endoscopic surveillance versus no surveillance. Endoscopic surveillance every 3 years provided an ICER of € 18,336, below the adopted threshold of € 36,575 which corresponds to the proposed guideline limit of USD 50,000 and this strategy dominated surveillance every 5 or 10 years. Utilities for endoscopic treatment were relevant in deterministic analysis, while probabilistic analysis showed that in 78% of cases the model was cost-effective. Endoscopic surveillance every 3 years of patients with premalignant conditions is cost-effective. ”
“In spite of cytoprotective and anti-inflammatory actions, conventional licorice extracts (c-lico) were limitedly used due to serious side effects of glycyrrhizin.

A few studies reported that AFP may be

helpful for detection of HCC recurrence in patients with high pretreatment serum AFP levels.[3, 4] Particularly, in patients with a high pretreatment serum AFP that normalized after treatment, the subsequent elevation of AFP may suggest tumor recurrence or progression.[8] Therefore, the purpose of this study is to evaluate the diagnostic performance of serum AFP in detecting HCC recurrence after radiofrequency ablation (RFA), both in patients with high pretreatment AFP (AFP-producing HCC) levels and in patients with normal Selleck Napabucasin pretreatment AFP (non-AFP-producing HCC) levels. In addition, the false positive and true positive AFP results were analyzed to determine feasibility of improving the diagnostic performance of AFP after adjusting for significant confounding Proteasome inhibitor factors. Institutional Review Board approval was obtained for this retrospective study and the requirements for informed consent

were waived. The study was performed in compliance with the Health Insurance Portability and Accountability Act, United States 1996. From a database of patients with HCC who underwent RFA from January 1999 to September 2012, we selected those with solitary HCC, who had available follow-up by contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) at our institution (See below “imaging follow-up and end point determination”), and who had available and adequate AFP measurements (See below “AFP follow-up and abnormal cutoff”). The flow diagram

of patients is shown in Figure 1. Diagnosis of HCC was made either by using the AASLD imaging criteria guidelines, or by pathological confirmation of HCC on biopsy or surgical resection specimens. A typical diagnostic feature on dynamic CT/MRI included arterial phase hyperenhancement followed by hypoenhancement on the portal venous phase. HCC recurrence on imaging was defined as new nodular enhancement around the ablation site at more than 1 month post-ablation with demonstration Tideglusib of arterial hyperenhancement and venous hypoenhancement, or as interval growth on subsequent follow-up. In cases with rising AFP but no imaging detection, the patients received either a short-term imaging follow-up within 1–2 month or a complimentary contrast study (e.g. if contrast-enhanced CT did not detect recurrence, then the patient was further evaluated with contrast-enhanced liver MRI). At our institution, the protocol for post-RFA follow-up includes CT/MRI within 1 month after the initial treatment, then at 3 months, then every 3 months up to 1 year, and at least every 3–6 months thereafter. The end points were considered in two circumstances. First, if tumor recurrence occurred, the date of imaging that first detected the recurrence was considered the date of recurrence.