Background c-Met, a high-affinity receptor for Hepatocyte Growth Factor (HGF), plays a critical role in cancer growth, invasion and metastasis. Hepatocellular carcinoma (HCC) patients with an active HGF/c-Met signaling pathway have a significantly worse prognosis. Although targeting the HGF/c-Met pathway has been proposed for the treatment of multiple cancers, the effect of c-Met inhibition in HCC remains unclear. Human HCC cell lines, Huh7, Hep3B, MHCC97-L and MHCC97-H, were utilized in this study to investigate the effect of c-Met inhibition using the small molecule, selective c-Met tyrosine kinase inhibitor PHA665752. Results MHCC97-L and MHCC97-H cells demonstrate a mesenchymal phenotype with decreased expression of E-cadherin and increased expression of c-Met, Fibronectin and Zeb2 compared to Huh7 and Hep3B cells, which have an epithelial phenotype. PHA665752 treatment blocked phosphorylation of c-Met and downstream PI3K/Akt and MAPK/Erk pathways, inhibited cell proliferation and induced apoptosis in c-Met positive MHCC97-L and MHCC97-H cells. In xenograft models, administration of PHA665752 significantly inhibited c-Met positive MHCC97-L and MHCC97-H tumor growth, and PHA665752 treated tumors demonstrated marked reduction of both c-Met phosphorylation and cell proliferation. c-Met negative Huh7 and Hep3B cells were not affected by c-Met inhibitor treatment in vitro or in vivo. In addition, c-Met positive MHCC97-L and MHCC97-H cells demonstrated cancer stem cell-like characteristics, such as resistance to chemotherapy, tumor sphere-formation, and increased expression of CD44 and ABCG2, and PHA665752 treatment suppressed tumor sphere-formation and inhibited CD44 expression. Conclusion c-Met represents a potential target of personalized treatment for HCC with an active HGF/c-Met pathway.

Glucose-regulated protein 78 (GRP78) has been implicated in the protection of tumor cells from cytotoxic damage and apoptosis and thus assists cells in survival under oxygen-deprivation and nutrient-stress conditions. However, its expression and potential role in gastric cancer development and progression have not been reported. In the present study, we determined the level of GRP78 expression in the primary tumor in 86 cases of resected gastric cancer by using immunohistochemistry and analyzed the relationships between GRP78 and clinicopathological characteristics. We found that GRP78 was overexpressed in the tumor specimens when compared with the expression in adjacent tumor-free gastric mucosa. Furthermore, the level of GRP78 expression in both primary tumors and metastatic lymph nodes was inversely correlated with patient survival. Overexpression of GRP78 was directly correlated with Sp1 expression and increased lymph node metastasis. Knocking down GRP78 expression inhibited tumor cell invasion in vitro and growth and metastasis in a xenograft nude mouse model. Therefore, our data imply that dysregulated expression of GRP78 may contribute to the development and progression of gastric cancer.

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Upon T cell activation, IkappaB kinases (IKKs) are transiently recruited to the plasma membrane-associated lipid raft microdomains for activation of NF-kappaB in promoting T cell proliferation. Retroviral Tax proteins from human T cell leukemia virus type 1 and type 2 (HTLV-1 and -2) are capable of activating IKK, yet only HTLV-1 infection causes T cell leukemia, which correlates with persistent activation of NF-kappaB induced by Tax1. Here, we show that the Tax proteins exhibit differential modes of IKK activation. The subunits of IKK are constitutively present in lipid rafts in activated forms in HTLV-1-infected T cells that express Tax. Disruption of lipid rafts impairs IkappaB kinase activation by Tax1. We also show that the cytoplasmic Tax1 protein persistently resides in the Golgi-associated lipid raft microdomains. Tax1 directs lipid raft translocation of IKK through selective interaction with IKKgamma and accordingly, depletion of IKKgamma impairs Tax1-directed lipid raft recruitment of IKKalpha and IKKbeta. In contrast, Tax2 activates NF-kappaB in a manner independent of lipid raft recruitment of IKK. These findings indicate that Tax1 actively recruits IKK to the lipid raft microdomains for persistent activation of NF-kappaB, thereby contributing to HTLV-1 oncogenesis.

were originally discovered as transcription factors involved in interferon-induced gene expression (1, 2). The STATs were subsequently shown, also, to be involved in mediating signal transduction of a large number of cytokines that are important for differentiation and maturation of immune cells. Binding of a type I or type II cytokine to its cognate receptor results in its dimerization and recruitment and activation of a specific tyrosine kinase(s) of the Janus kinase (JAK) family. Tyrosine phosphorylation of the cytoplasmic domain of the cytokine receptor generates sites for the binding of STAT proteins via their SH2 domain. Subsequent tyrosine phosphorylation at the carboxyl domain of STATs catalyzes the dimerization, which is followed by translocation to nucleus, and functions as an activated transcriptional factor. To date, seven STATs (1-6, including 5a and 5b) and four JAKs

Background: The use of single agent cytotoxic or targeted agent as maintenance following combination therapy represents a useful strategy to improve patient outcomes in advanced stage NSCLC. An earlier study with gemcitabine as maintenance therapy demonstrated improved time to progression (TTP) compared to BSC (6.6 mos. vs 5.0 mos., p < 0.001) (Brodowicz et al, Lung Cancer, 2006; 52:155-163). Based on this, we conducted a randomized phase III study to compare G + BSC versus BSC as maintenance therapy for patients with advanced NSCLC. Methods: Patients with stage IIIB (wet)/IV NSCLC were initially treated with gemcitabine (1,000 mg/m 2 on day 1 and 8) and carboplatin (AUC = 5 mg/mL.min on d 1) every 3 weeks for 4 cycles. Subsequently, patients with CR/PR or SD were randomized 1:1 to receive maintenance G (1,000 mg/m 2 on d 1 and 8), every 3 weeks with BSC or BSC alone until disease progression. The primary endpoint was the comparison of overall survival between the two arms and the secondary endpoint was progression free survival (PFS). Results: 519 patients were enrolled (median age-67 years, stage IV disease-86%, ECOG performance status 0/1-75%). With G-Cb, the RR was 28% (CR-1.2%, PR-26.8%), and 37% had SD. Following 4 cycles of G-Cb, 255 non-progressors were randomized to receive G + BSC (n = 128) or BSC (n = 127). The median PFS was 3.9 m (95% CI:3.3, 5.6) for G + BSC and 3.8 m (95% CI: 2.6, 5.5) for BSC. Median survival was 8.0 m (95% CI: 6.0, 10.2) for G+ BSC and 9.3 m (95% CI: 7.7, 12.7) for BSC. The differences in survival between the two arms were not statistically significant (HR = 0.97 [95% CI: 0.72, 1.30], p = 0.84). Maintenance therapy was tolerated well despite a higher incidence of grade 3/4 toxicity (anemia 9.4% vs. 2.4%; neutropenia 13.3% vs. 1.6%; thrombocytopenia 9.4% vs. 1.4%; and fatigue 3.9% vs. 1.6%). Conclusions: The use of gemcitabine as maintenance therapy failed to improve survival following G-Cb in patients with advanced NSCLC.

Neuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase b/f (RPTPb), we postulated that simultaneous binding of MAGI proteins to RPTPb and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTPb. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTPb for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n = B1400). PTPRZ1, which codes for RPTPb, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P = 0.0003; gene-wide P = 0.0064; hypothesiswide P = 0.026). The data provide evidence for a role of PTPRZ1, and for RPTPb signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTPb in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia.

These studies show that nanoliposomal ceramide is an efficacious antineoplastic agent for the treatment of in vitro and in vivo models of human HCC.