Tgf-β1 transcriptionally promotes 90K expression: possible implications for cancer progression.

The 90K protein, also known as Mac-2 BP or LGALS3BP, can activate the immune response in part by increasing major histocompatibility (MHC) class I levels. In studies on a non-immune cell model, the rat FRTL-5 cell line, we observed that transforming growth factor (TGF)-β1, like γ-interferon (IFN), increased 90K levels, despite its immunosuppressive functions and the ability to decrease MHC class I. To explain this paradoxical result, we investigated the mechanisms involved in the TGF-β1 regulation of 90K expression with the aim to demonstrate that TGF-β1 utilizes different molecular pathways to regulate the two genes. We found that TGF-β1 was able to increase the binding of Upstream Stimulatory Factors, USF1 and USF2, to an E-box element, CANNTG, at -1926 to -1921 bp, upstream of the interferon response element (IRE) in the 90K promoter. Thyrotropin (TSH) suppressed constitutive and γ-IFN-induced 90K expression by decreasing USF binding to the E-box. TGF-β1 was able to overcome TSH suppression at the transcriptional level by increasing USF binding to the E-box. We suggest that the ability of TGF-β1 to increase 90K did not result in an increase in MHC class I because of a separate suppressive action of TGF-β1 directly on the MHC class I gene. We propose that the increased levels of 90K may play a role, rather than in immune response, in the context of the TGF-β1-induced changing of the cellular microenvironment that predisposes to cell motility and cancer progression. Consistently, analyzing the publicly available cancer patient data sets cBioPortal, we found that 90K expression directly correlated with TGF-β1 and USFs and that high levels of 90K were significantly associated with increased mortality in patients affected by different types of cancer

90K immunostimulatory glycoprotein in children with juvenile idiopathic arthritis.

OBJECTIVES: To assess whether circulating levels of 90K glycoprotein are increased in children with juvenile idiopathic arthritis (JIA) at different stages of the disease, compared to healthy controls and to evaluate potential over time changes in its concentrations following treatment with the antitumor-necrosis factor (TNF) drug etanercept. METHODS: 90K glycoprotein, C-reactive protein, erythrocyte sedimentation rate, TNF, antinuclear antibodies, rheumatoid factor and the Juvenile Arthritis Disease Activity Score were assessed in 71 children: 23 with newly diagnosed JIA, 23 with established and active JIA and 25 healthy controls. Patients, eligible for anti-TNF treatment, underwent a similar clinical/laboratory assessment after 6- and 12-month etanercept therapy. RESULTS: At baseline, significant differences were found in 90K levels between the three study groups: JIA at onset (157.7 [131.4-241.5] μg/ml), JIA on treatment (90.0 [68.8-120.2] μg/ml) and control group (58.0 [44.5-79.0] μg/ml), (p for trend <.001), with the JIA at onset group showing the highest values. In the JIA on treatment group, following one-year etanercept treatment, a significant reduction in 90K was detected already at 6 months (74.3 [56.0-104.1] μg/ml p = .001) and a further decline was observed at 12 months (49.3 [46.0-67.6] μg/ml p < .001). CONCLUSION: Our study showed that 90K glycoprotein levels are increased in JIA children compared to healthy controls, suggesting a potential pathogenetic role in the JIA. Besides, 12 months of therapy with etanercept can reduce 90K levels

Elevated serum levels of 90K/MAC-2 BP predict unresponsiveness to alpha-interferon therapy in chronic HCV hepatitis patients

Background: The clinical outcome of hepatitis virus infections is thought to depend on the complex interplay between the host immune response profile and virus factors, 90K/MAC-2 BP is a novel member of the Scavenger Receptor Cysteine Rich protein superfamily that functions as a molecular alarm signal for the cellular immune system against both cancer cells and virus infections. Methods: To assess the significance and the potential clinical usefulness of testing for serum levels of 90K/MAC-2 BP in chronic viral hepatitis patients we studied 115 consecutive patients with chronic HCV hepatitis, 28 HBsAg chronic hepatitis patients, 12 asymptomatic HCV carriers and 11 asymptomatic HBV carriers, 103 out of the 115 HCV patients have been treated with recombinant alpha 2a-interferon at the dose of 3 Mega Units (MU) t.i.w. for 6 months followed by 1.5 M.U. t.i.w. for 6 months, and have been followed up for a further 12 months, Serum levels of 90K/MAC-2 BP were measured by an immunoradiometric assay based on the specific SP-2 monoclonal antibody. Results and Conclusions: Serum 90K/MAC-2 BP levels are increased in chronic viral hepatitis patients, being significantly higher in HCV than in HBV patients, In chronic HCV hepatitis, serum 90K/MAC-2 BP levels are related to both the degree of disease severity and duration of infection, Moreover, elevated 90K/MAC-2 BP serum levels are an independent predictor of failure to respond to alpha-interferon treatment in a cohort of community-acquired chronic hepatitis C patients

Synthetic inhibitors of galectin-1 and -3 selectively modulate homotypic cell aggregation and tumor cell apoptosis

Galectins have emerged as critical regulators of tumor progression and metastasis, by modulating different biological events including homotypic cell aggregation, apoptosis, migration, angiogenesis and immune escape. Therefore, galectin inhibitors might represent novel therapeutic agents for cancer. A series of structural analogs of the disaccharide methyl beta-lactosaminide were screened as potential galectin inhibitors by examining their capability to block binding of galectin-1 and/or galectin-3 to LGalS3BP in solid-phase assays. To demonstrate any functional role in vitro, oligosaccharides were characterized by their ability to regulate tumor cell apoptosis and LGalS3BP-induced homotypic cell aggregation.Fil: Iurisci, Ida. Fondazione Università G. d’Annunzio; Italia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Cumashi, Albana. Fondazione Università G. d’Annunzio; Italia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Sherman, Andrei. Russian Academy of Sciences; Rusia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Tsvetkov, Yuri E.. Russian Academy of Sciences; Rusia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Tinari, Nicola. Fondazione Università G. d’Annunzio; Italia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Piccolo, Enza. Fondazione Università G. d’Annunzio; Italia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: D'Egidio, Maurizia. Fondazione Università G. d’Annunzio; Italia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Adamo, Vincenzo. Università degli Studi di Messina; Italia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Natoli, Clara. Fondazione Università G. d’Annunzio; Italia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Iacobelli, Stefano. Fondazione Università G. d’Annunzio; Italia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; ItaliaFil: Nifantiev, Nikolay E.. Russian Academy of Sciences; Italia. Consorzio Interuniversitario Nazionale Per la Bio-Oncologia; Itali