Majority of cancer cells upregulate co-inhibitory molecule B7-H1 which confers resistance to anti-tumor immunity, allowing cancers to escape from host immune surveillance. We addressed the molecular mechanism underlying the regulation of cancer-associated B7-H1 expression in response to interferon-c (IFN-c). Using promoter constructs in luciferase assay, the region between 202 and 320 bp from the translational start site is responsible for B7-H1 expression. Electrophoretic mobility shift assay, site-directed mutagenesis and knockdown experiment using siRNA revealed that interferon regulatory factor-1 (IRF-1) is primarily responsible for the constitutive B7-H1 expression as well as for the IFN-c-mediated B7-H1 upregulation in a human lung cancer cell line A549. Additionally, AG490, a Janus activated kinase/signal transducer and activator of transcription inhibitor, greatly abolished the responsiveness of A549 cells to IFN-c by reducing the IRF-1 transcription. Our findings support a critical role of IRF-1 in the regulation of constitutive and IFN-c-induced expression of B7-H1 in cancer cells.

Proteolytic degradation of the extracellular matrix and tumor metastasis correlate with the expression of endopeptidases known as matrix metalloproteinases (MMPs). The expression of MMPs is regulated by cytokines and signal transduction pathways, including those activated by phorbol myristate acetate (PMA). We found that resveratrol, a phytoalexin present in grapes, significantly inhibits the PMA-induced increase in MMP-9 expression and activity. These effects of resveratrol are dose dependent and correlate with the suppression of MMP-9 mRNA expression levels. PMA caused about a 23-fold increase in MMP-9 promoter activity, which was suppressed by resveratrol. Transient transfection utilizing MMP-9 constructs, in which specific transcriptional factors were mutagenized, indicated that the effects of PMA and resveratrol were mediated via an activator protein-1 and nuclear factor-kappaB response element. Resveratrol inhibited PMA-mediated activation of c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)-delta activation. Therefore, we conclude that the MMP-9 inhibition activity of resveratrol and its inhibition of JNK and PKC-delta may have a therapeutic potential, given that a novel means of controlling growth and invasiveness of tumors.

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This study was performed to identify clinical factors that facilitate the diagnosis of typical cow's milk protein-induced enterocolitis (CMPIE). Data from 142 consecutive patients (aged 15 to 45 days, cow's milk formula- or cow's milk and breast milk mixed-fed) admitted due to vomiting and/or diarrhea were retrospectively analyzed. These 142 subjects were divided into three groups: the CMPIE, infection, and non-infection group. Each group was composed of 16 (11.3%), 102 (71.8%), and 24 (16.9%) patients, respectively. On admission, poor weight gain (p=0.003), hypoalbuminemia (p=0.035), peripheral leukocytosis (p=0.012), and metabolic acidosis (p=0.015) were found to be more significant in the CMPIE group than those in other two groups. In CMPIE, serum albumin levels decreased from 3.3±0.9 g/dL on admission to 2.6±0.3 g/dL during admission (p<0.05), and methemoglobinemia was observed in 3 patients (18.8%) (p=0.012). Multiple logistic regression analysis showed that the independent predictors of CMPIE versus the infection group were failure to gain weight (OR, 10.75 [95% CI, 1.53-66.12]) (p=0.014) and hypoalbuminemia (OR, 9.53 [95% CI, 1.62-49.01]) (p=0.010). The early recognition of indexes of suspicion for CMPIE may be of help in the diagnosis and treatment of this disorder.

Our data suggest that the HCV core protein promotes cell proliferation through upregulation of the cyclin E expression levels, implying this property of HCV core protein plays an important role in hepatocarcinogenesis.