miR-489 is a tumour-suppressive miRNA target PTPN11 in hypopharyngeal squamous cell carcinoma (HSCC).

BACKGROUND: Hypopharyngeal squamous cell carcinoma (HSCC) is an aggressive malignancy with one of the worst prognoses among all head and neck cancers. Greater understanding of the pertinent molecular oncogenic pathways could help improve diagnosis, therapy, and prevention of this disease. The aim of this study was to identify tumour-suppressive microRNAs (miRNAs), based on miRNA expression signatures from clinical HSCC specimens, and to predict their biological target genes. METHODS: Expression levels of 365 human mature miRNAs from 10 HSCC clinical samples were screened using stem-loop real-time quantitative PCR. Downregulated miRNAs were used in cell proliferation assays to identify a tumour-suppressive miRNA. Genome-wide gene expression analyses were then performed to identify the target genes of the tumour-suppressive miRNA. RESULTS: Expression analysis identified 11 upregulated and 31 downregulated miRNAs. Gain-of-function analysis of the downregulated miRNAs revealed that miR-489 inhibited cell growth in all head and neck cancer cell lines examined. The gene PTPN11 coding for a cytoplasmic protein tyrosine phosphatase containing two Src Homology 2 domains was identified as a miR-489-targeted gene. Knockdown of PTPN11 resulted in the inhibition of cell proliferation in head and neck SCC cells. CONCLUSION: Identification of the tumour-suppressive miRNA miR-489 and its target, PTPN11, might provide new insights into the underlying molecular mechanisms of HSCC.

Seasonal changes in antigen-specific T-helper clone sizes in patients with Japanese cedar pollinosis: a 2-year study.

BACKGROUND: Allergic rhinitis (AR) is a typical type I allergic disease that occurs through the induction of allergen-specific effector T cells. Once established, new effector T cells derive mostly from memory T cells that are capable of surviving for extended periods, although the mechanisms by which these memory functions are maintained have not yet been clarified. In particular, the exact life-span of memory T cells is still not well understood. OBJECTIVE: Pollinosis patients seemed to be suitable subjects to investigate because such patients are exposed to antigens strongly for only a limited period once a year. We compared the seasonal changes in memory T-helper type 2 (Th2) between pollinosis and perennial allergic subjects. METHODS: The clone sizes of the Japanese cedar pollen-specific memory Th cells were measured by an ELISPOT assay using specific peptides from the patients with cedar pollinosis, and the seasonal changes were noted. This study was performed for 2 years. The cedar-specific IgE levels in the peripheral blood were also studied. Mite allergy patients were also enrolled in the study. RESULTS: The Japanese cedar-specific IL-4-producing Th2 cells were detected in all patients examined, although the number of cells was low. These Th memory cells increased during the pollen season and decreased during the off-season. However, more than 60% of the cedar-specific memory Th2 cells survived up to 8 months after the pollen season. The cedar-specific IgE levels exhibited changes similar to the cedar-specific Th cells. On the other hand, there was no drifting of Th memory clone size with the mite allergics, and the IgE levels also did not change. CONCLUSIONS: While pollen-specific Th cells decreased after pollen exposure, their memory functions continued. Memory clone size maintenance therefore requires repetitive antigen irritation.

Influence of viral infection on the development of nasal hypersensitivity.

BACKGROUND: The underlying relationship between viral infections and allergic diseases of the upper respiratory tract has not been well clarified. METHODS: In order to clarify the relationship between viral infection and nasal hypersensitivity, mice were sensitized with ovalbumin (OVA) and then infected intranasally with respiratory syncytial virus (RSV), after which their nasal sensitivity to histamine or antigen was examined. RESULTS: Non-sensitized mice showed transient mild nasal hypersensitivity following nasal administration of histamine after intranasal RSV inoculation. In mice sensitized with OVA, RSV infection significantly exaggerated their nasal hypersensitivity to histamine and OVA. Treatment of these mice with a neurokinin (NK)-1/NK-2 receptor antagonist, but not with anti-IL-5 antibodies, reduced their hypersensitivity. The infiltration of nasal mucosa with eosinophils was temporarily associated with accelerated rate of RSV elimination in these animals. CONCLUSION: RSV infection induced transient nasal hypersensitivity. Several mechanisms, including impairment of nasal epithelial cells are thought to mediate this effect. In allergen-sensitized mice, RSV inoculation strongly enhanced nasal hypersensitivity.

Suppressive effect of locally produced interleukin-10 on respiratory syncytial virus infection.

Interleukin (IL)-10 is known to be a multifunctional cytokine. This study was designed to evaluate the role of IL-10 during respiratory syncytial virus (RSV) infection using a C57BL/6 transgenic (TG) mouse model in which the expression of murine IL-10 cDNA was regulated by a human salivary amylase promoter (IL-10 TG mice). These mice expressed a large amount of IL-10 in the nasal mucosa and in salivary glands. Viral replication in the respiratory tract after intranasal infection with RSV was suppressed significantly in IL-10 TG mice compared to non-transgenic controls. This suppression was IL-10 specific, because it was prevented by treating mice with neutralizing anti-IL-10 antibodies. We also found that IL-10-stimulated T cells displayed cytotoxic activity against infected murine nasal epithelial cells. Previous data indicated that IL-10 induces Fas ligand (L) expression on mouse T cells. Taken together, these data suggest that Fas/Fas L mediated cytotoxicity is involved in the suppression of RSV replication observed in IL-10 TG mice after intranasal infection.