Connexin genes expressing gap junction proteins have tumor-suppressive effects on primary cancers with certain cell specificity, but the suppressive effects on metastatic cancers are still conflicting. In this study, we show that connexin32 (Cx32) has a strong tumor-suppressive effect on a human metastatic renal cell carcinoma cell line (Caki-1 cell). Cx32 expression in Caki-1 cells reduced in vitro malignant phenotypes of the cells such as anchorage independency and invasion capacity. Furthermore, the Cx32 expression drastically reduced the development of Caki-1 cells in nude mice. We also determined that Cx32 reduced the malignant phenotypes in Caki-1 cells mainly through the inactivation of Src signaling. Especially, Cx32-dependent inactivation of Src decreased the production of vascular epithelial growth factor (VEGF) via the suppression of signal transducers and activators of transcription 3 (Stat3) activation, and we confirmed this result using short interfering RNA. In nude mice, Cx32-transfected Caki-1 cells showed lower serum level of VEGF comparing mock transfectant, and the development of the cells in nude mice positively related to the VEGF level. These data suggest that Cx32 acts as a tumor suppressor gene in Caki-1 cells and that the tumor-suppressive effect partly depends on the inhibition of Src-Stat3-VEGF signal pathway.
While histamine H4 receptor (H4R) has been implicated in immune system disturbances in different organ tissues, the presence and possible roles of H4R in synovial cells (SC) of rheumatoid arthritis (RA) patients has not previously been documented. This study conclusively evidences H4R expression in SC of RA patients by use of RT-PCR method. As RA consists mainly of immunological disturbances in SC of RA patients, this study's findings document a novel histamine action site, and opens potential new avenues to investigate mechanisms and to develop pharmacotherapeutic agents for the disease.
Connexin (Cx) genes have negative growth effects on tumor cells with certain cell specificity. We have previously reported that Cx32 is specifically downregulated in human renal cell carcinoma cell (RCC) lines as well as cancerous regions of kidneys and that the Cx is expressed in the progenitor cells of the carcinoma. However, the precise role of Cx32 in growth control of RCC cells remains unknown. In this study, we examined whether Cx32 could act in growth control against a human RCC cell, Caki-2 cell. In order to estimate the cell growth control, we established Caki-2 cells that have stable expression of Cx32 genes. Cx32 expression in Caki-2 cells induced contact inhibition of growth and reduced anchorage-independent growth ability, but did not significantly affect lag phase growth rates. This growth control by Cx32 was dependent on the inhibition of the cell-cycle transition from G1 to S phase at high cell density, and the inhibition of the cell-cycle transition related to the suppression of Her-2 activation. Furthermore, the suppression of Cx32 expression in Caki-2 cells by short interfering RNA induced the activation of Her-2. These data suggest that Cx32 has negative growth control of Caki-2 cells, partly due to the inhibition of the Her-2 activation.
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