STAT3 inhibition by STA21 increases cell surface expression of MICB and the release of soluble MICB by gastric adenocarcinoma cells.

NKG2D is an activating receptor expressed on NK cells that binds to a variety of ligands, including MICA and MICB. These cell surface glycoproteins are overexpressed under cellular transformation, thus playing an important role in cell-mediated immune response to tumors. STAT3 is a transcription factor that is constitutively active in cancer. It negatively regulates MICA expression on target cells, while its inhibition enhances NK cell cytotoxicity against tumors. In this work, we aimed to describe the effect of STAT3 signaling inhibition by STA21 on the regulation of MICB expression in gastric adenocarcinoma cells and its effect on the cytotoxic function of NK cells. Treatment of gastric adenocarcinoma cells with STA21 induced an increase in MICB expression and soluble MICB secretion, as well as a variable pattern on effector cell degranulation. Soluble MICB secretion by gastric adenocarcinoma cells was not affected by metalloprotease inhibition. We also observed that primary gastric adenocarcinoma tissue released soluble MICB into the extracellular milieu. Recombinant MICB induced a significant decrease in the levels of NKG2D receptor on effector NK and CD8+ T cells, which correlated with an impaired cytotoxic function. Altogether, our data provide evidence that STAT3 signaling pathway regulates MICB expression on gastric adenocarcinoma cells and that recombinant soluble MICB compromises the cytolytic activity of NK cells.

Cell cycle control of septin ring dynamics in the budding yeast.

Septins constitute a cytoskeletal structure that is conserved in eukaryotes. In Saccharomyces cerevisiae, the Cdc3, Cdc10, Cdc11, Cdc12 and Shs1/Sep7 septins assemble as a ring that marks the cytokinetic plane throughout the budding cycle. This structure participates in different aspects of morphogenesis, such as selection of cell polarity, localization of chitin synthesis, the switch from hyperpolar to isotropic bud growth after bud emergence and the spatial regulation of septation. The septin cytoskeleton assembles at the pre-bud site before bud emergence, remains there during bud growth and duplicates at late mitosis eventually disappearing after cell separation. Using a septin-GFP fusion and time-lapse confocal microscopy, we have determined that septin dynamics are maintained in budding zygotes and during unipolar synchronous growth in pseudohyphae. By means of specific cell cycle arrests and deregulation of cell cycle controls we show that septin assembly is dependent on G1 cyclin/Cdc28-mediated cell cycle signals and that the small GTPase Cdc42, but not Rho1, are essential for this event. However, during bud growth, the septin ring shapes a bud-neck-spanning structure that is unaffected by failures in the regulation of mitosis, such as activation of the DNA repair or spindle assembly checkpoints or inactivation of the anaphase-promoting complex (APC). At the end of the cell cycle, the splitting of the ring into two independent structures depends on the function of the mitotic exit network in which the protein phosphatase Cdc14 participates. Our data support a role of cell cycle control mechanisms in the regulation of septin dynamics to accurately coordinate morphogenesis throughout the budding process in yeast.