Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.
The aims of this study are to demonstrate the increased lysis of stem cells but not their differentiated counterparts by the NK cells and to determine whether disturbance in cell differentiation is a cause for increased sensitivity to NK cell mediated cytotoxicity. Increased cytotoxicity and augmented secretion of IFN-γ were both observed when PBMCs or NK cells were co-incubated with primary UCLA oral squamous carcinoma stem cells (UCLA-OSCSCs) when compared to differentiated UCLA oral squamous carcinoma cells (UCLA-OSCCs). In addition, human embryonic stem cells (hESCs) were also lysed greatly by the NK cells. Moreover, NK cells were found to lyse human Mesenchymal Stem Cells (hMSCs), human dental pulp stem cells (hDPSCs) and human induced pluripotent stem cells (hiPSCs) significantly more than their differentiated counterparts or parental lines from which they were derived. It was also found that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFκB or targeted knock down of COX2 in monocytes significantly augmented NK cell cytotoxicity and secretion of IFN-γ. Taken together, these results suggest that stem cells are significant targets of the NK cell cytotoxicity. However, to support differentiation of a subset of tumor or healthy untransformed primary stem cells, NK cells may be required to lyse a number of stem cells and/or those which are either defective or incapable of full differentiation in order to lose their cytotoxic function and gain the ability to secrete cytokines (split anergy). Therefore, patients with cancer may benefit from repeated allogeneic NK cell transplantation for specific elimination of cancer stem cells.
The sodium pump is the enzyme responsible for the maintenance of Na+ and K+ gradients across the cell membrane. Four isoforms of the catalytic alpha subunit have been identified, but their individual roles remain essentially unknown. To investigate the necessary functions of the alpha2 subunit in vivo, we generated and analyzed mice defective in the alpha2 subunit gene. Mice homozygous for the alpha2 mutation died just after birth and displayed selective neuronal apoptosis in the amygdala and piriform cortex. In these regions, high expression of c-Fos before apoptosis indicated neural hyperactivity, and re-uptake of glutamic acid and GABA into P2 fraction containing crude synaptosome was impaired. These results indicate that the alpha2 subunit plays a critical role regulating neural activity in the developing amygdala and piriform cortex. Further supporting a role of the alpha2 subunit in the function of the amygdala, heterozygous adult mice showed augmented fear/anxiety behaviors and enhanced neuronal activity in the amygdala and piriform cortex after conditioned fear stimuli.
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