Hypoxic inactivation of glycogen synthase kinase‐3β promotes gastric tumor growth and angiogenesis by facilitating hypoxia‐inducible factor‐1 signaling

Since the molecular mechanism of hypoxic adaptation in cancer cells is cell‐type specific, we investigated whether glycogen synthase kinase‐3β (GSK‐3β) activation is involved in hypoxia‐induced gastric tumor promotion. Stable gastric cancer cell lines (SNU‐638, SNU‐484, MKN1, and MKN45) were cultured under hypoxic conditions. Cells overexpressing wild‐type GSK‐3β (WT‐GSK‐3β) or kinase‐dead mutant of GSK‐3β (KD‐GSK‐3β) were generated and used for cell culture and animal studies. In cell culture experiments, hypoxia decreased GSK‐3β activation in gastric cancer cells. Cell viability and the expressions of HIF‐1α protein and VEGF mRNA in gastric cancer cells were higher in KD‐GSK‐3β transfectants than in WT‐GSK‐3β transfectants under hypoxic conditions, but not under normoxic conditions. Gastric cancer xenografts showed that tumor growth, microvessel area, HIF‐1α activation, and VEGF expression were higher in KD‐GSK‐3β tumors than in WT‐GSK‐3β tumors in vivo. In addition, the expression of hypoxia‐induced HIF‐1α protein was regulated by GSK‐3β at the translational level. Our data suggest that GSK‐3β is involved in hypoxic adaptation of gastric cancer cells as an inhibitory upstream regulator of the HIF‐1α/VEGF signaling pathway.     

The Logistic Regression Model for Gene–Environment Interactions Using Both Case‐Parent Trios and Unrelated Case–Controls

One of the greatest challenges in genetic studies is the determination of gene–environment interactions due to underlying complications and inadequate statistical power. With the increased sample size gained by using case‐parent trios and unrelated cases and controls, the performance may be much improved. Focusing on a dichotomous trait, a two‐stage approach was previously proposed to deal with gene–environment interaction when utilizing mixed study samples. Theoretically, the two‐stage association analysis uses likelihood functions such that the computational algorithms may not converge in the maximum likelihood estimation with small study samples. In an effort to avoid such convergence issues, we propose a logistic regression framework model, based on the combined haplotype relative risk (CHRR) method, which intuitively pools the case‐parent trios and unrelated subjects in a two by two table. A positive feature of the logistic regression model is the effortless adjustment for either discrete or continuous covariates. According to computer simulations, under the circumstances in which the two‐stage test converges in larger sample sizes, we discovered that the performances of the two tests were quite similar; the two‐stage test is more powerful under the dominant and additive disease models, but the extended CHRR is more powerful under the recessive disease model.     

Paths taken towards NK cell–mediated immunotherapy of human cancer—a personal reflection

The discovery that NK cells are able to specifically recognize cells lacking the expression of self‐MHC class I molecules provided the first insight into NK cell recognition of tumour cells. It started a flourishing field of NK cell research aimed at exploring the molecular nature of NK cell receptors involved in tumour cell recognition. While much of the important early work was conducted in murine experimental model systems, studies of human NK cells rapidly followed. Over the years, human NK cell research has swiftly progressed, aided by new detailed molecular information on human NK cell development, differentiation, molecular specificity, tissue heterogeneity and functional capacity. NK cells have also been studied in many different diseases aside from cancer, including viral diseases, autoimmunity, allergy and primary immunodeficiencies. These fields of research have all, indirectly or directly, provided further insights into NK cell‐mediated recognition of target cells and paved the way for the development of NK cell‐based immunotherapies for human cancer. Excitingly, NK cell‐based immunotherapy now opens up for novel strategies aimed towards treating malignant diseases, either alone or in combination with other drugs. Reviewed here are some personal reflections of select contributions leading up to the current state‐of‐the‐art in the field, with a particular emphasis on contributions from our own laboratory. This review is part of a series of articles on immunology in Scandinavia, published in conjunction with the 50th anniversary of the Scandinavian Society for Immunology.