Hyperthermia is a cancer treatment where tumor tissue is heated to around 40 °C. Hyperthermia shows both cancer cell cytotoxicity and immune response stimulation via immune cell activation. Immunogenic responses encompass the innate and adaptive immune systems, involving the activation of macrophages, natural killer cells, dendritic cells, and T cells. Moreover, hyperthermia is commonly used in combination with different treatment modalities, such as radiotherapy and chemotherapy, for better clinical outcomes. In this review, we will focus on hyperthermia-induced immunogenic effects and molecular events to improve radiotherapy efficacy. The beneficial potential of integrating radiotherapy with hyperthermia is also discussed.

Normal fibroblasts surrounding tumor cells play a crucial role in cancer progression through formation of the tumor microenvironment. Because factors secreted from normal fibroblasts can modulate the tumor microenvironment, it is necessary to identify key factors associated with regulation of secreted factors and to investigate the molecular mechanisms contributing to the tumor microenvironment formation process. In this study, we found that radiation induced the expression and K63-linkage poly-ubiquitination of TRAF4 in normal lung fibroblasts. The K63-linkage poly-ubiquitinated TRAF4 formed complexes with NOX2 or NOX4 by mediating phosphorylated p47-phox in normal lung fibroblasts. Moreover, we showed that TRAF4 stabilized NOX complexes by decreasing lysosomal degradation of NOX2 and NOX4 after irradiation. NOX complexes increased endosomal ROS levels that were permeable into cytoplasm, leading to NF-κB-mediated ICAM1 up-regulation. Soluble ICAM1 was subsequently secreted into conditioned media of radiation-activated normal lung fibroblasts. The conditioned media from irradiated normal fibroblasts enhanced proliferation and epithelial-mesenchymal transition of non-small cell lung cancer cells both in vitro and in vivo. These results demonstrate that TRAF4 in irradiated fibroblasts is positively associated with aggressiveness of adjacent cancer cells by altering the tumor microenvironment. Thus, we suggest that regulation of TRAF4 might be a promising strategy for cancer therapy.

Radiotherapy has been a central part in curing non-small cell lung cancer (NSCLC). However, it is possible that not all of the tumor cells are destroyed by radiation; therefore, it is important to effectively control residual tumor cells that could become aggressive and resistant to radiotherapy. In this study, we aimed to investigate the molecular mechanism of decreased NSCLC radioresistance by low-dose radiation (LDR) pretreatment. The results indicated that miR-30a and miR-30b, which effectively inhibited plasminogen activator inhibitor-1 (PAI-1), were overexpressed by treatment of LDR to NSCLC cells. Phosphorylation of Akt and ERK, the downstream survival signals of PAI-1, was decreased by PAI-1 inhibition. Reduced cell survival and epithelial-mesenchymal transition by PAI-1 inhibition were confirmed in NSCLC cells. Moreover, in vivo orthotopic xenograft mouse models with 7C1 nanoparticles to deliver miRNAs showed that tumor growth and aggressiveness were efficiently decreased by LDR treatment followed by radiotherapy. Taken together, the present study suggested that PAI-1, whose expression is regulated by LDR, was critical for controlling surviving tumor cells after radiotherapy.Recent reports have suggested that increased expression of plasminogen activator inhibitor-1 (PAI-1) indicates poor prognosis of many cancer types, including NSCLC. 12,13 PAI-1 is an inhibitor of fibrinolysis. It is a physiological process that degrades fibrin and the extracellular matrix (ECM) proteins by inhibiting the urokinasetype plasminogen activator (uPA), which cleaves plasminogen to form plasmin. PAI-1, which is associated with the remodeling of the surrounding tissues, is a key factor in cancer proliferation, invasion, dissemination, and release of tumor growth factors and

Cranial irradiation is the main therapeutic strategy for treating primary and metastatic brain tumors. However, radiation is well-known to induce several unexpected side effects including emotional disorders. Although radiation-induced depression may cause decreased quality of life after radiotherapy, investigations of its molecular mechanism and therapeutic strategies are still insufficient. In this study, we found that behavioral symptoms of depression on mice models with the decrease of BrdU/NeuN- and Dcx-positive populations and MAP-2 expression in hippocampus were induced by cranial irradiation, and transthyretin (TTR) was highly expressed in hippocampus after irradiation. It was shown that overexpression of TTR resulted in the inhibition of retinol-mediated neuritogenesis. PAK1 phosphorylation and MAP-2 expression were significantly reduced by TTR overexpression following irradiation. Moreover, we observed that treatment of allantoin and neferine, the active components of Nelumbo nucifera, interrupted irradiation-induced TTR overexpression, consequently leading to the increase of PAK1 phosphorylation, neurite extension, BrdU/NeuN- and Dcx-positive populations, and MAP-2 expression. Behavioral symptoms of depression following cranial irradiation were also relieved by treatment of allantoin and neferine. These findings demonstrate that TTR plays a critical role in neurogenesis after irradiation, and allantoin and neferine could be potential drug candidates for recovering the effects of radiation on neurogenesis and depression.

Interferons (IFNs) are a crucial component in the innate immune response. Especially the IFN-β signaling operates in most cell types and plays a key role in the first line of defense upon pathogen intrusion. The induction of IFN-β should be tightly controlled, because its hyperactivation can lead to tissue damage or autoimmune diseases. Activation of the IFN-β promoter needs Interferon Regulatory Factor 3 (IRF3), together with Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator Protein 1 (AP-1). Here we report that a human noncoding RNA, nc886, is a novel suppressor for the IFN-β signaling and inflammation. Upon treatment with several pathogen-associated molecular patterns and viruses, nc886 suppresses the activation of IRF3 and also inhibits NF-κB and AP-1 via inhibiting Protein Kinase R (PKR). These events lead to decreased expression of IFN-β and resultantly IFN-stimulated genes. nc886′s role might be to restrict the IFN-β signaling from hyperactivation. Since nc886 expression is regulated by epigenetic and environmental factors, nc886 might explain why innate immune responses to pathogens are variable depending on biological settings.