Defects in DNA double-strand break (DSB) repair signaling permit cancer cells to accumulate genomic alterations that confer their aggressive phenotype. Nevertheless, tumors depend on residual DNA repair abilities to survive the DNA damage induced by genotoxic stress. This is why only isolated DNA repair signaling is inactivated in cancer cells. DNA DSB repair signaling contributes to general mechanism for various types of lesions in diverse cell cycle phases. DNA DSB repair genes are frequently mutated and amplified in cancer; however, limited data exist regarding the overall genomic prospect and functional result of these modifications. We list the DNA repair genes and related E3 ligases. Mutation and expression frequencies of these genes were analyzed in COSMIC and TCGA. The 11 genes with a high frequency of mutation differed between cancers, and mutations in many DNA DSB repair E3 ligase genes were related to a higher total mutation burden. DNA DSB repair E3 ligase genes are involved in tumor suppressive or oncogenic functions, such as RNF168 and FBXW7, by assisting the functionality of these genomic alterations. DNA damage response-related E3 ligases, such as RNF168, FBXW7, and HERC2, were generated with more than 10% mutation in several cancer cells. This study provides a broad list of candidate genes as potential biomarkers for genomic instability and novel therapeutic targets in cancer. As a DSB related proteins considerably appear the possibilities for targeting DNA repair defective tumors or hyperactive DNA repair tumors. Based on recent research, we describe the relationship between unstable DSB repairs and DSB-related E3 ligases.

Cancer immunotherapy has been acknowledged as a new paradigm for cancer treatment, with notable therapeutic effects on certain cancer types. Despite their significant potential, clinical studies over the past decade have revealed that cancer immunotherapy has low response rates in the majority of solid tumors. One of the key causes for poor responses is known to be the relatively low immunogenicity of solid tumors. Because most solid tumors are immune desert 'cold tumors' with antitumor immunity blocked from the onset of innate immunity, combination therapies that combine validated T-based therapies with approaches that can increase tumor-immunogenicity are being considered as relevant therapeutic options. This review paper focuses on immunogenic cell death (ICD) as a way of enhancing immunogenicity in tumor tissues. We will thoroughly review how ICDs such as necroptosis, pyroptosis, and ferroptosis can improve anti-tumor immunity and outline clinical trials targeting ICD. Finally, we will discuss the potential of ICD inducers as an adjuvant for cancer immunotherapy.

The tumor microenvironment (TME) is a complex system composed of many cell types and an extracellular matrix (ECM). During tumorigenesis, cancer cells constantly interact with cellular components, biochemical cues, and the ECM in the TME, all of which make the environment favorable for cancer growth. Emerging evidence has revealed the importance of substrate elasticity and biomechanical forces in tumor progression and metastasis. However, the mechanisms underlying the cell response to mechanical signals-such as extrinsic mechanical forces and forces generated within the TME-are still relatively unknown. Moreover, having a deeper understanding of the mechanisms by which cancer cells sense mechanical forces and transmit signals to the cytoplasm would substantially help develop effective strategies for cancer treatment. This review provides an overview of biomechanical forces in the TME and the intracellular signaling pathways activated by mechanical cues as well as highlights the role of mechanotransductive pathways through mechanosensors that detect the altering biomechanical forces in the TME.

Retinoic acid receptor-related orphan receptor α (RORα) plays a vital role in various physiological processes, including metabolism, cancer, circadian rhythm, cerebellar development, and inflammation. Although RORα is expressed in the skin, its role in skin physiology remains poorly elucidated. Herein, Rorα was expressed in the basal and suprabasal layers of the epidermis; however, keratinocyte-specific Rorα deletion did not impact normal epidermal formation. Under pathophysiological conditions, Rorα-deficient mice exhibited alleviated psoriasis-like symptoms, including relatively intact epidermal stratification, reduced keratinocyte hyperproliferation, and low-level expression of inflammatory cytokines in keratinocytes. Unexpectedly, the splenic population of Th17 cells was significantly lower in keratinocyte-specific RORα deficient mice than in the control. Additionally, Rorα-deficiency reduced imiquimod-induced activation of nuclear factor-κB and STAT3 in keratinocytes. Therefore, we expect that RORα inhibitors act on immune cells and keratinocytes to suppress the onset and progression of psoriasis.

Lyn, a tyrosine kinase that is activated by double-stranded DNA-damaging agents, is involved in various signaling pathways, such as proliferation, apoptosis, and DNA repair. Ribosomal protein S3 (RpS3) is involved in protein biosynthesis as a component of the ribosome complex and possesses endonuclease activity to repair damaged DNA. Herein, we demonstrated that rpS3 and Lyn interact with each other, and the phosphorylation of rpS3 by Lyn, causing ribosome heterogeneity, upregulates the translation of p-glycoprotein, which is a gene product of multidrug resistance gene 1. In addition, we found that two different regions of the rpS3 protein are associated with the SH1 and SH3 domains of Lyn. An in vitro immunocomplex kinase assay indicated that the rpS3 protein acts as a substrate for Lyn, which phosphorylates the Y167 residue of rpS3. Furthermore, by adding various kinase inhibitors, we confirmed that the phosphorylation status of rpS3 was regulated by both Lyn and doxorubicin, and the phosphorylation of rpS3 by Lyn increased drug resistance in cells by upregulating p-glycoprotein translation.

Phenotypic features such as ataxia and loss of motor function, which are characteristics of Parkinson's disease (PD), are expected to be very closely related to cerebellum function. However, few studies have reported the function of the cerebellum. Since the cerebellum, like the cerebrum, is known to undergo functional and morphological changes due to neuroinflammatory processes, elucidating key functional factors that regulate neuroinflammation in the cerebellum can be a beneficial therapeutic approach. Therefore, we employed PD patients and MPTP-induced PD mouse model to find cytokines involved in cerebellar neuroinflammation in PD and to examine changes in cell function by regulating related genes. Along with the establishment of a PD mouse model, abnormal shapes such as arrangement and number of Purkinje cells in the cerebellum were confirmed based on histological finding, consistent with those of cerebellums of PD patients. As a result of proteome profiling for neuroinflammation using PD mouse cerebellar tissues, fetuin-A, a type of cytokine, was found to be significantly reduced in Purkinje cells. To further elucidate the function of fetuin-A, neurons isolated from cerebellums of embryos (E18) were treated with fetuin-A siRNA. We uncovered that not only the population of neuronal cells, but also their morphological appearances were significantly different. In this study, we found a functional gene called fetuin-A in the PD model's cerebellum, which was closely related to the role of cerebellar Purkinje cells of mouse and human PD. In conclusion, morphological abnormalities of Purkinje cells in PD mice and patients have a close relationship with a decrease of fetuin-A, suggesting that diagnosis and treatment of cerebellar functions of PD patients might be possible through regulation of fetuin-A.

Sepsis is a life-threatening multi-organ dysfunction with high mortality caused by the body's improper response to microbial infection. No new effective therapy has emerged that can adequately treat patients with sepsis. We previously demonstrated that interferon-β (IFN-β) protects against sepsis via sirtuin 1-(SIRT1)-mediated immunosuppression. Another study also reported its significant protective effect against acute respiratory distress syndrome, a complication of severe sepsis, in human patients. However, the IFN-β effect cannot solely be explained by SIRT1-mediated immunosuppression, since sepsis induces immunosuppression in patients. Here, we show that IFN-β, in combination with nicotinamide riboside (NR), alleviates sepsis by blocking endothelial damage via SIRT1 activation. IFN-β plus NR protected against cecal ligation puncture-(CLP)-induced sepsis in wild-type mice, but not in endothelial cell-specific Sirt1 knockout (EC-Sirt1 KO) mice. IFN-β upregulated SIRT1 protein expression in endothelial cells in a protein synthesis-independent manner. IFN-β plus NR reduced the CLP-induced increase in in vivo endothelial permeability in wild-type, but not EC-Sirt1 KO mice. IFN-β plus NR suppressed lipopolysaccharide-induced up-regulation of heparinase 1, but the effect was abolished by Sirt1 knockdown in endothelial cells. Our results suggest that IFN-β plus NR protects against endothelial damage during sepsis via activation of the SIRT1/heparinase 1 pathway.