Immune mediated support of metastasis: Implication for bone invasion.

Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we described the changes in various immune cells during bone metastasis and discussed their related mechanisms. Osteoblasts, adipocytes, and other non-immune cells closely related to bone metastasis were also included. This review also summarized the existing treatment methods and potential therapeutic targets, and provided insights for future studies of cancer bone metastasis.

Evolutionary trajectory of TRPM2 channel activation by adenosine diphosphate ribose and calcium.

Ion channel activation upon ligand gating triggers a myriad of biological events and, therefore, evolution of ligand gating mechanism is of fundamental importance. TRPM2, a typical ancient ion channel, is activated by adenosine diphosphate ribose (ADPR) and calcium and its activation has evolved from a simple mode in invertebrates to a more complex one in vertebrates, but the evolutionary process is still unknown. Molecular evolutionary analysis of TRPM2s from more than 280 different animal species has revealed that, the C-terminal NUDT9-H domain has evolved from an enzyme to a ligand binding site for activation, while the N-terminal MHR domain maintains a conserved ligand binding site. Calcium gating pattern has also evolved, from one Ca2+-binding site as in sea anemones to three sites as in human. Importantly, we identified a new group represented by olTRPM2, which has a novel gating mode and fills the missing link of the channel gating evolution. We conclude that the TRPM2 ligand binding or activation mode evolved through at least three identifiable stages in the past billion years from simple to complicated and coordinated. Such findings benefit the evolutionary investigations of other channels and proteins.

Eriodictyol regulated ferroptosis, mitochondrial dysfunction, and cell viability via Nrf2/HO-1/NQO1 signaling pathway in ovarian cancer cells.

This study aimed to investigate the antitumor effect and the underlying molecular mechanism of eriodictyol on ovarian cancer cells. CaoV3 and A2780 were exposed to eriodictyol at different concentrations of 0-800 µM. Cell apoptosis and viability were determined by TdT-mediated dUTP Nick-End Labeling (TUNEL) assay and Cell Counting Kit-8 (CCK-8) assay, respectively. Mitochondrial membrane potential was evaluated by flow cytometers with a JC-1 detection kit. Fe2+ content was evaluated using an iron assay kit. The section of tumor tissues was observed using hematoxylin-eosin (H&E) staining and nuclear factor erythroid 2-related factor 2 (Nrf2) expression was detected by immunohistochemistry (IHC) staining. Eriodictyol suppressed cell viability and induced cell apoptosis of CaoV3 and A2780 cells. Half maximal inhibitory concentration (IC50 ) value of CaoV3 at 24 and 48 h was (229.74 ± 5.13) µM and (38.44 ± 4.68) µM, and IC50 value of A2780 at 24 and 48 h was (248.32 ± 2.54) µM and (64.28 ± 3.19) µM. Fe2+ content and reactive oxygen species production were increased and protein levels of SLC7A11 and GPX4 were decreased by eriodictyol. Besides, eriodictyol reduced the ratio of JC-1 fluorescence ratio, glutathione and malondialdehyde contents but elevated Cytochrome C level. Nrf2 phosphorylation were obviously downregulated by eriodictyol. Finally, eriodictyol suppressed tumor growth, aggravated mitochondrial dysfunction and downregulated Nrf2 expression in tumor tissue in mice. Eriodictyol regulated ferroptosis, mitochondrial dysfunction and cell viability via Nrf2/HO-1/NQO1 signaling pathway in ovarian cancer.

Microarray data analysis of neuroblastoma: Expression of SOX2 downregulates the expression of MYCN.

The present study aimed to identify the genes directly or indirectly correlated with the amplification of MYCN in neuroblastoma (NB). Microarray data (GSE53371) were downloaded from Gene Expression Omnibus, and included 10 NB cell lines with MYCN amplification and 10 NB cell lines with normal MYCN copy numbers. Differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Data package, and a false discovery rate of <0.05 and |log2FC (fold change)|>1 were selected as cut­off criteria. Hierarchical clustering analysis and Gene Ontology analysis were respectively performed for the DEGs using the Pheatmap package in R language and The Database for Annotation, Visualization and Integrated Discovery. A protein­protein interaction network (PPI) was constructed for the DEGs using the Search Tool for the Retrieval of Interacting Genes database. Pathway analysis was performed for the DEGs in the PPI network using the WEB­based GEne SeT AnaLysis Toolkit. The correlation between MYCN and the key gene associated with MYCN was determined using Pearson's correlation coefficient. In total, 137 downregulated and 35 upregulated DEGs were identified. Functional enrichment analysis indicated that KCNMB4 was involved in the regulation of action potential in neuron term, and the FOS, GLI3 and GLI1 genes were involved in the extracellular matrix­receptor interaction pathway. The PPI network and correlation analysis revealed that the expression of SOX2 was directly correlated with the expression of MYCN, and the correlation coefficient of SOX2 and MYCN was ­0.83. Therefore, SOX2, KCNMB4, FOS, GLI3 and GLI1 may be involved in the pathogenesis of NB, with the expression of SOX2 downregulating the expression of MYCN.