Breast cancer stem cells (BCSCs), a small subset of breast cancer cells with stem cell–like properties, are essential in tumor formation, metastasis, resistance to anticancer therapies, and cancer recurrence. MicroRNAs (miRNAs) are involved in tumorigenicity by regulating specific oncogenes and tumor‐suppressor genes, and their roles in BCSCs are becoming apparent. A novel, 3‐dimensional (3D), semisolid culture system was established to culture MCF‐7 spheroid cells with high percentage of BCSCs. The differences in miRNA expression among the MCF‐7 parental cells, BCSC‐enriched MCF‐7 spheroid cells, and CD44 ⁺ /CD24 ⁻ MCF‐7 cells were evaluated by miRNA microarray, and the high expression of miR‐210 in MCF‐7 spheroid cells and CD44 ⁺ /CD24 ⁻ MCF‐7 cells was verified by quantitative RT‐PCR. MCF‐7 cells were cultured in a hypoxic chamber to detect the effect of hypoxia on miR‐210 expression and the sternness of the cells. The 3‐(4,5‐dimethylthiazol‐2‐ yl )‐2,5‐diphenyl tetrazolium bromide (MTT), transwell, and sphere‐formation assays were performed to detect the proliferation, migration, and self‐renewal ability of miR‐210– overexpressed MCF‐7 cells and MCF‐7 spheroid cells with miR‐210 knocked down. The target of miR‐210 was validated with a dual‐luciferase reporter assay and Western blotting. In vivo xenograft assay and metastasis assay were performed to study the effects of miR‐210 targeting E‐cadherin on BCSCs growth and lung metastasis, and the tumors were assessed by immunohistochemistry and immunofluorescence. We developed a novel 3D, semisolid culture system to culture MCF‐7 spheroid cells, which are enriched in BCSCs, and found, by performing miRNAs expression profiling, miR‐210 was up‐regulated in those cells compared with MCF‐7 parental cells. High miR‐210 expression was also detected in CD44 ⁺ /CD24 ⁻ MCF‐7 cells and human CD44 ⁺ /CD24 ⁻ breast cancer cells, which was demonstrated to be partially due to the hypoxic microenvironment around BCSCs in MCF‐7 spheroids or solid tumors. Ectopic expression of miR‐210 in MCF‐7 cells promoted their migration, invasion, proliferation, and selfrenewal in both in vitro and in vivo studies. We further reported that miR‐210 suppressed E‐cadherin expression by targeting the open reading frame region of E‐cadherin mRNA and by up‐regulation of E‐cadherin transcription repressor, Snail. Accordingly, E‐cadherin overexpression compromises the migration, invasion, proliferation, and self‐renewal ability of miR‐210–overexpressed MCF‐7 both in vitro and in vivo . These findings reveal a novel regulatory pathway centered on hypoxia‐mediated miR‐210 targeting of E‐cadherin, which contributes to the properties and breast tumorigenesis of BCSCs.—Tang, T., Yang, Z., Zhu, Q., Wu, Y., Sun, K., Alahdal, M., Zhang, Y., Xing, Y., Shen, Y., Xia, T., Xi, T., Pan, Y., Jin, L. Up‐regulation of miR‐210 induced by a hypoxic microenvironment promotes breast cancer stem cell metastasis, proliferation, and self‐renewal by targeting E‐cadherin. FASEB J. 32, 6965–6981 (2018). www.fasebj.org

IRE1 is an important central regulator of unfolded protein response (UPR) in the endoplasmic reticulum (ER) because of its ability to regulate cell fate as a function of stress sensing. When misfolded proteins accumulated in chondrocytes ER, IRE1 disintegrates with BIP/GRP78 and undergoes dimer/oligomerization and transautophosphorylation. These two processes are mediated through an enzyme activity of IRE1 to activate endoribonuclease and generates XBP1 by unconventional splicing of XBP1 messenger RNA. Thereby promoting the transcription of UPR target genes and apoptosis. The deficiency of inositol‐requiring enzyme 1α (IRE1α) in chondrocytes downregulates prosurvival factors XBP1S and Bcl‐2, which enhances the apoptosis of chondrocytes through increasing proapoptotic factors caspase‐3, p‐JNK, and CHOP. Meanwhile, the activation of IRE1α increases chondrocyte viability and reduces cell apoptosis. However, the understanding of IRE1 responses and cell death fate remains controversial. This review provides updated data about the role IRE1 plays in chondrocytes and new insights about the potential efficacy of IRE1 regulation in cartilage repair and osteoarthritis treatment.

Poor antigenic presentation of tumor tissues and a lack of specific targets currently limit the success of nanoparticle delivery system. Cellular carrier technique has been recently explored extensively as a substitutive or supplement for traditional targeting delivery system. Here, we demonstrate the usage of mesenchymal stem cells (MSCs) loaded with doxorubicin containing polymer nanoparticles in pulmonary melanoma metastases therapy, as a modified technique of targeted delivery system. The characterizations of prepared nanoparticles and MSCs sensitivity to DOX and PLGA-DOX were measured. In vitro tumor tropism, and in vivo distributions of nanoparticles loaded MSCs were also investigated. The findings have demonstrated that, the modified system not only integrates the controlled-release property of nanoparticles but also exhibits tumor tropism and penetrative characteristics of MSCs. Furthermore, the in vitro and in vivo anti-tumor study has demonstrated that drug loaded MSCs had potent efficacy in lung melanoma metastases treatment.

Exhaustion of immune cells in COVID-19 remains a serious concern for infection management and therapeutic interventions. As reported, immune cells such as T effector cells (Teff), T regulatory cells (Tregs), natural killer cells (NKs), and antigen-presenting cells (APCs) exhibit uncontrolled functions in COVID-19. Unfortunately, the mechanisms that orchestrate immune cell functionality and virus interaction are still unknown. Recent studies linked adaptive immune cell exhaustion to underlying epigenetic mechanisms that regulate the epigenetic transcription of inhibitory immune checkpoint receptors (ICs). Further to that, the over-activation of T cells accompanied by the dysfunctionality of DCs and Tregs may enhance uncontrollable alveoli inflammation and cytokine storm in COVID-19. This might explain the reasons behind the failure of DC-based vaccines in inducing sufficient anti-viral responses. This review explains the processes behind the over-activation and exhaustion of innate and adaptive immune cells in COVID-19, which may contribute to developing novel immune intervention strategies.

Dendritic cells (DCs) are a cluster of heterogeneous antigen-presenting cells that play a pivotal role in both innate and adaptive immune responses. Rare reports have discussed their role in OA immunopathogenesis. Recently, DCs derived from the synovial fluid of OA mice were shown to have increased expression of toll-like receptors. Moreover, from in vitro studies it was concluded that DCs derived from OA patients had secreted high levels of inflammatory cytokines. Likewise, a significant increase in CD123+BDCA-2 plasmacytoid DCs has been observed in the synovial fluid of OA patients. Furthermore, DCs have a peripheral tolerance potential and can become regulatory under specific circumstances. This could be exploited as a promising tool to eliminate immunoinflammatory manifestations in OA disease. In this review, the potential roles DCs could play in OA pathogenesis have been described. In addition, suggestions for the development of new immunotherapeutic strategies involving intra-articular injections of tolerogenic plasmacytoid DCs for treating OA inflammations have been made.

Background: To date, standardising clinical predictive biomarkers for assessing the response to immunotherapy remains challenging due to variations in personal genetic signatures, tumour microenvironment complexities and epigenetic onco‐mechanisms.Main body: Early monitoring of key non‐coding RNA (ncRNA) biomarkers may help in predicting the clinical efficacy of cancer immunotherapy and come up with standard predictive ncRNA biomarkers. For instance, reduced miR‐125b‐5p level in the plasma of non‐small cell lung cancer patients treated with anti‐PD‐1 predicts a positive outcome. The level of miR‐153 in the plasma of colorectal cancer patients treated with chimeric antigen receptor T lymphocyte (CAR‐T) cell therapy may indicate the activation of T‐cell killing activity. miR‐148a‐3p and miR‐375 levels may forecast favourable responses to CAR‐T‐cell therapy in B‐cell acute lymphoblastic leukaemia. In cancer patients treated with the GPC3 peptide vaccine, serum levels of miR‐1228‐5p, miR‐193a‐5p and miR‐375‐3p were reported as predictive biomarkers of good response and improved overall survival. Therefore, there is a critical need for further studies to elaborate on the key ncRNA biomarkers that have the potential to predict early clinical responses to immunotherapy.Conclusion: This review summarises important predictive ncRNA biomarkers that were reported in cancer patients treated with different immunotherapeutic modalities, including monoclonal antibodies, small molecule inhibitors, cancer vaccines and CAR‐T cells. In addition, a concise discussion on forthcoming perspectives is provided, outlining technical approaches for the optimal utilisation of immunomodulatory ncRNA biomarkers as predictive tools and therapeutic targets.