Zinc finger E-box binding homeobox 1 (ZEB1, also termed TCF8 and δEF1) is a crucial member of the zinc fingerhomeodomain transcription factor family, originally identified as a binding protein of the lens-specific δ1-crystalline enhancer and is a pivotal transcription factor in the epithelial-mesenchymal transition (EMT) process. ZEB1 also plays a vital role in embryonic development and cancer progression, including breast cancer progression. Increasing evidence suggests that ZEB1 stimulates tumor cells with mesenchymal traits and promotes multidrug resistance, proliferation, and metastasis, indicating the importance of ZEB1-induced EMT in cancer development. ZEB1 expression is regulated by multiple signaling pathways and components, including TGF-β, β-catenin, miRNA and other factors. Here, we summarize the recent discoveries of the functions and mechanisms of ZEB1 to understand the role of ZEB1 in EMT regulation in breast cancer.

Interleukin-33 (IL-33) is a recently identified cytokine, an important member of the interleukin-1 family. IL-33 binds to its receptor ST2 to induce type 2 cytokines and exert both pro-inflammatory and protective functions in host defense and disease. Murine breast carcinoma models suggest disruption of ST2 signaling may enhance the anti-tumor immune response, suggesting IL-33 impedes anti-tumor immunity. However, the role of IL-33 in patients with breast cancers (BC) is not elucidated. We detected the expression of IL-33 in tumor tissue, and IL-33 and its related cytokines in serum from BC patients. Using Luminex and immunohistochemistry methods, we found that serum levels of IL-33 were nearly twofold higher in patients with BC, compared to patients with benign breast diseases. In cancer tissues, expression of IL-33 was higher than matched normal breast tissues from the same patients, and was also associated with a well-differentiated phenotype, HER2 overexpression, more lymph nodes involvement, and a family history of malignant carcinoma. These results suggest that IL-33 may play an important role in the progress of BC and may be a useful biomarker for predicting the progress and metastasis of BC.

The human Interleukin-33 (IL-33), a member of the IL-1 family, is the cytokine as a cell endogenous alarmin, released by damaged or necrotic barrier cells (endothelial and epithelial cells). The signal transduction of IL-33 relies on recognition and interaction with specific receptor ST2, mainly expressed in immune cells. In both innate and adoptive immunity, IL-33 regulates the homeostasis in response to stress from within/out the microenvironment. Various, even negative biofunctions of IL-33 pathways have now been widely verified in pathogenesis among immunological mechanisms, like Th2-related immune-stimuli, inflammation/infection-induced tissue protectors. A larger versatility in studies of IL-33 on malignancies now focuses on: (1) promoting myeloid-derived suppressor cells (MDSC), (2) intervention toward CD8+ T, Natural Killer (NK) cell infiltration, group 2 innate lymphoid cells (ILC2) proliferation, dendritic cells (DC) activation, and (3) inhibiting tumor growth and/or further metastasis as an immunoadjuvant. Although IL-33 functioned pro-tumorigenically in various cancers, for some cancer types the findings so far are controversial. This review begins from a summarized introduction of IL-33, to its remarkable implications and molecular transduction pathway in malignant neoplasms, ends with latest inspiration for IL-33 in treatment.

RationaleAcute lung injury (ALI) is a fatal but undertreated condition with severe neutrophilic inflammation, while little is known about the functions of eosinophils in pathogenesis of ALI.ObjectivesTo investigate the roles and molecular mechanisms of eosinophils in ALI.MethodsPulmonary eosinophils were identified by flow cytometry. Mice with abundant or deficient eosinophils were used. Cellularity of eosinophils and neutrophils in BALF, inflammatory assessment, and survival rate were detected. Human samples were also used for validating experimental results.ResultsBlood eosinophils were increased in survived individuals of patients with acute respiratory distress syndrome independent of the corticosteroid usage. There existed homeostatic eosinophils in lung parenchyma in mice, and these homeostatic eosinophils in originating from the bone marrow were predominantly CD101−. More CD101− eosinophils could be recruited earlier than lipopolysaccharide (LPS)-initiated neutrophilic inflammation. Loss of eosinophils augmented LPS-induced pulmonary injury. Homeostatic CD101− eosinophils ameliorated, while allergic CD101+ eosinophils exacerbated, the neutrophilic inflammation induced by LPS. Likewise, CD101 expression in eosinophils from ARDS patients did not differ from the healthy subjects. Mechanistically, CD101− eosinophils exhibited higher levels of Alox15 and Protectin D1. Administration of Protectin D1 isomer attenuated the neutrophilic inflammation.ConclusionsCollectively, our findings identify an uncovered function of native CD101− eosinophils in suppressing neutrophilic lung inflammation and suggest a potential therapeutic target for ALI.

IntroductionEosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs).MethodsEosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation.ResultsTreatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo.ConclusionsFINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.

Identification of modifiable dietary factors, which are involved in the development of gestational diabetes mellitus (GDM), could inform strategies to prevent GDM. Therefore, we examined the dietary nutrient patterns and evaluated their relationship with GDM risk in a Chinese population using a case control study design. A total of 1,464 GDM cases and 8,092 non-GDM controls were included in the final analysis. Dietary intake was assessed using a 33-item food frequency questionnaire, and nutrients were estimated using the Chinese Standard Tables of Food Consumption. Dietary nutrient patterns were identified using factor analysis, and their associations with GDM risk were evaluated using unconditional logistic regression models adjusting for total energy intake, maternal age, high blood pressure, education, maternal body mass index (BMI), parity, and family history of diabetes. A “vitamin” nutrient pattern was characterized as the consumption of diet rich in vitamin A, carotene, vitamin B2, vitamin B6, vitamin C, dietary fiber, folate, calcium, and potassium. For every quartile increase in the vitamin factor score during one year prior to conception, the first trimester, and the second trimester of pregnancy, the GDM risk decreased by 9% (OR: 0.91, 95%CI: 0.86-0.96), 9% (OR: 0.91, 95%CI: 0.86-0.96), and 10% (OR: 0.90, 95%CI: 0.85-0.95), respectively. The significant reduced GDM risk was seen in women regardless of age and parity, and slightly stronger effect was found in women whose age≤30 and women who are nulliparous across the three time periods. The significant association was also found in women whose BMI≤24 with similar effect size across the three time periods. Our study suggests that the vitamin nutrient pattern diet is associated with decreased GDM risk. Additional studies are necessary to explore the underlying mechanism of this relationship.

Objective. To investigate the expression patterns and prognostic values of STEAP family members in the occurrence and development of breast cancer. Materials and Methods. The Human Protein Atlas was used to analyze the expression level of STEAPs in human normal tissues and malignant tumors. ONCOMINE datasets were analyzed for the comparison of the STEAPs levels between malignant cancers and corresponding normal tissues. Kaplan-Meier plotter was used to analyze the prognostic value of STEAPs in breast cancer patients. Results. STEAPs were widely distributed in human normal tissues with diverse levels. Normally, it is predicted that STEAP1 and STEAP2 were involved in the mineral absorption process, while STEAP3 participated in the TP53 signaling pathway and iron apoptosis. The results from ONCOMINE showed downregulation of STEAP1, STEAP2, and STEAP4 in breast cancers. Survival analysis revealed that breast cancer patients with high levels of STEAP1, STEAP2, and STEAP4 had a good prognosis, while those with low expression had high overall mortality. Conclusion. STEAP1, STEAP2, and STEAP4 are predicted to be the potential prognostic biomarkers for breast cancer patients, providing novel therapeutic strategies for them.

Long non-coding RNA (lncRNA) forkhead box P4 antisense RNA 1 (FOXP4-AS1) has been determined to function as an oncogene in various types of cancer. However, the biological function and the underlying mechanisms of FOXP4-AS1 in mantle cell lymphoma (MCL) remain to be uncovered. The expression and the associated clinicopathological characteristics and prognostic significance of FOXP4-AS1 were explored in MCL clinical samples. The effects of FOXP4-AS1 on MCL cellular behaviors, including proliferation, migration and invasion were analyzed using CCK-8, crystal violet and Transwell assays. The downstream molecules of FOXP4-AS1 were explored using bioinformatics analysis and dual luciferase assay. Our results showed that FOXP4-AS1 expression was upregulated in MCL patients, and that the high expression of FOXP4-AS1 was correlated with the unfavorable prognosis of patients. Functionally, while FOXP4-AS1 downregulation inhibited proliferation, migration and invasion of MCL cells, FOXP4-AS1 overexpression had promotive effects on these cellular processes. Mechanistically, FOXP4-AS1 was found to act as a competing endogenous (ce)RNA for miR-423-5p to regulate the expression of nucleus accumbens-associated 1 (NACC1). The negative regulation of FOXP4-AS1 on miR-423-5p compared to that of miR-423-5p on NACC1 was determined at the mRNA or protein levels in MCL cells. Moreover, an inverse expression correlation between FOXP4-AS1 and miR-423-5p, and that between miR-423-5p and NACC1 was confirmed in MCL clinical samples. In addition, rescue assay showed that miR-423-5p upregulation or NACC1 knockdown abolished the promoting effects of FOXP4-AS1 on MCL cell proliferation, migration and invasion. In conclusion, FOXP4-AS1 promotes MCL progression through the upregulation of NACC1 expression by inhibiting miR-423-5p. FOXP4-AS1 may serve as a novel therapeutic target for patients with MCL.