Bile salt hydrolase plays an important role in bile acid-mediated signaling pathways, which regulate lipid absorption, glucose metabolism, and energy homeostasis. Several reports suggest that changes in the composition of bile acids are found in many diseases caused by dysbacteriosis. Here, we present the taxonomic identification of bile salt hydrolase (BSH) in human microbiota and elucidate the abundance and activity differences of various bacterial BSH among 11 different populations from six continents. For the first time, we revealed that bile salt hydrolase protein sequences (BSHs) are distributed in 591 intestinal bacterial strains within 117 genera in human microbiota, and 27.52% of these bacterial strains containing BSH paralogs. Significant variations are observed in BSH distribution patterns among different populations. Based on phylogenetic analysis, we reclassified these BSHs into eight phylotypes and investigated the abundance patterns of these phylotypes among different populations. From the inspection of enzyme activity among different BSH phylotypes, BSH-T3 showed the highest enzyme activity and is only found in Lactobaclillus. The phylotypes of BSH-T5 and BSH-T6 mainly from Bacteroides with high percentage of paralogs exhibit different enzyme activity and deconjugation activity. Furthermore, we found that there were significant differences between healthy individuals and patients with atherosclerosis and diabetes in some phylotypes of BSHs though the correlations were pleiotropic. This study revealed the taxonomic and abundance profiling of BSH in human gut microbiome and provided a phylogenetic-based system to assess BSHs activity by classifying the target sequence into specific phylotype. Furthermore, the present work disclosed the variation patterns of BSHs among different populations of geographical regions and health/disease cohorts, which is essential to understand the role of BSH in the development and progression of related diseases.

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

Breast cancer is the most prevalent cancer in women worldwide, which remains incurable once metastatic. Breast cancer stem cells (BCSCs) are a small subset of breast cancer cells which are essential in tumor formation, metastasis, and drug resistance. microRNAs (miRNAs) play important roles in the breast cancer cells and BCSCs by regulating specific genes. In this study, we found that miR-29a was up-regulated in BCSCs, in aggressive breast cancer cell line and in breast cancer tissues. We also confirmed suppressor of variegation 4–20 homolog 2 (SUV420H2), which is a histone methyltransferase that specifically trimethylates Lys-20 of histone H4 (H4K20), as the target of miR-29a. Both miR-29a overexpression and SUV420H2 knockdown in breast cancer cells promoted their migration and invasion in vitro and in vivo. Furthermore, we discovered that SUV420H2-targeting miR-29a attenuated the repression of connective tissue growth factor (CTGF) and growth response protein-1 (EGR1) by H4K20 trimethylation and promoted the EMT progress of breast cancer cells. Taken together, our findings reveal that miR-29a plays critical roles in the EMT and metastasis of breast cancer cells through targeting SUV420H2. These findings may provide new insights into novel molecular therapeutic targets for breast cancer.

B cell dysfunction due to obesity can be associated with alterations in the levels of micro-RNAs (miRNAs). However, the role of miRNAs in these processes remains elusive. Here, we show that miR-802 is increased in the pancreatic islets of obese mouse models and demonstrate that inducible transgenic overexpression of miR-802 in mice causes impaired insulin transcription and secretion. We identify Foxo1 as a transcription factor of miR-802 promoting its transcription, and NeuroD1 and Fzd5 as targets of miR-802-dependent silencing. Repression of NeuroD1 in β cell and primary islets impairs insulin transcription and reduction of Fzd5 in β cell, which, in turn, impairs Ca²⁺ signaling, thereby repressing calcium influx and decreasing insulin secretion. We functionally create a novel network between obesity and β cell dysfunction via miR-802 regulation. Elucidation of the impact of obesity on microRNA expression can broaden our understanding of pathophysiological development of diabetes.

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.

Pancreatic β-cell compensation is a major mechanism in delaying T2DM progression. Here we report the abnormal high expression of circGlis3 in islets of male mice with obesity and serum of people with obesity. Increasing circGlis3 is regulated by Quaking (QKI)-mediated splicing circularization. circGlis3 overexpression enhances insulin secretion and inhibits obesity-induced apoptosis in vitro and in vivo. Mechanistically, circGlis3 promotes insulin secretion by up-regulating NeuroD1 and Creb1 via sponging miR-124-3p and decreases apoptosis via interacting with the pro-apoptotic factor SCOTIN. The RNA binding protein FUS recruits circGlis3 and collectively assemble abnormal stable cytoplasmic stress granules (SG) in response to cellular stress. These findings highlight a physiological role for circRNAs in β-cell compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to prevent β-cell dysfunction and apoptosis after obesity.