Cell Death Dis. 2019 Mar 4;10(3):223. doi: 10.1038/s41419-019-1443-2.
MicroRNA-184 promotes apoptosis of trophoblast cells via targeting WIG1 and induces early spontaneous abortion.
Zhang Y1, Zhou J2, Li MQ3, Xu J2, Zhang JP4, Jin LP5.
Author information
1 Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, People's Republic of China.
2 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, 215123, People's Republic of China.
3 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, 200011, People's Republic of China.
4 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, 215123, People's Republic of China. j_pzhang@suda.edu.cn.
5 Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, People's Republic of China. jinlp01@163.com.
Abstract
Recurrent spontaneous abortion (RSA) refers to the unintentional termination of two or more consecutive pregnancies that severely threatens human reproductive health. Our previous study has shown that miR-184 is expressed more highly in RSA than in normal pregnancy, whether in the villus or decidua. In this study, compared with normal pregnant women, the expression of miR-184 in decidual stromal cells (DSCs) and decidual immune cells (DICs), as well as in peripheral blood, from RSA patients was enhanced similarly. Moreover, we found miR-184 could promote the apoptosis and repress the proliferation of trophoblast cells. Further exploration indicated that miR-184 upregulated the expression of Fas by targeting WIG1 thus inducing cell apoptosis. Finally, after miR-184 overexpression in vivo, the embryo resorption rate in pregnant mice was increased significantly. Therefore, our study outlines the pivotal role of miR-184 in maintaining successful pregnancy, providing a new diagnostic and therapeutic target for RSA.
Immunol Cell Biol. 2019 Feb;97(2):142-151. doi: 10.1111/imcb.12204. Epub 2018 Oct 21.
LPS expands MDSCs by inhibiting apoptosis through the regulation of the GATA2/let-7e axis.
Yang Y1, Sun D1, Zhou J1, Tan C1, Zhang H2, Chen Z3, Hao C3, Zhang J1.
Author information
1 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
2 Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
3 Department of Respiratory Disease, Children's hospital of Soochow University, Suzhou, China.
Abstract
Myeloid-derived suppressor cells (MDSCs) represent a group of immature myeloid cells composed of myeloid progenitor cells and immature myeloid cells that can negatively regulate immune responses by inhibiting T-cell function. In mice, MDSCs are broadly defined by the expression of CD11b and Gr1. We and others have shown that injection of a lethal or sublethal dose of lipopolysaccharide (LPS) into mice could result in the expansion of MDSCs in the bone marrow (BM), spleen and blood. Until now, the molecular mechanisms responsible for this expansion are poorly studied; specifically, the roles of the individual microRNAs (miRNAs) which may be involved remain largely unknown. We performed microarray analysis to compare the miRNA expression profiles of CD11b+ Gr1+ cells sorted from the BM of LPS-injected and phosphate-buffered saline-injected mice. We identified let-7e, which was highly upregulated in the LPS-treated group, as a potent regulator of LPS-induced MDSC expansion. Furthermore, let-7e overexpression in BM chimeric mice led to a noticeable increase in the population of CD11b+ Gr1+ cells, which resulted from reduced cellular apoptosis. Further studies showed that let-7e could directly target caspase-3 to inhibit cell apoptosis, and upregulation of let-7e in LPS-stimulated MDSCs could be due to the relieved repression of let-7e transcription exerted by downregulated GATA2. Our findings suggest that LPS expands MDSCs by inhibiting apoptosis through the regulation of the GATA2/let-7e axis.
Exp Cell Res. 2018 Oct 15;371(2):364-371. doi: 10.1016/j.yexcr.2018.08.030. Epub 2018 Aug 25.
Melanoma-released exosomes directly activate the mitochondrial apoptotic pathway of CD4+ T cells through their microRNA cargo.
Zhou J1, Yang Y1, Wang W1, Zhang Y2, Chen Z3, Hao C3, Zhang J4.
Author information
1 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, People's Republic of China.
2 Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, People's Republic of China.
3 Department of respiratory disease, Children's hospital of Soochow University, Suzhou, Jiangsu Province 215025, People's Republic of China.
4 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, People's Republic of China. Electronic address: j_pzhang@suda.edu.cn.
Abstract
Tumor-derived exosomes (TEX) play an important role in the escape of tumor cells from immune surveillance. However, the details of the mechanism are not fully understood. In this study, the apoptosis of CD4+ T cells increased during treatment with B16-derived exosomes in vitro and in vivo, resulting in accelerated growth of melanoma cells in mice. While the release of exosomes was blocked by disrupting the expression of Rab27a, tumor growth was clearly inhibited, and the percentage of T cells in the tumor environment increased. At the same time, Western blot showed that TEX could increase the activation of caspase-3, caspase-7 and caspase-9 but not caspase-8, down-regulating the anti-apoptotic proteins, including BCL-2, MCL-1 and BCL-xL in CD4+ T cells, and indicating that the TEX activates the mitochondrial apoptotic pathway of CD4+ T cells. These reductions were probably associated with the release of microRNAs, such as miR-690, from TEX to T cells. Our present study reveals for the first time that melanoma-released exosomes may directly activate the mitochondrial apoptotic pathway of CD4+ T cells through their microRNA cargo.
J Biol Chem. 2018 Aug 17;293(33):12934-12944. doi: 10.1074/jbc.RA117.001267. Epub 2018 Jun 15.
The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice.
Yang Y1,2, Kong S2, Zhang Y2,3, Melo-Cardenas J2, Gao B2, Zhang Y2, Zhang DD4, Zhang B5, Song J6, Thorp E2, Zhang K7, Zhang J8, Fang D9.
Author information
1 From the Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
2 the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
3 the Department of Otolaryngology, Head and Neck Surgery of Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, China.
4 the Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721.
5 the Department of Medicine, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
6 the Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 16801, and.
7 the Department of Immunology and Microbiology, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48201.
8 From the Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China, j_pzhang@suda.edu.cn.
9 the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, fangd@northwestern.edu.
Abstract
Humoral immunity involves multiple checkpoints that occur in B cell development, maturation, and activation. The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy-chain gene, and sSignalsing through the pre-BCR are required for the differentiation of pre-B cells into immature B cells. However, the molecular mechanisms controlling the pre-BCR expression and signaling strength remain undefined. Herein, we probed the role of the endoplasmic reticulum-associated, stress-activated E3 ubiquitin ligase HMG-CoA reductase degradation 1 (Hrd1) in B cell differentiation. Using mice with a specific Hrd1 deletion in pro-B cells and subsequent B cell developmental stages, we showed that the E3 ubiquitin ligase Hrd1 governs a critical checkpoint during B cell development. We observed that Hrd1 is required for degradation of the pre-BCR complex during the early stage of B cell development. As a consequence, loss of Hrd1 in the B cell lineage resulted in increased pre-BCR expression levels and a developmental defect in the transition from large to small pre-B cells. This defect, in turn, resulted in reduced fewer mature B cells in bone marrow and peripheral lymphoid organs. Our results revealed a novel critical role of Hrd1 in controlling a critical checkpoint in B cell-mediated immunity and suggest that Hrd1 may functioning as an E3 ubiquitin ligase of the pre-BCR complex.