Can Lin

Human FOXP3 shows two isoforms due to exon 2 skipping, and the exon 2 is critical for FOXP3 function in T _reg cells. However, the factor(s) regulating its splicing remain unknown. Here, we show that SRSF3 regulates FOXP3 exon 2 function and determines T _reg cell fate and function in autoimmunity and tumor immunity. Mechanistically, SRSF3 promoted FOXP3 exon 2 inclusion and protein expression and thus safeguarded T _reg cells, as deletion of Srsf3 gene specifically in T _reg cells resulted in profound deficiency of T _reg cells in mice, leading to lethal systemic inflammation. T _reg cells in human tumor showed high SRSF3 expression. SRSF3 was required for human T _reg cell–suppressive function. Humanized mice generated with human FOXP3 exon 2 and adjacent introns showed significantly reduced tumor formation with the decreased T _reg cell function and consequently increased intratumoral CD8 ⁺ T cell infiltration. We have thus revealed a previously unrecognized role of SRSF3 in controlling T _reg cell fate and function in antitumor immunity and autoimmunity by regulating FOXP3 exon 2 inclusion and protein expression.

Cryotherapy is a common non-pharmacological method to relieve pain and inflammation. Clinical studies have shown that cryotherapy can reduce postoperative pain after root canal therapy, but the mechanism remains unclear. In this study, we aimed to investigate the underlying molecular mechanisms by which cryotherapy reduces inflammation in lipopolysaccharide (LPS)-stimulated periodontal ligament cells through transcriptome sequencing analysis. We found that cryotherapy significantly reduced the expression of multiple proinflammatory cytokines and chemokines, and NFKB1 was the key regulator down-regulated by cryotherapy. Importantly, we discovered that lncRNA SNHG1 expression level significantly decreased after cold treatment. SNHG1 expression was positively related to NFKB1 while negatively correlated with miR-9-5p, which formed a novel ceRNA regulatory pathway. Knockdown of SNHG1 significantly reduced the expression of NFKB1, IL1B, and IL6, while overexpression of SNHG1 significantly increased the expression of these genes. In conclusion, our study demonstrated that cryotherapy can effectively reduce inflammation in LPS-induced periodontal ligament cells by suppressing the lncRNA SNHG1/miR-9-5p/NFKB1 axis.

Ki67 is a well-known proliferation marker with a large size of around 350 kDa, but its biological function remains largely unknown. The roles of Ki67 in tumor prognosis are still controversial. Ki67 has two isoforms generated by alternative splicing of exon 7. The roles and regulatory mechanisms of Ki67 isoforms in tumor progression are not clear. In the present study, we surprisingly find that the increased inclusion of Ki67 exon 7, not total Ki67 expression level, was significantly associated with poor prognosis in multiple cancer types, including head and neck squamous cell carcinoma (HNSCC). Importantly, the Ki67 exon 7-included isoform is required for HNSCC cell proliferation, cell cycle progression, cell migration, and tumorigenesis. Unexpectedly, Ki67 exon 7-included isoform is positively associated with intracellular reactive oxygen species (ROS) level. Mechanically, splicing factor SRSF3 could promote exon 7 inclusion via its two exonic splicing enhancers. RNA-seq revealed that aldo-keto reductase AKR1C2 is a novel tumor-suppressive gene targeted by Ki67 exon 7-included isoform in HNSCC cells. Our study illuminates that the inclusion of Ki67 exon 7 has important prognostic value in cancers and is essential for tumorigenesis. Our study also suggested a new SRSF3/Ki67/AKR1C2 regulatory axis during HNSCC tumor progression.

Regulatory T (Treg) cells play crucial roles in maintaining immune self-tolerance and immune homeostasis, and closely associated with many human diseases. Recently, Treg cells-derived extracellular vesicles (Treg-EVs) have been demonstrated as a novel cell-contact independent inhibitory mechanism of Treg cells. Treg-EVs contain many specific biological molecules, which are delivered to target cells and modulate immune responses by inhibiting T cell proliferation, inducing T cell apoptosis, and changing the cytokine expression profiles of target cells. The abnormal quantity or function of Treg-EVs is associated with several types of human diseases or conditions, such as transplant rejection, inflammatory diseases, autoimmune diseases, and cancers. Treg-EVs are promising novel potential targets for disease diagnosis, therapy, and drug transport. Moreover, Treg-EVs possess distinct advantages over Treg cell-based immunotherapies. However, the therapeutic potential of Treg-EVs is limited by some factors, such as the standardized protocol for isolation and purification, large scale production, and drug loading efficiency. In this review, we systematically describe the structure, components, functions, and basic mechanisms of action of Treg-EVs and discuss the emerging roles in pathogenesis and the potential application of Treg-EVs in human diseases.