Tanshinone I limits inflammasome activation of macrophage via docking into Syk to alleviate DSS-induced colitis in mice.

Tanshinone I (Tan I) has been proven to exert an anti-inflammatory effect, but the complete mechanism remains unclear. In this study, Tan I was described to have no effect on Syk expression in resting or LPS-stimulated macrophages ex vivo, but dramatically suppressed Syk phosphorylation and CD80, CD86, and IL-1ß expression of macrophages. The inflammatory activity of macrophages in ApoC3-transgenic (ApoC3TG) mice is upregulated by Syk activation. Tan I was determined to downregulate Syk phosphorylation and inflammatory activity of macrophages in ApoC3TG mice, both ex vivo and in vivo. Intraperitoneal injection of Tan I (4 mg/kg) effectively alleviated DSS-induced colitis in mice, accompanying with suppressing the activation of intestinal macrophages. Mechanistically, Tan I-treated macrophages exhibited a decrease in cytoplasmic ROS, NLRP3, GSDMD, and IL-1ß, which suggested that the alternative pathway of inflammasome activation in macrophages was suppressed. The SPR assay demonstrated that Tan I bound to Syk protein with a dissociation constant (KD) of 2.473 × 10-6 M. When Syk expression was knocked down by its shRNA, the inhibitory effects of Tan I on macrophages were blocked. Collectively, Tanshinone I effectively alleviated DSS-induced colitis in mice by inhibiting Syk-stimulated inflammasome activation, hence suppressing the inflammatory activity of macrophages.

Yin Yang 1-Induced Long Noncoding RNA DUXAP9 Drives the Progression of Oral Squamous Cell Carcinoma by Blocking CDK1-Mediated EZH2 Degradation.

LncRNAs play a critical role in oral squamous cell carcinoma (OSCC) progression. However, the function and detailed molecular mechanism of most lncRNAs in OSCC are not fully understood. Here, a novel nuclear-localized lncRNA, DUXAP9 (DUXAP9), that is highly expressed in OSCC is identified. A high level of DUXAP9 is positively associated with lymph node metastasis, poor pathological differentiation, advanced clinical stage, worse overall survival, and worse disease-specific survival in OSCC patients. Overexpression of DUXAP9 significantly promotes OSCC cell proliferation, migration, invasion, and xenograft tumor growth and metastasis, and upregulates N-cadherin, Vimentin, Ki67, PCNA, and EZH2 expression and downregulates E-cadherin in vitro and in vivo, whereas knockdown of DUXAP9 remarkably suppresses OSCC cell proliferation, migration, invasion, and xenograft tumor growth in vitro and in vivo in an EZH2-dependent manner. Yin Yang 1 (YY1) is found to activate the transcriptional expression of DUXAP9 in OSCC. Furthermore, DUXAP9 physically interacts with EZH2 and inhibits EZH2 degradation via the suppression of EZH2 phosphorylation, thereby blocking EZH2 translocation from the nucleus to the cytoplasm. Thus, DUXAP9 can serve as a promising target for OSCC therapy.

Unveiling the Noncanonical Autophagy-Independent Role of ATG7 and ATG9B in Head and Neck Squamous Cell Carcinoma (HNSCC).

The role of autophagy in cancer remains elusive, and nontargeted autophagy inhibitors have limited therapeutic effects in HNSCC. Here, we systematically analyzed the correlation of autophagy-related genes in HNSCC through TCGA and single-cell sequencing data (GSE103322). ATG9B and ATG7 were found to have noncanonical autophagy-independent functions in HNSCC. Specifically, ATG9B was a protective factor in HNSCC patients through downregulating cancer cell EMT, and ATG7 was correlated with the immunosuppressive environment in HNSCC. Mechanistically, single-cell analysis revealed that ATG9B increased the epithelial phenotype of cancer cells but did not influence EMT signaling pathways. ATG7 was strongly correlated with elevated immunosuppressive checkpoints like PD-1, PD-L1, and CTLA4 in HNSCC. Further single-cell analysis and multiple immunofluorescence colocalization analyses indicated that ATG7 contributed to the high expression of PD-L1 in myeloid cells but not cancer cells. Collectively, our results revealed noncanonical autophagy-independent functions of autophagy-related genes. These results increase understanding of the intricacies of autophagy and may contribute to precision treatment using autophagy-targeted therapies.

The CC ligand chemokine family members CCL17/CCL22 predict the survival and response to immune checkpoint blockade therapy of patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is considered an immunosuppressive malignancy. Cross-talk between cancer cells and immune cells is modulated in part by CC ligand (CCL) chemokines, having a major effect on tumor progression. However, the predictive value and function of CCL family members in HNSCC have not been elucidated. Here, the predictive value of CCL members in cancer prognosis and Immune checkpoint blockade therapy response was investigated. CCL17 and CCL22 were screened as the key CCL chemokines in HNSCC through co-expression analysis. Further, the correlation between CCL17/CCL22 expression and cancer immune infiltration were evaluated based on TIMER and were validated by a set of scRNA-seq data. Moreover, the expression level of CCL17/CCL22 we evaluated to predict the response to Immune checkpoint blockade therapy in a panel of cancer types by using the TIDE database. Results indicated that CCL17/CCL22 had a high co-expression correlation and had a marginally statistical significance with the overall survival in HNSCC patients (P value = 0.057 and 0.055, respectively). Our findings showed high expression of CCL17/CCL22 was positively correlated with CD4+ T cell infiltration levels in HNSCCs and activate mTORC1 signaling pathway in CD4+ T cells. Further analysis from TIDE showed the high expression of CCL17/CCL22 might predict favorable responses to immune checkpoint blockade therapy in HNSCC patients. These findings provide an insight into the predictive roles of CCL17/CCL22 in HNSCC.

Survivin Impairs the Apoptotic Machinery in CD4+ T Cells of Patients with Ulcerative Colitis.

BACKGROUND: The increase in CD4+ T cell infiltration and overproduction of CD4+ T cell-associated cytokines have been observed in the inflamed colon mucosa of patients with ulcerative colitis (UC); the underlying mechanisms are not fully understood. Survivin plays a critical role in the interference with apoptotic machinery. This study aims to elucidate the role of survivin in the interference with the apoptotic machinery in CD4+ T cells of UC patients. METHODS: Peripheral blood samples were collected from UC patients (UC group) and healthy subjects (healthy group). The apoptotic status in CD4+ T cells was analyzed by flow cytometry. RESULTS: We observed that the expression of survivin was significantly higher in CD4+ T cells of UC patients than in healthy subjects. UC CD4+ T cells were resistant to apoptosis induction. A complex of survivin and c-Myc, the transcription factor of FasL, was detected in CD4+ T cells in UC patients, which prevented the binding of c-Myc to the FasL promoter and interfered with the expression of FasL. Increased expression of survivin prevented the activation-induced CD4+ T cells from apoptosis. CONCLUSIONS: The data indicate that UC CD4+ T cells express high levels of survivin, which impairs the apoptotic machinery in CD4+ T cells and prevents the activation-induced CD4+ T cell apoptosis. Therefore, target therapy against survivin has translational potential in the treatment of UC patients.

Survivin induces defects in apoptosis in eosinophils in intestine with food allergy.

Survivin is an anti-apoptosis protein that may be associated with the development of eosinophilia; the latter is associated with the pathogenesis of many immune disorders. Here we report that less apoptotic eosinophils (Eos) were induced in those isolated from mice suffering from food allergy (FA) than those from naive mice after treating with cisplatin in vitro. Exposure to cisplatin induced more Fas ligand (FasL) expression in Eos isolated from naive mice than in those of FA mouse. Survivin was detected in the intestinal tissue extracts in much higher amounts in the FA group than in the naive group. Immunohistochemistry showed that epithelial cells were the major source of survivin in the intestine. Exposure to IL-4 or IL-13 up-regulated the expression of survivin in intestinal epithelial cells. Survivin interfered with the expression of FasL in Eos. Inhibition of survivin attenuated the eosinophilia-related inflammation in the intestine. In conclusion, intestinal epithelial cell-produced survivin induced defects in apoptosis in Eos to contribute to eosinophilia in the intestine. Inhibition of survivin can suppress the eosinophilia-related intestinal inflammation. The data suggest that survivin may be a novel target for the treatment of FA.