The phosphorylation of hCDC14A modulated by ZIPK regulates autophagy of murine pancreatic islet ß-TC3 cells upon glucose stimulation.

OBJECTIVE: Depletion of islet ß cells plays a crucial role in the onset of diabetes mellitus. Cell autophagy, as a self-healing process, contributes to maintaining metabolic homeostasis and can protect islet ß cells from apoptosis upon starvation or high glucose stress. However, the underlying regulatory network of the autophagic process in islet ß cells has not been fully explored. MATERIALS AND METHODS: Murine ß-TC3 cells treated with different concentrations of glucose, and wild-type or the Ser484 mutant human cell division cycle gene 14A (hCDC14A) was transfected. Cell viability, proliferation and autophagy as well as islet secretion were studied. The mTOR and AMPK signaling pathways were investigated by western blots. Zipper-interacting protein kinase was studied using mass spectrometry and immunoprecipitation. RESULTS: Overexpression of wild-type hCDC14A, but not the Ser484 mutant hCDC14A, promoted cell viability, proliferation and autophagy accompanied by enhanced islet secretion and reduced cell apoptosis via mTOR pathway inhibition as well AMPK pathway activation in ß-TC3 cells and vice versa. Furthermore, Zipper-interacting protein kinase (ZIPK), also known as DAPK3, was found to interact with hCDC14A primarily for Ser484 phosphorylation, and ZIPK knockdown could affect the phosphorylation of hCDC14A and weaken cell death or cell cycle modulation. CONCLUSIONS: Taken together, our results may provide new insight into the role of hCDC14A in the autophagy of islet ß cells and suggest the potential therapeutic value of hCDC14A phosphorylation in the prevention and treatment of diabetes.

Intratumoral IL17-producing cells infiltration correlate with antitumor immune contexture and improved response to adjuvant chemotherapy in gastric cancer.

BACKGROUND: Tumor IL17-producing (IL17A+) cells infiltration has different prognostic values among various cancers. The objective of this study was to assess the effect of IL17A+ cells in gastric cancer. PATIENTS AND METHODS: The study included two patient cohorts, the Cancer Genome Atlas cohort (TCGA, n = 351) and the Zhongshan Hospital cohort (ZSHC, n = 458). The TCGA and ZSHC were used for mRNA-related and cells infiltration-related analyses, respectively. The roles of IL17A mRNA and IL17A+ cells in overall survival (OS), response to adjuvant chemotherapy (ACT), and immune contexture were evaluated. Another independent cohort was included to identify the correlation between mRNA of IL17A and IL17A+ cells infiltration (the preliminary Zhongshan Hospital cohort, PZSHC, n = 21). RESULTS: The infiltration of IL17A+ cells was positively correlated with the expression of IL17A mRNA (Spearman's ρ = 0.811; P < 0.001). High IL17A mRNA expression and intratumoral IL17A+ cells were correlated with improved OS and remained to be significant after adjusted for confounders. Patients with TNM II/III disease whose tumor present higher intratumoral IL17A+ cells or lower peritumoral IL17A+ cells can benefit more from ACT. Elevated IL17A mRNA expression and increased intratumoral IL17A+ cells infiltration was associated with more antitumor mast cells and nature killer cells infiltration and less pro-tumor M2 macrophages infiltration. High IL17A mRNA expression represented a Th17 cells signature and immune response process and was correlated with increased cytotoxic GZMA, GZMB, IFNG, PRF1, and TNFSF11 expression. CONCLUSIONS: IL17A mRNA expression and intratumoral IL17A+ cells infiltration were correlated with antitumor immune contexture. IL17A+ cells infiltration could be used as an independent prognostic biomarker for OS and predictive biomarker for superior response to ACT, and further prospective validation needs to be conducted.