MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways.

BACKGROUND & AIMS: Mucin 13 (MUC13) is reportedly overexpressed in human malignancies. However, the clinicopathological and biological significance of MUC13 in human intrahepatic cholangiocarcinoma (iCCA) remain unclear. The aim of this study was to define the role of MUC13 in the progression of iCCA. METHODS: Expression levels of MUC13 in human iCCA samples were evaluated by immunohistochemistry, western blot, and real-time PCR. In vitro and in vivo experiments were used to assess the effect of MUC13 on iCCA cell growth and metastasis. Crosstalk between MUC13 and EGFR/PI3K/AKT signaling was analyzed by molecular methods. The upstream regulatory effects of MUC13 were evaluated by Luciferase and DNA methylation assays. RESULTS: MUC13 was overexpressed in human iCCA specimens and iCCA cells. MUC13 overexpression positively correlated with clinicopathological characteristics of iCCA, such as vascular invasion and lymph node metastasis, and was independently associated with poor survival. Results from loss-of-function and gain-of-function experiments suggested that knockdown of MUC13 attenuated, while overexpression of MUC13 enhanced, the proliferation, motility, and invasiveness of iCCA cells in vitro and in vivo. Mechanistically, we found that the phosphatidylinositol 3-kinase-AKT signal pathway and its downstream effectors, such as tissue inhibitor of metalloproteinases 1 and matrix metallopeptidase 9, were required for MUC13-mediated tumor metastasis of iCCA. MUC13 interacted with epidermal growth factor receptor (EGFR) and subsequently activated the EGFR/PI3K/AKT signaling pathway by promoting EGFR dimerization and preventing EGFR internalization. We also found that MUC13 was directly regulated by miR-212-3p, whose downregulation was related to aberrant CpG hypermethylation in the promoter area. CONCLUSIONS: These findings suggest that aberrant hypermethylation-induced downregulation of miR-212-3p results in overexpression of MUC13 in iCCA, leading to metastasis via activation of the EGFR/PI3K/AKT signaling pathway. LAY SUMMARY: Mucin 13 overexpression has been implicated in the development of malignancies, although its role in intrahepatic cholangiocarcinoma has not been studied. Herein, we show that mucin 13 plays a critical role in intrahepatic cholangiocarcinoma. Mucin 13 could have therapeutic value both as a prognostic marker and as a treatment target.

[Kirenol relieves dextran sulfate sodium-induced ulcerative colitis in mice by inhibiting inflammatory cytokines and inducing CD4+ T lymphocyte apoptosis].

OBJECTIVE: To investigate whether kirenol, the major pharmacologically active compound of the Chinese medicinal herb Herba Siegesbeckiae, can protect mice from dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). METHODS: C57BL/6 mice with or without kirenol pretreatment were treated with DSS in drinking water for 7 days to induce UC. The symptoms of UC including weight loss, diarrhea and bloody stool were observed daily and graded using the disease activity index (DAI). Colon injury of the mice was assessed by measuring the length of the colon and HE staining of the colon tissue. The levels of inflammatory cytokines produced by the mesenteric lymph nodes (MLNs) lymphocytes were measured using enzyme-linked immunosorbent assay; the apoptosis of the lymphocytes and CD4+ T cells was analyzed using flow cytometry. RESULTS: The mice receiving pretreatment with kirenol showed obviously ameliorated symptoms of UC and milder pathological changes in the colon as compared with the control mice. Kirenol treatment significantly down-regulated the secretion of IFN-γ, IL-17A, IL-6 and TNF-α by the MLNs lymphocytes and increased the apoptosis of lymphocytes, especially CD4+ T cells in the DSS-treated mice. CONCLUSIONS: Kirenol can protect against T cell-mediated colon injury in DSS-treated mice possibly by suppressing the secretion of inflammatory mediators and inducing apoptosis of the inflammatory lymphocytes.

Kirenol relieves dextran sulfate sodium-induced ulcerative colitis in mice by inhibiting inflammatory cytokines and inducing CD4 T lymphocyte apoptosis / 南方医科大学学报

OBJECTIVE@#To investigate whether kirenol, the major pharmacologically active compound of the Chinese medicinal herb , can protect mice from dextran sulfate sodium (DSS)-induced ulcerative colitis (UC).@*METHODS@#C57BL/6 mice with or without kirenol pretreatment were treated with DSS in drinking water for 7 days to induce UC. The symptoms of UC including weight loss, diarrhea and bloody stool were observed daily and graded using the disease activity index (DAI). Colon injury of the mice was assessed by measuring the length of the colon and HE staining of the colon tissue. The levels of inflammatory cytokines produced by the mesenteric lymph nodes (MLNs) lymphocytes were measured using enzyme-linked immunosorbent assay; the apoptosis of the lymphocytes and CD4 T cells was analyzed using flow cytometry.@*RESULTS@#The mice receiving pretreatment with kirenol showed obviously ameliorated symptoms of UC and milder pathological changes in the colon as compared with the control mice. Kirenol treatment significantly down-regulated the secretion of IFN-γ, IL-17A, IL-6 and TNF-α by the MLNs lymphocytes and increased the apoptosis of lymphocytes, especially CD4 T cells in the DSS-treated mice.@*CONCLUSIONS@#Kirenol can protect against T cell-mediated colon injury in DSS-treated mice possibly by suppressing the secretion of inflammatory mediators and inducing apoptosis of the inflammatory lymphocytes.

Value of serum 25 hydroxy vitamin D ,homocysteine and apolipoprotein B/A1 in patients with essential hypertension / 国际检验医学杂志

Objective To investigate the value of serum 25 hydroxy vitamin D [25(OH)D] ,homocysteine (Hcy) and apolipoprotein B/A1 in patients with essential hypertension.Methods Totally 191 cases of essen-tial hypertension admitted in the hospital from May 2016 to May 2017 were selected as observation group ,and were divided into hypertension grade 1 group (54 cases) ,hypertension grade 2 group (78 cases) ,hypertension grade 3 group (59 cases) in accordance with the classification of hypertension.54 healthy people who under-went healthy assessment during the same period were selected as the control group.The changes of serum 25 (OH) D ,Hcy and apolipoprotein B/A1 ,and the sensitivity and the specificity of combined detection of 25 (OH)D ,Hcy and apolipoprotein B/A1 were compared.Results The serum 25 (OH) D level in the observa-tion group was lower than that in the control group ,while the levels of Hcy and apolipoprotein B/A1 were higher than those in the control group ,and the differences were statistically significant (P＜0.05).The level of serum 25 (OH) (OH) D in hypertension grade 3 group was lower than those in hypertension grade 2 group and hypertension grade 1 group ,but the levels of Hcy and apolipoprotein B/A1 were higher than those in hy-pertension grade 2 group and hypertension grade 1 group ,and the differencs were statistically significant (P＜0.05) ;the level of serum 25 (OH) D in hypertension grade 2 group was lower than that in hypertension grade 1 group ,but the levels of Hcy and apolipoprotein B/A1 were higher than those in hypertension grade 1 group , and the difference was statistically significant (P＜0.05).The sensitivity and the specificity of combined de- tection of 25 (OH) D ,Hcy and apolipoprotein B/A1 were higher than those of single detection of 25 (OH) D , Hcy and apolipoprotein B/A1.Conclusion Serum 25 (OH) D level decreased in patients with essential hyper-tension ,while Hcy and apolipoprotein B/A1 levels increased ,and the combined detection of 25(OH)D ,Hcy and apolipoprotein B/A1 had high sensitivity and specificity in diagnosis.