Epithelial ovarian cancer (EOC) is one of the most common gynecological cancers, with diagnosis often at a late stage. Metastasis is a major cause of death in patients with EOC, but the underlying molecular mechanisms remain obscure. Here, we utilized an integrated approach to find potential key transcription factors involved in ovarian cancer metastasis and identified STAT4 as a critical player in ovarian cancer metastasis. We found that activated STAT4 was overexpressed in epithelial cells of ovarian cancer and STAT4 overexpression was associated with poor outcome of ovarian cancer patients, which promoted metastasis of ovarian cancer in both in vivo and in vitro. Although STAT4 mediated EOC metastasis via inducing epithelial-to-mesenchymal transition (EMT) of ovarian cancer cells in vivo, STAT4 failed to induce EMT directly in vitro, suggesting that STAT4 might mediate EMT process via cancer-stroma interactions. Further functional analysis revealed that STAT4 overexpression induced normal omental fibroblasts and adipose- and bone marrow-derived mesenchymal stem cells to obtain cancer-associated fibroblasts (CAF)-like features via induction of tumor-derived Wnt7a. Reciprocally, increased production of CAF-induced CXCL12, IL6 and VEGFA within tumor microenvironment could enable peritoneal metastasis of ovarian cancer via induction of EMT program. In summary, our study established a model that STAT4 promotes ovarian cancer metastasis via tumor-derived Wnt7a-induced activation of CAFs.
Epidemiologic studies suggest an independent positive association of elevated serum uric acid with essential hypertension. However, to date, limited information is available in the old population. In the present study, we included 832 unrelated Chinese nonagenarians/centenarians (269 men and 563 women; ranged in age from 90 to 108 years (mean, 94.6±4.0)). The mean serum uric acid level was 320 lmol l À1 (standard deviation 87 lmol l À1). After adjustment for age, body mass index, waist-to-hip ratio, smoking habits, tea habits, alcohol consumption, fasting plasma glucose, plasma lipids and serum creatinine, the odds ratio comparing the highest with lowest quartile of serum uric acid were 0.67 (95% confidence interval (CI), 0.33-1.21) and 1.36 (95% CI, 0.88-2.22) in men and women, respectively. When compared with normotensive subjects, we did not observe statistical higher serum uric acid levels in subjects with hypertension. In summary, we found that serum uric acid level is not directly correlated with hypertension among Chinese nonagenarians/centenarians.
Type H vessel is a specific vessel subtype that is strongly positive for CD31 and endomucin (CD31hiEmcnhi). It has already been identified that it can tightly regulate the coupling of angiogenesis and osteogenesis in the long bone of mice and human beings. The long bone is formed through endochondral ossification, which is the same type of process happening in mandibular condyle. Although the ossification of long bone and mandibular condyle has the same developmental process, the existence of type H vessels in the mouse condyle remains unclear. To address this, we identified that abundant type H vessels existed in the subchondral bone of the mouse condylar head and endosteum of the mouse condylar neck. Meanwhile, immunofluorescence imaging of the condyles in different ages of male C57BL/6J mice demonstrated that type H vessels decreased while aging. Furthermore, we validated a positive correlation between type H vessels and Osterix+ osteoprogenitors in the condyle induced by mandibular advancement. Mechanistically, we confirmed that deferoxamine mesylate, which promoted the proliferation of type H endothelial cells by activating hypoxia-inducible factor 1α (HIF-1α) signaling pathways, largely prevented the osteopenia in the condyle induced by botulinum toxin type A. Collectively, these results demonstrate that in the mouse condyle, type H vessels in areas of high function positively correlate with bone formation. In addition, we show a novel influence of HIF-1α signaling on osteogenesis via an increase in type H vessels. In conclusion, promoting angiogenesis of type H vessels is a promising strategy for the therapeutic improvement of osteogenesis in mandibular condyle.
Purpose To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). Methods Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). Results Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. Conclusion Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.
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