Tet methylcytosine dioxygenase 1 promotes hypoxic gene induction and cell migration in colon cancer.

Ten-eleven translocation 1 (TET1), a widely reported DNA demethylation protein, has been associated with tumorigenesis and metastasis. However, whether TET1 is an oncogene or tumor suppressor gene has been controversial; the mechanism of how TET1 affects cancer progression remains unclear. The current study aims to investigate how TET1 is changed in the tumor microenvironment and to explore the mechanisms of how TET1 affects colon cancer progression. Because hypoxia prevails on solid tumors, we established an important connection between hypoxia and DNA demethylation in tumorigenesis. By qPCR and RNA interference (RNAi) technology, we found that hypoxia increased TET1 expression with a hypoxia-inducible factor-1-alpha (HIF-1α)-dependent manner. By CHIP-qPCR and pyrosequencing technology, we demonstrated that TET1 regulated the target gene expression of HIF-1α through HIF-1α binding to hypoxia-responsive elements (HREs), and HIF-1α binding to HREs depended on CpG methylation levels. By Cell Counting Kit-8 (CCK-8) and transwell assay, we showed that loss of TET1 did not affect cell proliferation but inhibited migration. We also identified two novel gene mutants of TET1 in 120 paired tumor/normal tissue specimens by DNA sequencing and found that TET1 E2082K mutant blocked the TET1-enhanced cell migration. Our results showed that the downregulation of TET1 rescued the abnormally high levels of gene expression resulting from hypoxia in tumors and reduced the migration activity of tumor cells, suggesting a therapeutic role by interference with TET1 in colon cancer treatment. By demonstrating that hypoxia upregulated TET1 and that TET1 drove HIF-1α-responsive genes, we showed that an epigenetic mechanism and tumor microenvironment-driven models coexisted and mutually affected colon cancer.

Prognostic value of galectin-3 on admission in Chinese patients with heart failure: a prospective observational study.

Objective We performed a prospective observational study to explore the prognostic value of plasma galectin-3, a biomarker for fibrosis and inflammation, in Chinese patients with heart failure (HF). Methods and results Galectin-3, N-terminal pro B-type natriuretic peptide (NT-proBNP) and other clinically related variables were measured in consecutive HF patients in Beijing Hospital. Specifically, galectin-3 was detected by an enzyme-linked immunosorbent assay. The primary end point was major adverse cardiac events (MACE), including all-cause mortality or readmission at the end of follow-up. The secondary end point was all-cause mortality. The adjusted hazard ratio (HR) was determined by COX regression model. In total, 272 patients were included in this study with a median age of 77 years, of whom 55.9% were male. During a median follow-up of 584 (415-813) days, 53 patients (19.5%) died and 103 patients (37.9%) died and/or required readmission. Plasma galectin-3 levels by tertiles were associated with an increased risk for the primary end point (P < 0.001). Kaplan-Meier survival curves showed that the third tertile of galectin-3 was associated with an increased rate of MACE, compared with the first and second tertiles, with the log rank P < 0.001 and P = 0.001, respectively. In addition, the multivariate COX regression model showed that the highest tertile of galectin-3 was associated with an increased risk for MACE (HR =2.13, 95% confidence interval: 1.24-3.68, P = 0.006), compared with the lowest tertile after adjustment for age, NT-proBNP, creatinine, uric acid, albumin, haemoglobin, and estimated glomerular filtration rate (eGFR). Conclusion Plasma galectin-3 is an independent predictor of all-cause mortality and/or readmission in Chinese patients with HF.