ABSTRACT
The incidence and mortality of colon cancer are increasing, and effective biomarkers for its diagnosis are limited. 5-methylcytosine (5mC), a vital DNA methylation marker, plays important roles in gene expression, genomic imprinting, and transposon inhibition. This study aimed to identify the predictors of colon cancer prognosis and lay the foundation for research on therapeutic targets by detecting the levels of 5mC, 5-hydroxymethylcytosine (5hmC), 5-formyl cytosine (5fC), and 5-carboxylcytosine (5caC) in colon cancer and adjacent non-tumor tissues. A tissue microarray including 100 colon cancer tissue samples and 60 adjacent non-tumor tissue samples was used. The expression levels of 5mC and its ramifications were assessed by immunohistochemistry. According to the expression levels, patients were divided into moderately positive and strongly positive groups, and the correlation between clinicopathological characteristics and methylation marks was assessed using 2-sided chi-square tests. The prognostic values of 5mC, 5hmC, 5fC, and 5caC were tested using Kaplan-Meier analyses. Compared with adjacent non-tumor tissues, the overall levels of DNA methylation were lower in colon carcinoma lesions. However, the clinical parameters were not significantly associated with these methylation markers, except for 5hmC, which was associated with the age of cancer patients (P value = .043). Kaplan-Meier analysis disclosed that moderate positive group had a significantly shorter disease specific survival than strong positive group for patients with different levels of 5mC (65.2 vs 95.2 months, P = .014) and 5hmC (71.2 vs 97.5 months, P = .045). 5mC and its ramifications (5hmC, 5fC, and 5caC) can serve as biomarkers for colon cancer. 5mC and 5hmC are stable predictors and therapeutic targets in colon cancer. However, further understanding of its function will help to reveal the complex tumorigenic process and identify new therapeutic strategies.
Subject(s)
5-Methylcytosine , Colonic Neoplasms , Humans , Prognosis , DNA MethylationABSTRACT
Background: Radiotherapy plays an important role in the treatment of lung cancer. However, radiation-related deaths from cardiovascular disease (CVD) are a concern in these patients, and few studies have examined CVD-related death associated with lung cancer. We aimed to evaluate the risk of CVD-related death after radiotherapy in patients with lung and bronchus cancer. Methods: Data were extracted from the surveillance, epidemiology, and end results database. Propensity score matching (PSM) was applied to reduce possible bias between patients who received radiotherapy and those who did not. The Kaplan-Meier method was used to estimate cardiovascular-specific survival (CVSS), and the log-rank test was used to compare CVSS between the radiotherapy and no radiotherapy groups. Cox proportional hazards regression analysis was performed to estimate the hazard ratio (HR) of CVD-related death. Results: A total of 225,570 patients with lung and bronchus cancer were included, and 201,282 patients remained after PSM. Radiotherapy was identified as an independent risk factor for CVSS among patients with lung and bronchus cancer before PSM (HR: 1.18, P < 0.001) and after PSM (HR: 1.18, P < 0.001). Patients treated with radiotherapy had a significantly worse CVSS than those who did not receive radiotherapy before PSM (25-year CVSS: 49.9 vs. 56.4%, P = 0.002) and after PSM (25-year CVSS: 48.4 vs. 56.7%, P < 0.001). Radiotherapy was associated with more deaths from heart disease before PSM (81.9 vs. 77.2%, P < 0.001) and after PSM (83.0 vs. 78.7%, P < 0.001). Conclusion: Radiotherapy is associated with an increased risk of CVD-related death, especially death from heart disease, in patients with lung and bronchus cancer. More efforts are needed to monitor cardiovascular health after radiotherapy.
ABSTRACT
The subset of regulatory T (Treg) cells, with its specific transcription Foxp3, is a unique cell type for the maintenance of immune homeostasis by controlling effector T (Teff) cell responses. Although it is common that a defect in Treg cells with Treg/Teff disorder causes autoimmune diseases; however, the precise mechanisms are not thoroughly revealed. Here, we report that miR-34a could attenuate human and murine Foxp3 gene expression via targeting their 3' untranslated regions (3' UTR). The human miR-34a, increased in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) patients, displayed a positive correlation with some serum markers of inflammation including rheumatoid factor (RF), anti-streptolysin antibody (ASO), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as well as Th17 signature gene RORγt, but inversely correlated with the mRNA expression levels of FOXP3. In addition, murine miR-34a levels were downregulated in TGF-ß-induced Treg cells but upregulated in Th17â¯cells induced in vitro compared to activated CD4+ T cells. It has also been demonstrated that elevated miR-34a disrupting Treg/Th17 balance in vivo contributed to the progress of pathogenesis of collagen induced arthritis (CIA) mice. Furthermore, IL-6 and TNF-α were responsible for the upregulation of miR-34a and downregulation of Foxp3, which was reverted by the addition of NF-κB/p65 inhibitor BAY11-7082, thus indicating that NF-κB/p65 inhibited Foxp3 expression in an miR-34a-dependent manner. Finally, IL-6 or TNF-α-activated p65 could bind to the miR-34a promotor and enhance its activity, resulting in upregulation of its transcription. Taken together, we show that NF-κB activated by inflammatory cytokines, such as IL-6 and TNF-α, ameliorates Foxp3 levels via regulating miR-34a expression, which provides a new mechanistic and therapeutic insight into the ongoing of autoimmune diseases.
Subject(s)
Arthritis, Rheumatoid/immunology , Forkhead Transcription Factors/metabolism , Interleukin-6/immunology , Lupus Erythematosus, Systemic/immunology , MicroRNAs/genetics , Transcription Factor RelA/metabolism , Tumor Necrosis Factor-alpha/immunology , 3' Untranslated Regions/genetics , Adult , Aged , Animals , Antistreptolysin/blood , Blood Sedimentation , C-Reactive Protein/analysis , Cell Line , Female , HEK293 Cells , Humans , Leukocytes, Mononuclear/immunology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Nuclear Receptor Subfamily 1, Group F, Member 3/blood , Promoter Regions, Genetic , Rheumatoid Factor/blood , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/immunology , Th17 Cells/cytology , Th17 Cells/immunology , Transcription Factor RelA/antagonists & inhibitorsABSTRACT
Metazoan microRNAs (miRNAs) are commonly encoded by primary mRNA-like characteristics (mlRNAs). To investigate whether mlRNAs are subject to miRNA control, we compared the expression of mlRNAs to that of tissue-specific miRNAs. We show that, like mRNAs, the expression levels of predicted mlRNA targets are significantly reduced in tissues where a targeting miRNA is expressed. On the basis of these results, we describe a potential network for posttranscriptional miRNA-miRNA control.