Aberrant DNA methylation on CpG islands is one of the most consistent epigenetic changes in human cancers, and the methylation process is catalyzed by DNA methyltransferase (DNMT). We evaluated i) the mRNA levels of three DNMTs; DNMT1, DNMT3a and DNMT3b, in 25 hepatocellular carcinomas (HCCs), in their corresponding noncancerous liver tissues and in 7 normal livers by using realtime reverse transcriptase-polymerase chain reaction; ii) nuclear expression of DNMT1 and DNMT3a proteins in the HCCs by immunohistochemistry, iii) the methylation status of 5 genes; p16, p15, E-cadherin, HIC-1 and RASSF1A in the same tissues, and iv) the relationships between the above results and the clinicopathological characteristics, including prognosis. The differences in mRNA expression levels for DNMT1, DNMT3a and DNMT3b were statistically significant between HCC and normal livers (p<0.001), HCC and chronic hepatitis (p<0.001) and HCC and cirrhosis (p<0.001). An increase in mRNA expression levels of >4-fold for DNMT3b in HCCs was significantly associated with a poorer overall survival (p=0.027) and shorter metastasis-free survival (p=0.0299). A poorer recurrence-free survival was noted in HCCs with a >4-fold increase in DNMT3a mRNA (p=0.0120). The average numbers of methylated genes were 0, 1.27, 1.38 and 2.72 for normal livers, chronic hepatitis, cirrhosis and HCCs, respectively, and this progressive increase from normal livers to chronic hepatitis/cirrhosis through HCC may suggest that tumor suppressor gene methylation is an early event in hepatocarcinogenesis. These results first suggest that hepatocarcinogenesis involves an increased expression of DNMT1, DNMT3a and DNMT3b mRNA and a progressive increase in the number of methylated genes from normal liver, chronic hepatitis/cirrhosis to HCC and secondly that an increase in the DNMT3a and DNMT3b mRNA levels in HCCs relative to their non-cancerous tissues may be a predictor of poor survival.
Glioblastoma multiforme (GBM) is the most common brain tumor with very aggressive and infiltrative. Extracellular matrix (ECM) plays pivotal roles in the infiltrative characteristics of GBM.To understand the invasive characteristic of GBM, it is necessary to study cell-ECM interaction in the physiologically relevant biomimetic model that recapitulates the GBM-specific ECM microenvironment. Here, we propose biomimetic GBM-specific ECM microenvironment for studying mode and dynamics of glioblastoma cell invasion. Using tissue decellularization process, we constructed a patient tissuederived ECM (pdECM)-based three-dimensional in vitro model. In our model, GBM cells exhibited heterogeneous morphology and altered the invasion routes in a microenvironment-adaptive manner. We further elucidate the effects of inhibition of ECM remodeling-related enzymatic activity (Matrix metalloproteinase (MMP) 2/9, hyaluronan synthase (HAS)) on GBM cell invasion. Interestingly, after blocking both enzyme activity, GBM cells underwent morphological transition and switch the invasion mode. Such adaptability could render cell invasion resistant to anti-cancer target therapy. There results provide insight of how organ-specific matrix differentially regulates cancer cell phenotype, and have significant implications for the design of matrix with appropriate physiologically relevant properties for in vitro tumor model.Invasion and dissemination of cancer cells cause migration of neoplastic cells into surrounding tissues, resulting in mortality in tumor patients 1-3 . In particular, cancer cell invasion is of enormous clinical importance, since it involves both distant metastasis and local spreading, whereby cancer cells degrade and migrate through the tissue. The significance of cancer cell invasion is evident in the glioblastoma multiforme (GBM), which shows infiltrative and rapid growth into the surrounding brain tissue. The invasive and migratory characteristics of GBM cells provide a wealth of information about tumors within a patient 3 .Three-dimensional (3D) in vitro culture systems are increasingly employed to assess cell-ECM interactions and invasion of tumor cells. Indeed, cell behavior and responsiveness are dramatically different in a 3D physiological environment versus two-dimensional (2D) Petri dish conditions 4,5 . Importantly, in 3D cultures, ECM is an essential determinant of the cellular response to invasion and migration processes 6 . Brain ECM has a distinct composition from ECM in other tissues and organs, with a low stiffness and loosely connected cellular network. The ECM component of brain tissues contains high amounts of hyaluronic acid (HA), glycosaminoglycans (GAGs), and proteoglycans, but lacks fibrous materials such as collagen, fibronectin, etc 7,8 .In fact, the interaction between GBM cells and unique extracellular environment of the brain could impact on the invasive characteristics of GBM cells. Accumulated experimental and clinical data demonstrate that invasion
Telomerase reactivation and telomere maintenance are crucial in carcinogenesis and tumor progression. In this study, the relationships between telomere parameters, chromosomal instability and clinicopathological features were evaluated in hepatocellular carcinomas (HCCs). Telomere length (TL), telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) mRNA levels were measured in 49 hepatitis B virus (HBV)-related HCCs and corresponding non-tumorous tissues. The results were compared with clinicopathological data, including differentiation, multipolar mitosis (MM), anaphase bridge, immunohistochemical stain results for cytokeratin 19 (CK19) and patient outcome. TL of HCCs ranged from 4.7 to 13.1 kb, and 44.4% of HCCs showed telomere lengthening. hTERT mRNA levels and TA were closely related (P ¼ 0.008), and were significantly higher in HCCs than non-tumorous tissues. TL was significantly higher in HCCs with strong TA (P ¼ 0.048), high hTERT mRNA levels (P ¼ 0.001) and poor differentiation (P ¼ 0.041). Frequent MM was associated with poor differentiation (P ¼ 0.007) and advanced stage (Po0.001). TA was positively correlated with MM, anaphase bridges and advanced stage (P ¼ 0.019, P ¼ 0.017 and P ¼ 0.029). Thirteen (28.3%) HCCs were CK19 þ and demonstrated longer telomeres than CK19À HCCs (P ¼ 0.046). Overall survival was poor in HCCs with MM 40.4 per field (P ¼ 0.016), high TA (P ¼ 0.009) and high TL ratio (HCC/non-HCC) 40.8 (P ¼ 0.044). Our results show that long telomeres, high TA and high mitotic instability are poor prognostic markers for HBV-related HCCs and their close association suggests that telomere maintenance may be important for the progression of HCCs with high chromosomal instability to more aggressive ones.
Mesenchymal stem cell (MSC) has been applied for the therapy of allergic disorders due to its beneficial immunomodulatory abilities. However, the underlying mechanisms for therapeutic efficacy are reported to be diverse according to the source of cell isolation or the route of administration. We sought to investigate the safety and the efficacy of human adipose tissue-derived MSCs (hAT-MSCs) in mouse atopic dermatitis (AD) model and to determine the distribution of cells after intravenous administration. Murine AD model was established by multiple treatment of Dermatophagoides farinae. AD mice were intravenously infused with hAT-MSCs and monitored for clinical symptoms. The administration of hAT-MSCs reduced the gross and histological signatures of AD, as well as serum IgE level. hAT-MSCs were mostly detected in lung and heart of mice within 3 days after administration and were hardly detectable at 2 weeks. All of mice administered with hAT-MSCs survived until sacrifice and did not demonstrate any adverse events. Co-culture experiments revealed that hAT-MSCs significantly inhibited the proliferation and the maturation of B lymphocytes via cyclooxygenase (COX)-2 signaling. Moreover, mast cell (MC) degranulation was suppressed by hAT-MSC. In conclusion, the intravenous infusion of hAT-MSCs can alleviate AD through the regulation of B cell function.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.