ABSTRACT
Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12-6.38; P = 2.7 × 10(-2)). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs).
Subject(s)
Homocysteine/blood , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Multiple Myeloma/genetics , Humans , Mendelian Randomization Analysis , Plasma/chemistry , Polymorphism, Single NucleotideABSTRACT
Erythroid differentiation-associated gene (EDAG) is differentially expressed in normal hematopoietic progenitor/stem cells and a variety of embryonic tissues. High EDAG-1 expression is also found in human thyroid cancer cells and peripheral blood of patients with leukemia, but its functional significance was unclear. Current study aims to further clarify the expression pattern of EDAG-1 and tests its roles in proliferation and invasion of human thyroid cancer cells in vitro and in vivo. To this end, we have performed gain-of-function and loss-of-function studies to clarify how EDAG-1 regulates the proliferation, invasion, and adhesion ability of human thyroid cancer cells SW579cells. We found that overexpression of EDAG-1 promoted the proliferation, invasion, and adhesion of human thyroid cancer cells, whereas silencing of EDAG-1 reversed all these changes and reduced the tumorigenesis risk of nude mice. Mechanistically, we found that overexpression of EDAG-1 activated the MAPK/Erk and AKT signal pathways. These findings provide novel insights of the role of EDAG-1 in thyroid tumors, and may have direct clinical implication.
Subject(s)
Immunohistochemistry/methods , Mitogen-Activated Protein Kinase Kinases/genetics , Nuclear Proteins/genetics , Oncogene Protein v-akt/metabolism , Thyroid Neoplasms/genetics , Animals , Cell Proliferation , Down-Regulation , Humans , Mice , Mice, Nude , Mitogen-Activated Protein Kinase Kinases/metabolism , Nuclear Proteins/metabolism , Signal Transduction , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , TransfectionABSTRACT
Protein-tyrosine phosphatase SHP2 is encoded by the gene PTPN11. SHP2 is hypothesized to have a critical role in cancer, via the activation of mutations that have been detected in several types of leukaemia and in certain solid tumours, including liver, breast, gastric and cervical cancer. However, to the best of our knowledge, there have been no previous reports evaluating the significance of SHP2 expression in thyroid cancer. The present study evaluated SHP2 expression in 65 thyroid cancer specimens, 40 specimens of self-matched adjacent peritumour tissues and 40 specimens of normal thyroid tissue, using immunohistochemical and western blot analyses with an anti-SHP2 antibody. Western blotting was also used to assess SHP2 expression in thyroid cancer cell lines (SW579, IHH-4, FTC-133, TPC-1, DRO, TA-K, and ML-1) and Nthy-ori3-1 normal thyroid cells. In addition, SHP2 antisense oligonucleotides were used to block SHP2 expression in SW579 cells, and growth inhibition assays were conducted. Increased SHP2 expression was detected in the tumour tissues compared with that of the normal thyroid tissues (P<0.05). SHP2 expression was significantly correlated with poor tumour differentiation (P<0.05), late TNM stage (P<0.05) and lymph node metastasis (P<0.05), suggesting that SHP2 may represent a potential target for thyroid cancer therapy.
ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related death in human. Alcohol is a known risk factor for HCC. However it is still unclear whether and how alcohol enhances the progression and metastasis of existing HCC. METHODS AND RESULTS: We first retrospectively investigated 52 HCC patients (24 alcohol-drinkers and 28 non-drinkers), and found a positive correlation between alcohol consumption and advanced Tumor-Node-Metastasis (TNM) stages, higher vessel invasion and poorer prognosis. In vitro and in vivo experiments further indicated that alcohol promoted the progression and migration/invasion of HCC. Specifically, in a 3-D tumor/endothelial co-culture system, we found that alcohol enhanced the migration/invasion of HepG2 cells and increased tumor angiogenesis. Consistently, higher expression of VEGF, MCP-1 and NF-κB was observed in HCC tissues of alcohol-drinkers. Alcohol induced the accumulation of intracellular reactive oxygen species (ROS) and the activation of NF-κB signaling in HepG2 cells. Conversely, blockage of alcohol-mediated ROS accumulation and NF-κB signaling inhibited alcohol-induced expression of VEGF and MCP-1, the tumor growth, angiogenesis and metastasis. CONCLUSION: This study suggested that chronic moderate alcohol consumption may promote the progression and metastasis of HCC; the oncogenic effect may be at least partially mediated by the ROS accumulation and NF-ĸB-dependent VEGF and MCP-1 up-regulation.
Subject(s)
Carcinoma, Hepatocellular/genetics , Cell Movement/genetics , Ethanol/adverse effects , NF-kappa B/genetics , Neoplasm Invasiveness/genetics , Signal Transduction/genetics , Animals , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Chemokine CCL2/genetics , Disease Progression , Female , Hep G2 Cells , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice , Mice, Nude , Middle Aged , NIH 3T3 Cells , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Retrospective Studies , Vascular Endothelial Growth Factor A/geneticsABSTRACT
Arsenite (AS) is a ubiquitous environmental element that is widely present in food, soil, and water. Environmental exposure to AS represents a major global health concern, because AS is a well-established human carcinogen. We hypothesize that low concentration of AS could enhance metastasis and proliferation of transformed cancer cells by promoting EMT. To test this hypothesis, we treated human colorectal cancer cells with low concentration of AS, and then measured the multiple readouts of cell viability, proliferation, migration, and adhesion in vitro and in vivo. Collectively, our data indeed strongly support our hypothesis and shed novel light into this important pathophysiological process. These novel insights are not only of high interests to basic cancer research, but may also have direct implications in cancer prevention and treatment.
