Publications (35)67.51 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: MicroRNAs (miRNAs) affect cancer cell glucose metabolism by targeting mRNAs of diverse enzymes that have been implicated in oxidative phosphorylation (OXPHOS) and glycolytic pathways. However, the mechanisms that underlie miRNA-mediated regulation of phosphofructokinase (PFK), a key rate-limiting enzyme in glycolysis, remain largely unknown. Here, we show that miR-128 directly targets PFK liver type (PFKL) in lung cancer cells and regulates endogenous expression of PFKL at both the mRNA and protein levels. In line with this, overexpression of miR-128 decreased glucose uptake and lactate production, as well as increased cellular ATP content. Interestingly, knockdown of miR-128 was shown to promote lung cancer cell growth and colony formation. Moreover, we observed that miR-128 expression inversely correlated with PFKL mRNA levels in clinic lung cancer samples and that increased PFKL expression predicted poor overall survival in lung cancer patients. Mechanistically, we showed that miR-128 regulates PFKL via a feedback loop that involves inhibition of the AKT signaling pathway. Together, our results suggest that miR-128 acts as a metabolic regulator in lung cancer cells that may be therapeutically exploited.
- [Show abstract] [Hide abstract] ABSTRACT: Understanding the molecular mechanism by which epithelial mesenchymal transition (EMT)-mediated cancer metastasis and how microRNA (miRNA) regulates lung cancer progression via Twist1-activated EMT may provide potential therapeutic targets for cancer therapy. Here we found that miR-33a, an intronic miRNA located within the sterol regulatory element-binding protein 2 (SREBP-2) gene, is expressed at low levels in metastatic non-small cell lung cancer (NSCLC) cells and is inversely correlated with Twist1 expression. Conversely, miR-33a knockdown induces EMT and miR-33a overexpression blocks EMT by regulating of Twist1 expression in NSCLC cells. Bioinformatical prediction and luciferase reporter assay confirm that Twist1 is a direct target of miR-33a. Additionally, Twist1 knockdown blocks EMT-related metastasis and forced expression of miR-33a inhibits lung cancer metastasis in a xenograft animal model. Clinically, miR-33a is found to be at low levels in NSCLC patients and down-regulation of miR-33a predicts a poor prognosis. These findings suggest that miR-33a targets Twist1 and inhibits invasion and metastasis in NSCLC. Thus, miR-33a might be a potential prognostic marker and of therapeutic relevance for NSCLC metastasis intervention.
- [Show abstract] [Hide abstract] ABSTRACT: Circular RNAs (circRNAs) are a large class of RNAs that, unlike linear RNAs, form covalently closed continuous loops and have recently shown huge capabilities as gene regulators in mammals. These circRNAs mainly arise from exons or introns, and are differentially generated by back splicing or lariat introns. Interestingly, they are found to be enormously abundant, evolutionally conserved and relatively stable in cytoplasm. These features confer numerous potential functions to circRNAs, such as acting as microRNA (miRNA) sponges, binding to RNA-associated proteins to form RNA-protein complexes and then regulating gene transcription. Importantly, circRNAs associate with cancer-related miRNAs and the circRNA-miRNA axes are involved in cancer-related pathways. Some synthetic circRNAs have shown the remarkable anti-cancer effects. Though circRNAs are ancient molecules, the huge therapeutic potentials of circRNAs are recently being discovered from the laboratory to the clinic. Here, we review the current understanding of the roles of circRNAs in cancers and the potential implications of circRNAs in cancer targeted therapy.
- [Show abstract] [Hide abstract] ABSTRACT: Distant metastasis of tumor cell is a series of continuous, selectable cascades of events regulated by multiple factors and genes. Epithelial-mesenchymal transition (EMT) is a critical step during cancer metastasis. However, the mechanism of EMT in tumor is not yet fully elucidated. MicroRNAs (miRNAs) are a class of non-coding small endogenous RNAs that negatively regulate EMT-related genes at the post-transcriptional level and play critical roles in cancer metastasis. This review mainly focuses on the topics that include the relationship of EMT and tumor metastasis, transcription factors involved in EMT, and the effect of miRNAs on tumor metastasis by targeting the EMT-related transcription factors.
- [Show abstract] [Hide abstract] ABSTRACT: Background: The GCK gene encodes hexokinase 4, which catalyzes the first step in most glucose metabolism pathways. The purpose of our study is to assess the contribution of GCK methylation to type 2 diabetes (T2D). Methods and results: GCK methylation was evaluated in 48 T2D cases and 48 age- and gender-matched controls using the bisulphite pyrosequencing technology. Among the four CpG sites in the methylation assay, CpG4 and the other three CpGs (CpG1-3) were not in high correlation (r<0.5). Significantly elevated methylation levels of GCK CpG4 methylation were observed in T2D patients than in the healthy controls (P=0.004). A breakdown analysis by gender indicated that the association between CpG4 methylation and T2D was specific to males (P=0.002). It is intriguing that another significant male-specific association was also found between GCK CpG4 methylation and total cholesterol (TC) concentration (r=0.304, P=0.036). Conclusion: Our results showed that elevated GCK CpG4 methylation might suggest a risk of T2D in Chinese males. Gender disparity in GCK CpG4 methylation might provide a clue to elaborate the pathogenesis of T2D.
- [Show abstract] [Hide abstract] ABSTRACT: Lung cancer is one of the most common malignant tumors and is the leading cause of cancer mortality worldwide. However, drug resistance induced by chemotherapeutants to lung cancer cells is the primary issue during the chemotherapy of lung cancer. Many mechanisms such as the changes of drug metabolism related genes and signal pathways are involved in the chemoresistance. MicroRNAs (miRNAs) are a class of endogenetic, non-coding, short-chain and small RNAs that regulate cell growth, apoptosis and signal transduction. There are growing numbers of evidence suggesting that miRNA polymorphisms associate with drug metabolism and resistance. In addition, differentially expressed miRNAs play critical roles in prediction of the sensitivity to chemotherapeutic agents in lung cancer. The recent progress demonstrates that regulation of specific miRNA expression will break novel paths for overcoming lung cancer resistance and the personalized therapy. Together, in this review we have discussed the current understanding of the role of miRNA on drug resistance, and the potential implications of miRNA in lung cancer targeted therapy.
- [Show abstract] [Hide abstract] ABSTRACT: Objectives: Glucokinase encoded by GCK is a key enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Variants of GCK gene were shown to be associated with type 2 diabetes (T2D) and coronary heart disease (CHD). The goal of this study was to investigate the contribution of GCK gene-body methylation to the risk of CHD. Design and methods: 36 patients (18 males and 18 females) and 36 age- and sex-matched controls were collected for the current methylation research. DNA methylation level of the CpG island (CGI) region on the GCK gene-body was measured through the sodium bisulfite DNA conversion and pyrosequencing technology. Results: Our results indicated that CHD cases have a much lower methylation level (49.77 ± 6.43%) compared with controls (54.47 ± 7.65%, P = 0.018). In addition, GCK gene-body methylation was found to be positively associated with aging in controls (r = 0.443, P = 0.010). Conclusions: Our study indicated that the hypomethylation of GCK gene-body was significantly associated with the risk of CHD. Aging correlates with an elevation of GCK methylation in healthy controls.
- [Show abstract] [Hide abstract] ABSTRACT: Lung cancer is one of the most common malignant tumors and is the leading cause of cancer mortality worldwide. However, drug resistance induced by chemotherapeutants to lung cancer cells is the primary issue during the chemotherapy of lung cancer. Many mechanisms such as the changes of drug metabolism related genes and signal pathways are involved in the chemoresistance. MicroRNAs (miRNAs) are a class of endogenetic, non-coding, short-chain and small RNAs that regulate cell growth, apoptosis and signal transduction. miRNA polymorphisms associate with drug metabolism and drug resistance formation. Furthermore, differentially expressed miRNAs play critical roles in prediction of the sensitivity to chemotherapeutic agents in lung cancer. Regulation of specific miRNA expression will break a new path for overcoming lung cancer resistance and the personalized therapy. Together, in this chapter we have discussed the current understanding of the role of miRNA on drug resistance, and the potential implications of miRNA in lung cancer targeted therapy. © Springer International Publishing Switzerland 2014. All rights reserved.
Dataset: Supplementary material 1
- [Show abstract] [Hide abstract] ABSTRACT: Previous studies have shown that apolipoprotein A5 (APOA5) gene variants are genetic determinants of the concentration of triglycerides, which are a known risk factor for coronary heart disease (CHD). Using the standardized coronary angiography method, 290 CHD patients and 198 non‑CHD controls were recruited from Ningbo Lihuili Hospital. In addition, 331 unrelated healthy volunteers were recruited as healthy controls from Ningbo Ximen Community residents. Three variants of the APOA5 gene, S19W, ‑1131T>C and 553G>T, were analyzed for their association with CHD. Under a dominant inheritance model, ‑1131CT>C was shown to be a CHD risk factor (P=0.030; OR, 1.422; 95% CI, 1.036‑1.952). The single nucleotide polymorphism, 553G>T, was found to correlate with the severity of CHD in males (P=0.032). Meta‑analysis showed that ‑1131T>C was significantly associated with CHD (P<0.0001). By contrast, negative correlations with CHD were observed for S19W and 553G>T. In the present case‑control study, APOA5 gene variants were not found to correlate with the risk of CHD in the populations studied; however, ‑1131CT>C was shown to be a CHD risk factor under a dominant inheritance model. Meta‑analysis showed a significant contribution of ‑1131T>C to the risk of CHD, implying an ethnic difference in APOA5 gene variants.
- [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to evaluate the combined contribution of 12 genetic variants to the risk of coronary heart disease (CHD). Through a comprehensive literature search for genetic variants involved in the CHD association study, we harvested a total of 10 genes (12 variants) for the current meta-analyses. These genes consisted of GPX1 (rs1050450), PPARD (rs2016520), ALOX15 (rs34210653), SELPLG (rs2228315), FCGR2A (rs1801274), CCL5 (rs2107538), CYP1A1 (rs4646903), TP53 (rs1042522), CX37 (rs1764391), and PECAM1 (rs668, rs12953, and rs1131012). A total of 45 studies among 23314 cases and 28430 controls were retrieved for the meta-analyses of 12 genetic variants. The results showed a significant association between the GPX1 rs1050450 polymorphism and CHD (odd ratio (OR) = 1.61, 95% confidence interval (CI) = 1.25-2.07, P = 0.0002). Other meta-analyses of the rest 11 variants suggested a lack of association with the risk of CHD. Our results confirmed that GPX1 rs1050450 was associated with susceptibility to CHD in Chinese and Indian populations.
- [Show abstract] [Hide abstract] ABSTRACT: As a candidate gene for type 2 diabetes (T2D), insulin receptor substrate-1 (IRS‑1) gene variations were found to be associated with the risk of T2D. The aim of our study was to investigate the contribution of promoter DNA methylation of the IRS‑1 gene to the risk of T2D. Using bisulphite pyrosequencing technology, the DNA methylation levels of 3 CpG dinucleotides within the IRS‑1 gene promoter were measured in 48 T2D patients and 48 age‑ and gender‑matched healthy controls. Our results indicated that there was no significant association between the methylation of the IRS‑1 gene promoter and the risk of T2D (P>0.1). A breakdown analysis by gender revealed that IRS‑1 promoter methylation was not associated with an increased risk of T2D for either gender (P>0.1), although there were significantly lower methy-lation levels of CpG1 (P=0.002) and CpG2 (P=0.043) within the IRS‑1 gene promoter in males than in females.
- [Show abstract] [Hide abstract] ABSTRACT: HFE gene variants can cause hereditary haemochromatosis (HH) that often comes along with an increased risk of coronary heart disease (CHD). The goal of our study is to assess the contribution of four HFE gene variants to the risk of CHD. We conducted four meta-analyses of the studies examining the association between four HFE gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical. Meta-analyses showed that HFE rs1799945-G allele was associated with a 6% increased risk of CHD (P = 0.02, odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.01-1.11). However, no association between the other three HFE gene variants (rs1800562, rs1800730, and rs9366637) and CHD risk was observed by the meta-analyses (all P values > 0.05). In addition, the results of our case-control study indicated that rs1800562 and rs1800730 were monomorphic, and that rs1799945 and rs9366637 were not associated with CHD in Han Chinese. Our meta-analysis suggested a significant association existed between rs1799945 mutation and CHD, although this mutation was rare in Han Chinese.
- [Show abstract] [Hide abstract] ABSTRACT: The goal of our study is to investigate the contribution of promoter DNA methylation of α-adducin (ADD1) gene to the risk of essential hypertension (EH). Using the bisulphite pyrosequencing technology, DNA methylation levels of five CpG dinucleotides on ADD1 promoter were measured among 33 EH cases and 28 healthy controls. Significantly higher ADD1 DNA methylation levels were observed in the females than in the males (CpG1: P = 0.016; CpG2-5: P = 0.021). A breakdown analysis by gender showed that lower CpG1 methylation was associated with an increased risk of EH in females (adjusted P = 0.042). A much more significant association between lower CpG2-5 methylation levels and the increased risk of EH was found in males (adjusted P = 0.008). CpG1 methylation was inversely correlated with age in females (r = -0.407, P = 0.019) but not in males. ADD1 CpG1 and CpG2-5 methylation levels were significantly lower in post-menopausal (>50 years) women than pre-menopausal (≤50 years) women (CpG1: P = 0.006; CpG2-5: P = 0.034). A significant interaction between CpG1 methylation and age was found in females (CpG1*age: P = 0.029). CpG2-5 methylation was shown as a significant predictor of EH in males [area under curve (AUC) = 0.855, P = 0.001], in contrast that CpG1 methylation was a trend toward indicator in females (AUC = 0.699, P = 0.054). In addition, significant differences were observed between males and females for alanine aminotransferase (ALT, P = 0.001), aspartate aminotransferase (AST, P = 0.005) and uric acid (P<0.001). The concentration of AST was inversely correlated with ADD1 CpG2-5 methylation levels in female controls (r = -0.644, P = 0.024). These observations may bring new hints to elaborate the pathogenesis of EH.
Dataset: Figure S3[Show abstract] [Hide abstract] ABSTRACT: Pearson correlation between ADD1 methylation and metabolic phenotypes in males (A–C) and in females (D–F). (TIF)
- [Show abstract] [Hide abstract] ABSTRACT: Four gene variants related to lipid metabolism (including the rs562338 and rs503662 variants of the APOB gene, the rs7767084 variant of the LPA gene and the rs2246942 variant of the LIPA gene) have been shown to be associated with coronary heart disease (CHD). The aim of the present study was to assess their association with CHD in the Han Chinese population and to assess the contribution of these gene variants to CHD. Using the standardized coronary angiography method, we enrolled 290 CHD patients and 193 non-CHD patients as non-CHD controls from Lihuili Hospital (Ningbo, China). In addition, we recruited 330 unrelated healthy volunteers as healthy controls from the Xi Men Community (Ningbo, China). Our results demonstrated that the rs503662 and rs562338 variants of the APOB gene were extremely rare in the Han Chinese population (minor allele frequency <1%). Genotype rs2246942-GG of the LIPA gene was associated with an increased risk of CHD [CHD cases versus healthy controls: P=0.04; odds ratio (OR)=1.63; 95% confidence interval (CI)=1.02-2.60). Genotype rs7767084-CC of the LPA gene was identified as a protective factor against CHD in females (CHD cases versus non-CHD controls: P=0.04, OR=0.21; CHD cases versus healthy controls: P=0.02, OR=0.21). The results of our meta-analysis indicated that rs7767084 was not associated with a high risk of CHD (P=0.83; combined OR=0.93; 95% CI=0.47-1.85). In the present study, two single nucleotide polymorphisms (SNPs) of genes involved in lipid metabolism (rs2246942 and rs7767084) were identified to be significantly associated with CHD in the Han Chinese population. Specifically, rs2246942-GG of the LIPA gene was a risk factor for CHD, while rs7767084-CC of the LPA gene was a protective factor against CHD in females. However, our meta-analysis indicated that rs7767084 is not associated with a higher risk of CHD.
- [Show abstract] [Hide abstract] ABSTRACT: Background: MicroRNAs (miRNAs) play a crucial role in carcinogenesis; however, it largely remains unclear whether miRNAs in gastric juice, which is specific for gastric tissues, can be used as biomarkers for gastric cancer. The objective of the current study was to investigate the feasibility of using gastric juice miRNAs as potential biomarkers to assist in screening for gastric cancer. Methods: Gastric juice samples were collected from 141 patients who underwent upper gastrointestinal endoscopy examination between September 2010 and December 2011. Gastric cancer and adjacent normal biopsy specimens also were collected. The existence and stability of miRNAs in gastric juices were determined by real-time reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and sequencing. miRNA levels in tissues and gastric juices were detected by RT-qPCR. A receiver operating characteristic (ROC) curve was constructed for differentiating gastric cancer from benign gastric diseases. Results: Levels of miRNA-21 (miR-21) and miR-106a in gastric cancer tissues were significantly higher compared with the levels in adjacent tissues (P = .006 and P = .001, respectively). Patients who had gastric cancer had significantly different levels of gastric juice miR-21 and miR-106a compared with patients who had benign gastric diseases (both P < .001). There were significant correlations between miR-21/miR-106a levels and Borrmann types. miR-21 levels in intestinal type gastric cancer specimens were higher than that in diffuse (P = .003) or mixed (P < .001) gastric cancer types. The area under the ROC curve was up to 0.969 for miR-21 and 0.871 for miR-106a. Conclusions: The current results indicated that certain miRNAs in gastric juice are potential biomarkers that can assist in screening for gastric cancer.
- [Show abstract] [Hide abstract] ABSTRACT: PLA2G7 gene product is a secreted enzyme whose activity is associated with coronary heart disease (CHD). The goal of our study is to investigate the contribution of PLA2G7 promoter DNA methylation to the risk of CHD. Using the bisulphite pyrosequencing technology, PLA2G7 methylation was measured among 36 CHD cases and 36 well-matched controls. Our results indicated that there was a significant association between PLA2G7 methylation and CHD (adjusted P = 0.025). Significant gender-specific correlation was observed between age and PLA2G7 methylation (males: adjusted r = -0.365, adjusted P = 0.037; females: adjusted r = 0.373, adjusted P = 0.035). A breakdown analysis by gender showed that PLA2G7 methylation was significantly associated with CHD in females (adjusted P = 0.003) but not in males. A further two-way ANOVA analysis showed there was a significant interaction between gender and status of CHD for PLA2G7 methylation (gender*CHD: P = 6.04E-7). Moreover, PLA2G7 methylation is associated with the levels of total cholesterols (TC, r = 0.462, P = 0.009), triglyceride (TG, r = 0.414, P = 0.02) and Apolipoprotein B (ApoB, r = 0.396, P = 0.028) in females but not in males (adjusted P>0.4). Receiver operating characteristic (ROC) curves showed that PLA2G7 methylation could predict the risk of CHD in females (area under curve (AUC) = 0.912, P = 2.40E-5). Our results suggest that PLA2G7 methylation changes with aging in a gender-specific pattern. The correlation between PLA2G7 methylation and CHD risk in females is independent of other parameters including age, smoking, diabetes and hypertension. PLA2G7 methylation might exert its effects on the risk of CHD by regulating the levels of TC, TG, and ApoB in females. The gender disparities in the PLA2G7 methylation may play a role in the molecular mechanisms underlying the pathophysiology of CHD.
Dataset: Figure S2
Dataset: Figure S1[Show abstract] [Hide abstract] ABSTRACT: Comparison of PLA2G7 methylation levels between cases and controls in different age groups in femalesa. a) P values were adjusted for age, the history of smoking, diabetes and hypertension. (TIF)