Enhancer of Zeste homolog 2 (EZH2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone H3. Here, we show that Akt phosphorylates EZH2 at serine 21 and suppresses its methyltransferase activity by impeding EZH2 binding to histone H3, which results in a decrease of lysine 27 trimethylation and derepression of silenced genes. Our results imply that Akt regulates the methylation activity, through phosphorylation of EZH2, which may contribute to oncogenesis.
Hormone-refractory relapse is an inevitable and lethal event for advanced prostate cancer patients after hormone deprivation. A growing body of evidence indicates that hormone deprivation may promote this aggressive prostate cancer phenotype. Notably, androgen receptor (AR) not only mediates the effect of androgen on the tumor initiation but also plays the major role in the relapse transition. This provides a strong rationale for searching new effective agents targeting the down-regulation of AR to treat or prevent advanced prostate cancer progression. Here, we show that emodin, a natural compound, can directly target AR to suppress prostate cancer cell growth in vitro and prolong the survival of C3(1)/SV40 transgenic mice in vivo. Emodin treatment resulted in repressing androgen-dependent transactivation of AR by inhibiting AR nuclear translocation. Emodin decreased the association of AR and heat shock protein 90 and increased the association of AR and MDM2, which in turn induced AR degradation through proteasomemediated pathway in a ligand-independent manner. Our work indicates a new mechanism for the emodin-mediated anticancer effect and justifies further investigation of emodin as a therapeutic and preventive agent for prostate cancer. (Cancer Res 2005; 65(6): 2287-95)
ObjectiveTo explore the associations between different dietary patterns and semen quality in a general Asian male population.MethodsCross-sectional study. Healthy Taiwanese men aged 18 years or older who participated in a standard medical screening program from 2008-2013 run by a private firm were included in this study. Semen parameters including sperm concentration (SC), total sperm motility (TSM), progressive motility (PRM) and normal sperm morphology (NSM) were recorded. A dietary questionnaire was used to categorize the participants into 5 groups: “Healthy diet”, “Western diet”, “High-carbohydrate diet”, “High sweet snacks & sugar-sweetened drinks” and “High-sodium diet”.ResultsA total of 7282 men completed the questionnaire regarding dietary pattern, and examination of anthropometric indexes was performed and laboratory data were obtained. A high intake of a “Western diet” resulted in statistically linear declines of SC and NSM (P < 0.001 and P < 0.001). Similarly, a greater intake of “High sweet snacks & sugar-sweetened drinks” was associated with a lower SC (P = 0.001). Increased intake of a “High-carbohydrate diet” was related to higher prevalences of abnormal TSM and PRM (P = 0.012 and P = 0.025). Similarly, a greater intake of a “High-sodium diet” was correlated with an elevated prevalence of abnormal NSM (P = 0.035).ConclusionsThis study showed that a greater intake of a “Western diet” is associated with poorer SC and NSM, a “High sweet snacks and sugar-sweetened drinks” intake is correlated with a lower SC, and high-carbohydrate food is related to elevated prevalences of abnormal TSM and PRM.
Pro-inflammatory cytokines and chemokines are involved in promoting tumorigenesis by facilitating tumor proliferation and metastasis. The serum levels of interleukin (IL)-6, IL-1β β β β, and tumor necrosis factor-alpha (TNF-α α α α) are significantly elevated in patients with renal cell carcinoma (RCC). However, the mechanisms of how these cytokines participate in the progression of RCC remains unknown. In the present study, we investigated the effects of tumorderived cytokines on invasion and the epithelial-mesenchymal transition (EMT) of RCC cells. We found that expression of IL-1β β β β, IL-6, TNF-α α α α, hypoxia-inducible factor-alpha (HIF-1α α α α), and matrix metalloproteinase-2 (MMP2) were significantly elevated in high malignancy A498 (1) Four types of RCC have been delineated clinically and the genes responsible for them have been characterized. Overall, 75% of RCC are the clear cell type (ccRCC), while the other 25% are made up of the papillary, chromophobe, and oncocytic types. (2) Defects in the von Hippel-Lindau (VHL) gene appear to be responsible for 60% of sporadic ccRCC. A quarter of patients present with locally invasive or metastatic RCC. A third of the patients after resection of the tumor will have a recurrence. Moreover, systemic theraputic treatments of advanced RCC are largely ineffective and do not improve patient survival.(1,2) Therefore, defining the factors involved in disease progression and metastasis will provide molecular targets for the development of effective therapies.A complex network of pro-inflammatory cytokines, chemokines, and their receptors influences the development of primary tumors and metastasis. (3,4) CXCR4 is most commonly found in malignant cells from different cancer types.(4) In addition to CXCR4, CCR3 has been found to be up-regulated in 28% RCC tissues and correlates with a higher grade of malignancy.(5) Furthermore, the levels of IL-6, IL-1β, and TNF-α in serum are significantly higher and correlated with tumor size in RCC.(6) IL-6 blood level is significantly higher in patients with lymph node invasion and distant metastases, while TNF-α level is significantly higher as the stage of the RCC increases.(6,7) Therefore, IL-6 may be one of the factors associated with poor prognosis of patients with RCC. In addition, TNF-α may be useful as marker for the early diagnosis of RCC.(6) However, little is known about how these cytokines affect RCC migration and progression.The epithelial-mesenchymal transition (EMT) is a process in which polarized epithelial cells are converted into motile mesenchymal cells. Alterations in adhesion, morphology, cellular architecture, and migration capacity are the major events that occur during this process.(8) Common molecular markers for the EMT include increased expression of vimentin, nuclear localization of β-catenin, and increased production of transcriptional factors that inhibit E-cadherin production. Phenotypic markers for EMT comprise an increased capacity for migration and three-dimensional invasion as well as resistance t...
TNF-a is a cytokine with antitumorigenic property. In contrast, low dose, chronic TNF-a production by tumor cells or stromal cells may promote tumor growth and metastasis. Serum levels of TNF-a are significantly elevated in renal cell carcinoma (RCC) patients. Here, we showed that TNF-a induced epithelial-mesenchymal transition (EMT) and promoted tumorigenicity of RCC by repressing E-cadherin, upregulating vimentin, activating MMP9, and invasion activities. In addition, TNF-a treatment inhibited glycogen synthase kinase 3b (GSK-3b) activity through serine-9 phosphorylation mediated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway in RCC cells. Inhibition of PI3K/AKT by LY294002 reactivated GSK-3b and suppressed the TNFa-induced EMT of RCC cells. Inactivation of GSK-3b by LiCl significantly increased MMP9 activity and EMT of RCC cells. Activation of GSK-3b by transduction of constitutively active GSK-3b into RCC cells suppressed TNFa-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient GSK-3b, in contrast, potentiated EMT, anchorage-independent growth and drastically enhanced tumorigenicity in vivo. Most importantly, a 15-fold inactivation of GSK-3b activity, 3-fold decrease of E-cadherin, and 2-fold increase of vimentin were observed in human RCC tumor tissues. These results indicated that inactivation of GSK-3b plays a pivotal role in the TNF-a-mediated tumorigenesis of RCC. Mol Cancer Res; 10(8); 1109-19. Ó2012 AACR. IntroductionRenal cell carcinoma (RCC) is the tenth most common cause of cancer-related deaths worldwide (1). Although surgery is often curative, 30% of patients will present with metastases at the time of initial diagnosis (1). The 5-year survival rate is only 5% in metastatic RCC as advanced RCC is resistant to chemotherapy and radiotherapy (2, 3). Previous studies indicated immunotherapy is relatively effective against RCC (2, 3). However, the response rate is only 15% to 20% (1-3). Therefore, defining the factors involved in disease progression and metastasis will provide novel molecular targets for the development of effective therapies.
Metastatic prostate cancer continues to pose a difficult therapeutic challenge. Prostate cancer progression is associated with aberrant O-glycosylation of cancer cell surface receptors, but the functional impact of such events is uncertain. Here we report spontaneous metastasis of human prostate cancer xenografts that express high levels of galectin-4 along with genetic signatures of EGFR-HER2 signaling and O-glycosylation. Galectin-4 expression in clinical specimens of prostate cancer correlated with poor patient survival. Galectin-4 binding to multiple receptor tyrosine kinases stimulated their autophosphorylation, activated expression of pERK, pAkt, fibronectin, and Twist1, and lowered expression of E-cadherin, thereby facilitating epithelial-mesenchymal transition, invasion, and metastasis. In vivo investigations established that galectin-4 expression enabled prostate cancer cells to repopulate tumors in orthotopic and heterotopic tissues. Notably, these effects of galectin-4 relied upon O-glycosylation mediated by C1GALT1, a galactosyltransferase implicated in other cancers. Parallel changes in galectin-4 and O-glycosylation triggered aberrant receptor signaling and more aggressive invasive character in prostate cancer cells, which through better survival in the circulation also contributed to the bulk cell progeny of distal tumors. Our findings establish galectin-4 and C1GALT1-mediated glycosylation in a signaling axis that is activated during prostate cancer progression, with implications for therapeutic targeting of advanced metastatic disease. Cancer Res; 76(19); 5756-67. ©2016 AACR.
To determine whether a relationship between obesity and varicocele occurrence exists, the prevalence and severity of varicoceles related to obesity were investigated in a general population of young males. A total of 1050 young males attending the Navy Recruit Training Center were evaluated from their physical screening examinations. All subjects underwent history taking and physical examinations to evaluate for the presence and severity of varicocele. The anthropometric indexes including body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) were recorded. All subjects were categorized by quartiles according to each anthropometric index. Means were compared with the Student's t-test. Severity was compared by analysis of variance testing and frequency was analysed using the chi-square method. Statistical significance was considered at p <0.05. A total of 490 (46.67%) subjects had varicoceles. The means of BMI, WC and WHR of those without varicoceles was 23.99 +/- 3.82 kg/m(2), 83.20 +/- 9.97 cm and 0.85 +/- 0.05, respectively. These judged values were greater than those with varicoceles (22.02 +/- 3.18 kg/m(2), 79.19 +/- 9.01 cm and 0.83 +/- 0.05) (p < 0.001). In the univariate regression analysis, BMI, WC and WHR all had a significantly negative correlation with severity of varicocele (all p < 0.001). Analysis comparing varicocele frequency based on each grade per anthropometric index group was performed. The logistic regression revealed that the prevalence of grade II and III varicoceles showed a statistically inverse association with all three anthropometric indexes. The prevalence and severity of varicoceles inversely correlated with obesity. The present data support the explanation that obesity may result in a decreased nutcracker effect, which accounts for prevention of the renal vein compression by the adipose tissue.
Galectin-1, a b-galactoside-binding lectin, is involved in many physiologic and pathologic processes, including cell adhesion, differentiation, angiogenesis, and tumor progression. However, the role of galectin-1 in kidney cancer remains elusive. This study evaluated the role of galectin-1 in the progression and clinical prognosis of renal cell carcinoma. We found significant overexpression of galectin-1 in both kidney cancer cell lines and metastatic tissue specimens from patients with renal cell carcinoma. Knockdown of galectin-1 gene expression in renal cancer cell lines reduced cell invasion, clonogenic ability, and epithelial-mesenchymal transition in vitro; reduced tumor outgrowth in vivo; and inhibited the angiogenesis-inducing activity of these cells in vitro and in vivo. Galectin-1 knockdown decreased CXCR4 expression levels in kidney cancer cells, and restoration of CXCR4 expression in galectin-1-silenced cells rescued cell motility and clonogenic ability. Additional studies suggested that galectin-1 induced CXCR4 expression through activation of nuclear factor-kB (NF-kB). Analysis of patient specimens confirmed the clinical significance and positive correlation between galectin-1 and CXCR4 expression levels and revealed concomitant overexpression of galectin-1 and CXCR4 associated adversely with overall and disease-free survival. Our findings suggest that galectin-1 promotes tumor progression through upregulation of CXCR4 via NF-kB. The coordinated upregulation of galectin-1 and CXCR4 may be a novel prognostic factor for survival in patients with renal cell carcinoma and the galectin-1-CXCR4 axis may serve as a therapeutic target in this disease. 25: 148625: -149525: , 201425: . doi: 10.1681 Renal cell carcinoma (RCC) accounts for approximately 4% of all adult malignancies. 1 More than one third of patients will present with locally advanced or metastatic disease at the time of diagnosis. 2 The 5-year survival rate of metastatic RCC is only 10% because of resistance to chemotherapy and radiation therapy. 3 Although cytokine therapy with IFN-a and IL-2 is the gold standard treatment, its overall efficacy rate is limited by its significant toxicity. 4 Recently, several molecular targeting drugs, including sunitinib and temsirolimus, have been approved for advanced RCC. 4 However, treatment response is not long-standing and overall survival remains poor. Thus, the identification of novel molecular targets in RCC is urgently needed for the development of effective therapies. J Am Soc Nephrol
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.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.