Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Silibinin is a natural flavonoid antioxidant with anti-hepatotoxic properties and pleiotropic anticancer capabilities. We tested the hypothesis that silibinin inhibits cellular invasiveness by down-regulating the focal adhesion kinase (FAK) and extracellular signal-regulated protein kinase (ERK)-dependent c-Jun/activator protein-1 (AP-1) induction, which leads to inhibition of urokinase-type plasminogen activator (u-PA) and matrix metalloproteinase-2 (MMP-2) expressions in human osteosarcoma MG-63 cells. We found that silibinin decreased cell adhesion and invasiveness, as well as inhibited u-PA and MMP-2 expressions. Silibinin reduced ERK 1/2 phosphorylation, but had no effects on the phosphorylation of c-Jun N-terminal kinases (JNKs) 1/2, p38 and Akt. Silibinin suppressed AP-1-binding activity and c-Jun levels and its phosphorylation without changes of c-Fos and Ets-1 levels. Silibinin also inhibited interleukin-6-induced ERK 1/2 and c-Jun phosphorylation, and cell invasiveness. Thus, silibinin may possess an anti-metastatic activity in MG-63 cells.
Carcinogenesis 2007 May
PMID:Silibinin suppresses human osteosarcoma MG-63 cell invasion by inhibiting the ERK-dependent c-Jun/AP-1 induction of MMP-2. 1711 26

In view of the recently found contribution of factors associated with thrombosis and inflammation to carcinogenesis, we investigated the possible association of interleukin-6 (IL-6) with an increased risk of oral cancer. In DNA samples of 162 patients with oral squamous cell carcinoma and 156 healthy controls of comparable ethnicity, age and sex, we studied the -174 G>C polymorphism in the IL-6 gene, which affects its transcription. C allele frequencies were significantly increased in patients compared to controls, 42.6% versus 23.1% (p<0.001). The CC homozygotes had a 7-fold greater risk of developing oral cancer (odds ratio 7.39, 95% CI 2.61-20.92), while the GC heterozygotes had a 4-fold greater risk (odds ratio 3.74, 95% CI 2.29-6.11). A significant increase in C alleles was observed in patients regardless of their smoking or alcohol consumption habits, early or advanced stage of cancer, and presence or absence of a family history for cancer or thrombophilia (p<0.001; Fisher's exact test). These findings suggest that the -174 G>C polymorphism, by affecting IL-6 gene expression, is strongly associated with oral oncogenesis.
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PMID:Strong association of interleukin-6 -174 G>C promoter polymorphism with increased risk of oral cancer. 1717 64

The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.
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PMID:JAK-STAT pathway in carcinogenesis: is it relevant to cholangiocarcinoma progression? 1816 17

The N terminus-truncated splicing variant of TAp63 is known as DeltaNp63. DeltaNp63 lacks transactivation function and is thought to antagonize the transcriptional regulation of the p53 and TAp63 target genes. Overexpression of DeltaNp63 has been observed in a number of human cancers, suggesting a role in carcinogenesis. In the present study we present data showing that the DeltaNp63 gene promoter activity is positively regulated by DeltaNp63alpha, and such positive autoregulation is mediated via activation of STAT3 activity. We show that expression of DeltaNp63alpha in Hep3B cells induces Stat3 phosphorylation on Tyr-705 and Ser-727. A putative STAT3-responsive element (STAT3-RE) is identified in the DeltaNp63 promoter region. Electrophoretic mobility shift and avidin biotin-Conjugated DNA assays show direct binding of STAT3 to STAT3-RE of the DeltaNp63 promoter, and such binding is stimulated by DeltaNp63alpha. Binding of the endogenous STAT3 to the DeltaNp63 promoter in Hep3B cells was demonstrated by a chromatin immunoprecipitation assay. The stimulation of the DeltaNp63 transcriptional activity by DeltaNp63alpha is abolished by Janus kinase 2 (JAK2)/STAT3 inhibitor AG490, dominant-negative STAT3, STAT3 small interfering RNA, and deletion of the STAT3-RE sequence from DeltaNp63 promoter. Taken together these observations clearly indicated that autoregulation of DeltaNp63 gene transcription is mediated through activation of STAT3 and its subsequent binding to the STAT3RE. Because the activation of STAT3 by interleukin-6 also leads to DeltaNp63 up-regulation and the blockade of DeltaNp63 or STAT3 expression by siRNA leads to repression of the cell growth, the identified regulatory pathway is presumably of cell physiological significance.
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PMID:Transcriptional activity of the DeltaNp63 promoter is regulated by STAT3. 1819 75

Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification.
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PMID:Obesity, metabolic syndrome, and prostate cancer. 1826 78

Adipocytokines are a group of adipocyte-secreted proteins that have significant effects on the metabolism of lipids and carbohydrates, as well as numerous other processes. A number of recent studies have indicated that some adipocytokines may significantly influence the proliferation of malignant cells in vitro, whereas it remains unclear whether they have similar roles in vivo. In this study, we determined serum levels of adipocytokines in mice with azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colon carcinogenesis. Five-week-old ICR mice were given a single intraperitoneal injection of AOM followed by 1% DSS in drinking water for 7 days. Nobiletin (NOB), a citrus flavonoid, was given in the diet (100 p.p.m) for 17 weeks. Thereafter, the incidence and number of colon tumors and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was six times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin and interleukin-6. Feeding with NOB abolished colonic malignancy and notably decreased the serum leptin level by 75%. Further, NOB suppressed the leptin-dependent, but not independent, proliferation of HT-29 colon cancer cells and decreased leptin secretion through inactivation of mitogen-activated protein kinase/extracellular signaling-regulated protein kinase, but not that of adiponectin in differentiated 3T3-L1 mouse adipocytes in a dose-dependent manner. Taken together, our results suggest that higher levels of leptin in serum promote colon carcinogenesis in mice, whereas NOB has chemopreventive effects against colon carcinogenesis, partly through regulation of leptin levels.
Carcinogenesis 2008 May
PMID:Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice. 1837 60

The etiology of esophageal mucosal injury is complex, since it may involve the reflux of gastric acid, bile acid, and pancreatic juice, external factors such as drugs and alcohol, or functional factors such as esophagogastric motility. The mechanism of esophageal mucosal injury has gradually been understood at the molecular biological level. It is particularly important that pro-inflammatory factors, such as inflammatory cytokines (interleukin-6 and -8), leukocytes and oxidative stress, have been demonstrated to be involved in the development of gastroesophageal reflux disease (GERD) including nonerosive reflux disease (NERD). In addition, nociceptors such as acid-sensitive vanilloid receptors, protease-activated receptors and substance P have also been implicated in the pathogenesis of neurogenic inflammation in NERD patients with esophageal hypersensitivity. The development of new therapy with anti-inflammatory and anti-oxidant effects is expected to assist in the treatment of intractable NERD/GERD and the prevention of carcinogenesis.
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PMID:Inflammation and oxidative stress in gastroesophageal reflux disease. 1843 9

Chronic inflammation plays a role in transformation from normal cell to malignant state. Interleukin-6 (IL-6) regulates inflammation and various physiological processes. IL-6 promoter polymorphism (-174G>C) is associated with transcription differences in vitro and in vivo. High expression of IL-6 may result in oxidative DNA damage and enhance risk of carcinogenesis. Therefore, we aimed to evaluate association of IL-6 -174G>C polymorphism with predisposition to esophageal cancer (EC) in 369 subjects (168 patients with EC and 201 controls). We observed significant association of IL-6 -174C non-carrier genotype with risk of EC, (OR=2.29; P=0.001), with squamous cell carcinoma (SCC) histology (OR=2.26; P=0.001) and tumor at upper and lower anatomical locations (OR=5.97; P=0.009 and OR=2.34; P=0.034). Patients having IL-6 -174C non-carrier genotype were at elevated risk of metastasis (OR=2.49; P=0.005). In conclusion, IL-6 -174G>C gene polymorphism may confer high risk for EC and its clinical characteristics.
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PMID:Association of interleukin-6 (-174G>C) promoter polymorphism with risk of squamous cell esophageal cancer and tumor location: an exploratory study. 1850 91

The only universally accepted risk factors for the development of pancreatic cancer are a positive family history or a history of smoking. Although the contribution of pancreatitis to pancreatic carcinogenesis has been debated for decades in the epidemiology literature, the actual mechanism is still unclear. With the rising epidemic of obesity, scientists have begun to focus on the contribution of chronic inflammatory state of morbidly obese patients in an effort to better understand the contribution of inflammation to the comorbidities of obesity. Notably, population studies are beginning to show that one of the most serious potential comorbidities of obesity is an increased lifetime risk of developing cancer. In this article, the current literature that exists supporting this Chronic Inflammatory Hypothesis as it pertains to obesity and pancreatic carcinogenesis is reviewed. To date, studies have focused on interleukin-6, a cytokine known to play a role in obesity, chronic pancreatitis and pancreatic cancer. The anti-inflammatory adipocytokine, adiponectin, has also shown promise as a key player in this mechanism and has recently been found to be more specific than standard tumor markers in differentiating pancreatic cancer from chronic pancreatitis. If the pathogenesis of pancreatic cancer is related to hormone levels associated with obesity, such as adipocytokines, and cytokines associated with chronic inflammation, this could potentially lead to the development of new pancreatic cancer tumor markers and ultimately new therapies and methods of prevention.
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PMID:Obesity, pancreatitis, and pancreatic cancer. 1856 97

The purpose of this study was to determine whether a dry bean (Phaseolus vulgaris, L.) containing diet exerts an inhibitory effect on mammary carcinogenesis in a well-characterized rodent model for breast cancer. Twenty-one-d-old female Sprague Dawley rats were given an intraperitoneal injection of 1-methyl-1-nitrosourea and 7 d after carcinogen injection were randomized to 1 of 5 groups fed a modification of the AIN-93G diet formulation containing 0, 7.5, 15, 30, or 60% (wt:wt) small red dry bean incorporated as cooked, freeze-dried, and milled powder. All experimental diets had the same macronutrient content based on proximate analysis. Compared with the control group, dry bean consumption resulted in dose-dependent reductions in mammary cancer incidence (P = 0.046), cancer multiplicity (P = 0.001), and tumor burden (P = 0.01). Dry bean consumption was associated with dose-dependent reductions in plasma concentrations of glucose, insulin, insulin-like growth factor-1, C-reactive protein, and interleukin-6 in food-deprived rats. Analysis of mammary adenocarcinomas indicated that a dominant mechanism accounting for reduced tumor burden was the induction of apoptosis. B cell lymphoma 2 and X-linked inhibitor of apoptosis protein levels decreased and BCL-2-associated X protein increased with increasing dry bean consumption, findings consistent with the induction of apoptosis via the mitochondrial pathway. These data demonstrate that a legume without noteworthy content of isoflavones inhibits the development of mammary carcinogenesis and are consistent with a recent report from the Nurses Health Study that bean or lentil intake is associated with a lower risk for breast cancer.
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PMID:Mechanisms associated with dose-dependent inhibition of rat mammary carcinogenesis by dry bean (Phaseolus vulgaris, L.). 1893 3


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