Elevation of methylated DNA in KILLIN/PTEN in the plasma of patients with thyroid and/or breast cancer

© 2014 Ng et al. Around 80% of mutations in the PTEN gene have been reported to be associated with diseases such as Cowden syndrome, which is an autosomal dominant disorder associated with an increased risk of developing breast, thyroid, and endometrial neoplasms. Recent studies have also demonstrated that KILLIN, which is located proximally to PTEN, shares the same transcription start site, and is assumed to be regulated by the same promoter, but is transcribed in the opposite direction. In this regard, we postulate that there may be a connection between KILLIN/PTEN genes and breast and thyroid cancers. Using real-time quantitative polymerase chain reaction (qPCR), we found that expression of KILLIN, but not PTEN, was significantly decreased in 23 Chinese women with a personal history of breast and thyroid cancer or a personal history of breast cancer and a family history of thyroid cancer, or vice versa, and at least two persons in the family with thyroid cancer or at a young age ,40 years, when compared with healthy controls (P<0.0001). No PTEN mutations were found in these 23 patients. We then developed a simple methylation-sensitive restriction enzyme digestion followed by real-time quantitative assay to quantify plasma methylated KILLIN/PTEN DNA in these patients. Plasma levels of methylated KILLIN/PTEN DNA were significantly increased in these patients when compared with healthy controls (P<0.05). This study shows that plasma methylated KILLIN/PTEN DNA was significantly elevated, suggesting hypermethylation of the KILLIN/PTEN promoter in breast and thyroid cancer patients.published_or_final_versio

Nicotine and gastric cancer

About 60 components in cigarette smoke are considered to be carcinogens, namely polycyclic aromatic hydrocarbons, nitrosamines, aromatic amine, trace metals, as well as nicotine. Nicotine is considered to be one of the active components in cigarette smoke, and its association with tumorigenesis is enigmatic. Nonsteroidal antiinflammatory drugs are widely accepted as antitumor agents to treat patients with cancer by inhibiting cyclooxygenase-2 activity. Stimulation of tumor growth by nicotine involves different processes of cell proliferation and angiogenesis. Study results, with the use of animal xenograft models and cell culture systems, show that nicotine stimulates the progression of tumor growth, through a cyclooxygenase-2-dependent pathway. On the basis of these findings, nicotine seems to be a potent mitogenic agent in modulating tumor cell proliferation, and selective cyclooxygenase-2 inhibitors are promising antitumor agents for gastric cancer in smokers. © 2005 Elsevier Inc. All rights reserved.link_to_subscribed_fulltex

Modulation of heme oxygenase in tissue injury and its implication in protection against gastrointestinal diseases

These journal issues contain invited, peer-reviewed papers written by participants of the 3rd International Symposium on Cell/Tissue Injury and Cytoprotection/Organoprotection (Long Beach, CA, February 24–27, 2000).Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme, followed by production of biliverdin, free iron and carbon monoxide (CO). There are three isoforms of HO: HO-1 is highly inducible, whereas HO-2 and HO-3 are constitutively expressed. In addition to heme, a variety of nonheme compounds, including heavy metals, cytokines, endotoxins and heat shock stress are strong inducers of HO-1 expression. Many studies indicated that induction of HO-1 is associated with a protective response due to the removal of free heme, which is shown to be toxic. However, recent studies demonstrated that the expression of HO-1 in response to different inflammatory mediators could contribute in part to the resolution of inflammation and have protective effects on brain, liver, kidney and lung against injuries. These beneficial effects seem to be due to the production of bile pigment biliverdin and bilirubin that is a potent antioxidant, as well as the release of iron and CO. However, there are few studies concerning the relationship between HO-1 and inflammation as well as injury in the gut. Interestingly, a preliminary study implicated that induction of HO-1 expression in a colonic damage model induced by trinitrobenzene sulfonic acid played a critical protective role, indicating that activation of HO-1 could act as a natural defensive mechanism to alleviate inflammation and tissue injury in the gastrointestinal tract. © Elsevier Science Inc. All rights reserved.link_to_subscribed_fulltex

Nicotine and gastrointestinal disorders: Its role in ulceration and cancer development

Cigarette smoke has always been the single most preventive cause of death in the world. In 2011, over 460,000 died from cigarette smoke-related diseases in US. The detrimental effects of cigarette smoke on human beings are due to the presence of many carcinogens and other components (e.g. nicotine and tar). Nicotine is now accepted as one of the major components responsible for gastrointestinal disorders. Cigarette smoking, nicotine and a nicotine-derived nitrosamine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered as risk factors for gastrointestinal cancer, however, the underlying mechanism remains largely unknown. Previous studies reported that cigarette smoke and nicotine aggravated inflammation not only in the stomach, but also in the colon. The carcinogenic actions of cigarette smoke, nicotine and NNK on gastrointestinal cancers development have been widely studied. The strong association of cyclooxygenase-2 (COX-2) with gastrointestinal diseases has been extensively studied, however, due to the unresolved cardiovascular risk, it is of great importance to develop other new anti-cancer drugs for the treatment of cancers. This current review aims to provide an overview of the effects of cigarette smoke, nicotine and NNK on gastrointestinal inflammation, and also the carcinogenic properties in cancer development (tumor growth, angiogenesis and epithelial-mesenchymal transition). In addition, current studies on nicotinic acetylcholine receptors, adrenergic receptors and miRNAs in nicotine-related cancer pathogenesis are also highlighted. © 2013 Bentham Science Publishers.link_to_subscribed_fulltex

A mechanistic study of colon cancer growth promoted by cigarette smoke extract

Substantial evidence indicates that significant exposure to cigarette smoke is associated with an elevated risk for colorectal cancer. However, the mechanisms underlying the causal relationship between cigarette smoking and colorectal cancer remain to be investigated. Our previous study showed that cigarette smoke promotes the formation of inflammation-associated colonic adenoma in mice through an angiogenic pathway. Therefore, in the present study, we used the human colon adenocarcinoma cell line, SW1116, and human umbilical vascular endothelial cells (HUVECs) to elucidate the possible mechanisms in vitro. Results showed that cigarette smoke extract enhanced cell proliferation and the expression of 5-lipoxygenase (5-LOX), vascular endothelium growth factor (VEGF), matrix metalloproteinases (MMPs) 2 and 9 in SW1116 cells. Inhibition of 5-LOX decreased cell proliferation and expressions of VEGF, MMP-2 and MMP-9 induced by cigarette smoke extract. In addition, cigarette smoke extract indirectly stimulated HUVEC proliferation, a biological activity closely related to angiogenesis during tumor growth. This was again blocked by the 5-LOX inhibitor. Taken together, the results of the present study demonstrate the central role of 5-LOX and its relationship with angiogenic mediators in the actions of cigarette smoke in the promotion of angiogenesis during colon cancer growth. © 2005 Elsevier B.V. All rights reserved.link_to_subscribed_fulltex

Effect of polysaccharides from Angelica sinensis on gastric ulcer healing

Our previous study showed that a crude extract from Angelica sinensis (ASCE), which mainly consisted of polysaccharides, significantly promoted migration and proliferation of normal gastric epithelial cells. These results strongly suggest that ASCE has a direct wound healing effect on gastric mucosa. However, there is no report concerning the effect of ASCE on gastric ulcer healing in animal models. In this study, we found that ASCE promoted ulcer healing. The area of the ulcer was reduced. This was accompanied with a significant increase in mucus synthesis when compared with the control. Angiogenesis was inhibited by the treatment of ASCE. Cell proliferation, ODC and EGFR protein expression was not affected in this process. Thus, the mechanism of how ASCE accelerates ulcer healing in addition to its effect on mucus synthesis remains to be investigated. © 2002 Elsevier Science Inc. All rights reserved.link_to_subscribed_fulltex

The modulating role of nuclear factor-κB in the action of α7-nicotinic acetylcholine receptor and cross-talk between 5-lipoxygenase and cyclooxygenase-2 in colon cancer growth induced by 4-(N-methyl-N- nitrosamino)-1-(3-pyridyl)-1-butanone

4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine, induces lung cancer in all animal species tested and is thought to contribute significantly to the high lung cancer burden associated with smoking. However, there is no report whether NNK could promote colon cancer growth. To address this hypothesis and the possible signaling pathways involved, we used SW1116 colon cancer cell line to study these biological events in vitro. Results showed that NNK, after 5-h treatment, stimulated cell proliferation, enhanced α7-nicotinic acetylcholine receptor (α7-nAChR) mRNA levels and nuclear factor-κB (NF-κB) DNA binding activity, as well as 5-lipoxygenase and cyclooxygenase-2 protein expressions. α-Bungarotoxin, the specific α7-nAChR antagonist, inhibited these biological effects. However, 5-lipoxygenase inhibition had no effect on α7-nAChR mRNA expression, but significantly inhibited cell proliferation and activation of NF-κB and cyclooxygenase-2, whereas NF-κB-specific inhibitor caffeic acid phenethyl ester reduced both cell proliferation and cyclooxygenase expression induced by NNK without affecting α7-nAChR mRNA level and 5-lipoxygenase expression. Together, the present study demonstrated that NNK promoted colon cancer growth in vitro. NF-κB not only conveys the biological effect of α7-nAChR activation but is also involved in the cross-talk between 5-lipoxygenase and cyclooxygenase-2 in response to NNK in colon cancer cell development.link_to_subscribed_fulltex

Contributory role of 5-lipoxygenase and its association with angiogenesis in the promotion of inflammation-associated colonic tumorigenesis by cigarette smoking

Our previous study shows that cigarette smoking can promote inflammation-associated adenoma formation in the mouse colon, but the underling mechanism remains unknown. Several studies suggest that there is a link between 5-lipoxygenase (5-LOX) and carcinogenesis in humans and animals. In the present study, we aims to investigate whether the promoting action of cigarette smoke on inflammation-associated colon cancer formation is associated with 5-LOX activation in mice. Results showed that exposure to the mainstream smoke of unfiltered cigarettes enhanced the 5-LOX protein expression in the inflammation-associated colonic adenomas. It was accompanied with an up-regulation of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF). Both are the key angiogenic factors for tumorigenesis. 5-LOX inhibitors decreased the incidence of colonic adenoma formation and reduced angiogenesis, MMP-2 activity and VEGF protein expression in the colons of these animals. Taken together, these results strongly suggest that cigarette smoke can induce 5-LOX expression which plays an important role in activation of MMP-2 and VEGF to induce angiogenic process and promotion of inflammation-associated adenoma formation in mice. © 2004 Elsevier Ireland Ltd. All rights reserved.link_to_subscribed_fulltex

Nicotine Promoted Colon Cancer Growth via Epidermal Growth Factor Receptor, c-Src, and 5-Lipoxygenase-Mediated Signal Pathway

Nicotine [3-(1-methyl-2-pyrrolidinyl)-pyridine], a major alkaloid in tobacco, has been implicated as playing a role in carcinogenesis. Our previous study showed that passive cigarette smoking promoted inflammation-associated colonic adenoma formation in mice, and 5-lipoxygenase (5-LOX) plays an important role in this process. In the present study, we aimed to investigate whether nicotine could stimulate colon cancer cell proliferation and tumor growth in nude mice xenograft model and the possible mechanisms involved. Results showed that nicotine stimulated SW1116 colon cancer cell proliferation in a dose-dependent manner. Epidermal growth factor receptor (EGFR) and c-Src phosphorylation levels together with protein expression of 5-LOX were also significantly enhanced in this proliferation process. Inhibitors of EGFR and c-Src alleviated the actions of nicotine on cell proliferation and 5-LOX protein expression. Combination of both agents produced additive effect. In contrast, 5-LOX inhibitor had no direct effect on the phosphorylation levels of EGFR and c-Src and yet inhibited cell proliferation. In the colon cancer xenograft model, nicotine also significantly enhanced tumor growth. This acceleration of tumor growth corresponded well with increased vascularization and its proangiogenic factors. Inhibitors of EGFR, c-Src, and 5-LOX all significantly impeded the tumor growth induced by nicotine. Together, nicotine can promote colonic tumorigenesis both in vitro and in vivo. Activation of the phosphorylated form of EGFR and c-Src followed by an increased 5-LOX expression are the prime pathogenic mechanisms in the tumorigenic process in the colon.link_to_subscribed_fulltex

Animal models of gastrointestinal inflammation and cancer

Inflammation and cancer are the two major disorders in the gastrointestinal tract. They are causally related in their pathogenesis. It is important to study animal models' causal relationship and, in particular, to discover new therapeutic agents for such diseases. There are several criteria for these models in order to make them useful in better understanding the etiology and treatment of the said diseases in humans. In this regard, animal models should be similar as possible to human diseases and also be easy to produce and reproducible and also economic to allow a continuous replication in different laboratories. In this review, we summarize the various animal models for inflammatory and cancerous disorders in the upper and lower gastrointestinal tract. Experimental approaches are as simple as by giving a single oral dose of alcohol or other noxious agents or by injections of multiple dosages of ulcer inducing agents or by parenteral administration or in drinking water of carcinogens or by modifying the genetic makeups of animals to produce relatively long-term pathological changes in particular organs. With these methods they could induce consistent inflammatory responses or tumorigenesis in the gastrointestinal mucosa. These animal models are widely used in laboratories in understanding the pathogenesis as well as the mechanisms of action for therapeutic agents in the treatment of gastrointestinal inflammation and cancer. © 2014 Elsevier Inc.link_to_subscribed_fulltex