EGCG oxidation-derived polymers induce apoptosis in digestive tract cancer cells via regulating the renin-angiotensin system.

Green tea polyphenol (-)-Epigallocatechin-3-gallate (EGCG) has been well studied for its biological activities in the prevention of chronic diseases. However, the biological activities of EGCG oxidation-derived polymers remain unclear. Previously, we found that these polymers accumulated in intraperitoneal tissues after intraperitoneal injection and gained an advantage over native EGCG in increasing insulin sensitivity via regulating the renin-angiotensin system (RAS) in type 2 diabetic mice. The present study determined the pro-apoptosis activities and anticancer mechanisms of the EGCG oxidation-derived polymer preparation (the >10 kDa EGCG polymers) in digestive tract cancer cells. Upon incubation of the >10 kDa EGCG polymers with CaCo2 colon cancer cells, these polymers coated the cell surface and regulated multiple components of the RAS in favor of cancer inhibition, including the downregulation of angiotensin-converting enzyme (ACE), angiotensin-II (AngII) and AngII receptor type 1 (AT1R) in the pro-tumor axis, as well as the upregulation of angiotensin-converting enzyme 2 (ACE2) and angiotensin1-7 (Ang(1-7)) in the anti-tumor axis. The treatment also markedly increased angiotensinogen (AGT), which is the precursor of the angiotensin peptides. The regulation of these RAS components occurred prior to apoptosis. Similar pro-apoptotic mechanisms of the >10 kDa EGCG polymers, were also observed in TCA8113 oral cancer cells. The >10 kDa EGCG polymers exhibited compromised activities in scavenging or initiating reactive oxygen species compared to EGCG, but gained a higher reactivity toward sulfhydryl groups, including protein cysteine thiols. We propose that the polymers bind onto the cell surface and regulate multiple RAS components by reacting with the sulfhydryl groups on the ectodomains of transmembrane proteins.

Corrigendum to "Dark tea: A popular beverage with possible medicinal application" [Chinese Herbal Medicines 15 (2023) 3315036].

[This corrects the article DOI: 10.1016/j.chmed.2022.08.005.].

Dark tea: A popular beverage with possible medicinal application.

Tea is a famous beverage that is produced from leaves of Camellia sinensis. Amongst the six major tea categories in China, dark tea is the only one that involves microbial fermentation in the manufacturing process, which contributes unique flavors and functions for the tea. In the recent decade, the reports about the biofunctions of dark teas have increased rapidly. Therefore it may be the proper time to consider dark tea as one potential homology of medicine and food. In this viewpoint, our current understanding of the chemical constituents, biological activities and possible health beneficial effects of dark teas were introduced. Some future directions and challenges to the development perspectives of dark teas were also discussed.

Polydatin, A Glycoside of Resveratrol, Is Better Than Resveratrol in Alleviating Non-alcoholic Fatty Liver Disease in Mice Fed a High-Fructose Diet.

Resveratrol (RES) is considered to be an activator of AMP-activated protein kinase (AMPK) with many reported health benefits. Polydatin (POD) is a natural precursor and glycosylated form of RES. The glycoside structure of POD alters the bioactivity. Overnutrition-stimulated reactive oxygen species (ROS) promote the AMPK suppression and metabolic dysregulation. The present work compared the effects of POD and RES in ameliorating energy homeostasis imbalance in mice fed a high-fructose diet and elucidated the underlying mechanisms of action. Our results showed that POD elevated the fecal levels of valeric acid and caproic acid via modification of gut microbiota, while RES did not significantly influence the levels of fecal short-chain fatty acids (SCFAs). Both POD and RES markedly decreased the oxidative stress and activated the AMPK signaling pathways in the liver. POD and RES exerted a similar effect in alleviating glucose dysmetabolism, but POD was more effective in ameliorating lipid dysmetabolism than RES. Furthermore, valeric acid and caproic acid alone can activate the AMPK and ameliorate hypercholesterolemia, and enhance the effects of POD on improving lipid metabolism in mice. Overall, for the first time, we demonstrated that POD administration elevated the fecal levels of valeric acid and caproic acid by modifying gut microbiota, thus promoting AMPK activation may be the underlying mechanism that POD is superior to RES in alleviating the lipid dysmetabolism. Our results suggest that POD may be an alternative for RES as an AMPK activator.

Redox and Other Biological Activities of Tea Catechins That May Affect Health: Mechanisms and Unresolved Issues.

The beneficial health effects of green tea have been attributed to tea catechins. However, the molecular mechanisms of action, especially those in vivo, remain unclear. This article reviews the redox and other activities of tea catechins, using (-)-epigallocatechin-3-gallate (EGCG), as an example. EGCG is a well-known antioxidant. However, EGCG can be oxidized to generate reactive oxygen species and EGCG quinone. We propose that EGCG quinone can react with Keap-1 to activate Nrf2-regulated cytoprotective enzymes. Tissue levels of catechins are important for their biological activities; a section is devoted to reviewing the biological fates of tea catechins after ingestion. Possible EGCG oxidation in vivo and whether the oligomeric forms are biologically active in animals are discussed. We also review the effects of EGCG on the activities of enzymes, receptors, and other signaling molecules through binding and raise a question about whether the autoxidation of EGCG in vitro may lead to artifacts or misinterpretation in some studies. Finally, we discuss the challenges in the extrapolation of in vitro results to situations in vivo and the translation of laboratory studies to humans.

Effective Regulation of Gut Microbiota With Probiotics and Prebiotics May Prevent or Alleviate COVID-19 Through the Gut-Lung Axis.

Coronavirus disease 2019 (COVID-19) can disrupt the gut microbiota balance, and patients usually have intestinal disorders. The intestine is the largest immune organ of the human body, and gut microbes can affect the immune function of the lungs through the gut-lung axis. Many lines of evidence support the role of beneficial bacteria in enhancing human immunity, preventing pathogen colonization, and thereby reducing the incidence and severity of infection. In this article, we review the possible approach of modulating microbiota to help prevent and treat respiratory tract infections, including COVID-19, and discuss the possibility of using probiotics and prebiotics for this purpose. We also discuss the mechanism by which intestinal micro-flora regulate immunity and the effects of probiotics on the intestinal micro-ecological balance. Based on this understanding, we propose the use of probiotics and prebiotics to modulate gut microbiota for the prevention or alleviation of COVID-19 through the gut-lung axis.

High-fat diet-induced hyperinsulinemia promotes the development of prostate adenocarcinoma in prostate-specific Pten-/- mice.

Metabolic syndrome (MetS) and its four clinical entities, central obesity, insulin resistance, hypertension and dyslipidemia, are implicated in increasing the risk and mortality of cancer in several organs. However, it is unclear how they are associated with increased risk of prostate cancer. To elucidate the mechanistic link between MetS and prostate carcinogenesis, we characterized the development of MetS and prostate adenocarcinoma in prostate-specific Pten-/- (Ptenp-/-) mice fed a high-fat (HF) diet. We found that male Ptenp-/- mice on an HF diet gained excess body weight and elevated blood glucose, insulin and insulin-like growth factor 1 (IGF1) levels at 20 weeks of age and were obese at 40 weeks. Prostate adenocarcinoma multiplicity at 40 weeks was significantly higher in the mice on an HF diet, suggesting that the HF diet promotes the development of prostate adenocarcinoma. Increased cell proliferation and enhanced AKT activation were found in the prostates of mice on an HF diet. Further transcriptome study revealed that receptor tyrosine kinase regulation, which mediates insulin/IGF1 signaling, was one of the top enriched pathways by HF diet-induced transcriptome changes. Together, our results suggest that HF diet-induced hyperinsulinemia leads to increased activation of insulin/IGF1/AKT signaling in lesioned prostates, promoting the development of adenocarcinoma.

δ-Tocotrienol is the Most Potent Vitamin E Form in Inhibiting Prostate Cancer Cell Growth and Inhibits Prostate Carcinogenesis in Ptenp-/- Mice.

Vitamin E compounds, consisting of α, ß, γ, and δ forms of tocopherols and tocotrienols, display different cancer preventive activities in experimental models. Tocotrienols may have higher potential for clinical use due to their lower effective doses in laboratory studies. However, most studies on tocotrienols have been carried out using cancer cell lines. Strong data from animal studies may encourage the use of tocotrienols for human cancer prevention research. To examine the cancer inhibitory activity of different vitamin E forms, we first investigated their inhibitory activities of different vitamin E forms in prostate cancer cell lines. We found that δ-tocotrienol (δT3) was the most effective form in inhibiting cell growth at equivalent doses. Because of this in vitro potency, δT3 was further studied using prostate-specific Pten-/- (Ptenp-/-) mice. We found that 0.05% δT3 in diet reduced prostate adenocarcinoma multiplicity by 32.7%, featuring increased apoptosis and reduced cell proliferation. The inhibitory effect of 0.05% δT3 in diet was similar to that of 0.2% δ-tocopherol (δT) in diet reported previously. Our further study on the δT3-induced transcriptome changes indicated that δT3 inhibited genes in blood vessel development in the prostate of Ptenp-/- mice, which was confirmed by IHC. Together, our results demonstrate that δT3 effectively inhibits the development of prostate adenocarcinoma in Ptenp-/- mice, which involves inhibition of proliferation and angiogenesis and promotion of apoptosis. PREVENTION RELEVANCE: We demonstrated that δ-tocotrienol is the most active vitamin E form in inhibiting the growth of several prostate cancer cell lines. In transgenic Ptenp-/- mice, δ-tocotrienol inhibited the formation of prostate cancer. This result would encourage and help design clinical studies for the application of δ-tocotrienol for prostate cancer prevention.

A review on chemical and physical modifications of phytosterols and their influence on bioavailability and safety.

Phytosterols have been shown to lower cholesterol levels and to have antioxidant, anti-inflammatory and other biological activities. However, the high melting point and poor solubility limit their bioavailability and practical application. It is advantageous to modify phytosterols chemically and physically. This article reviews and discusses the chemical and physical modifications of phytosterols, as well as their effects on the bioavailability and possible toxicity in vivo. The current research on chemical modifications is mainly focused on esterification to increase the oil solubility and water solubility. For physical modifications (mainly microencapsulation), there are biopolymer-based, surfactant-based and lipid-based nanocarriers. Both chemical and physical modifications of phytosterols can effectively increase the absorption and bioavailability. The safety of modified phytosterols is also an important issue. Phytosterol esters are generally considered to be safe. However, phytosterol oxides, which may be produced during the synthesis of phytosterol esters, have shown toxicity in animal models. The toxicity of nanocarriers also needs further studies.

An Unrecognized Fundamental Relationship between Neurotransmitters: Glutamate Protects against Catecholamine Oxidation.

Neurotransmitter catecholamines (dopamine, epinephrine, and norepinephrine) are liable to undergo oxidation, which copper is deeply involved in. Catecholamine oxidation-derived neurotoxicity is recognized as a pivotal pathological mechanism in neurodegenerative diseases. Glutamate, as an excitatory neurotransmitter, is enriched in the brain at extremely high concentrations. However, the chemical biology relationship of these two classes of neurotransmitters remains largely unknown. In the present study, we assessed the influences of glutamate on the autoxidation of catecholamines, the copper- and copper-containing ceruloplasmin-mediated oxidation of catecholamines, the catecholamine-induced formation of quinoprotein, catecholamine/copper-induced hydroxyl radicals, and DNA damage in vitro. The results demonstrate that glutamate, at a physiologically achievable molar ratio of glutamate/catecholamines, has a pronounced inhibitory effect on catecholamine oxidation, catecholamine oxidation-evoked hydroxyl radicals, quinoprotein, and DNA damage. The protective mechanism of glutamate against catecholamine oxidation could be attributed to its restriction of the redox activity of copper via chelation. This previously unrecognized link between glutamate, catecholamines, and copper suggests that neurodegenerative disorders may occur and develop once the built-in equilibrium is disrupted and brings new insight into developing more effective prevention and treatment strategies for neurodegenerative diseases.

The Effects of Green Tea on Diabetes and Gut Microbiome in db/db Mice: Studies with Tea Extracts vs. Tea Powder.

Green tea extracts and tea catechins have been shown to prevent or alleviate diabetes. The present study tests the hypothesis that green tea leaves in powder form (GTP), which also contain fiber and other water non-extractable materials, are more effective than the corresponding green tea extracts (GTE) in impeding the development of diabetes in db/db mice. Female db/db mice were treated with a diet containing 1% of GTE, 2% of GTE, 2% of GTP (with the same catechin content as 1% GTE) or 1% GTP. The 1% GTE group had lower food intake, water consumption, body weight and fasting blood glucose levels than the control group, while 2% GTP did not have any significant effect. Dietary 1% GTE also preserved ß-cell insulin secretion. However, 1% GTP increased food intake, water consumption and blood glucose levels. Microbiome analysis with 16S rRNA gene V4 sequencing showed that the gut microbiota was modified by GTE and GTP, and a few bacterial guilds were associated with blood glucose levels. In the Random Forest regression model, the leading predictor of metabolic outcome was food consumption, followed by changes in some bacterial guilds. The results illustrate the importance of food consumption and gut microbiota in affecting the progression of diabetes.

Potential protective mechanisms of green tea polyphenol EGCG against COVID-19.

BACKGROUND: The world is in the midst of the COVID-19 pandemic. In this comprehensive review, we discuss the potential protective effects of (-)-epigallocatechin-3-gallate (EGCG), a major constituent of green tea, against COVID-19. SCOPE AND APPROACH: Information from literature of clinical symptoms and molecular pathology of COVID-19 as well as relevant publications in which EGCG shows potential protective activities against COVID-19 is integrated and evaluated. KEY FINDINGS AND CONCLUSIONS: EGCG, via activating Nrf2, can suppress ACE2 (a cellular receptor for SARS-CoV-2) and TMPRSS2, which mediate cell entry of the virus. Through inhibition of SARS-CoV-2 main protease, EGCG may inhibit viral reproduction. EGCG via its broad antioxidant activity may protect against SARS-CoV-2 evoked mitochondrial ROS (which promote SARS-CoV-2 replication) and against ROS burst inflicted by neutrophil extracellular traps. By suppressing ER-resident GRP78 activity and expression, EGCG can potentially inhibit SARS-CoV-2 life cycle. EGCG also shows protective effects against 1) cytokine storm-associated acute lung injury/acute respiratory distress syndrome, 2) thrombosis via suppressing tissue factors and activating platelets, 3) sepsis by inactivating redox-sensitive HMGB1, and 4) lung fibrosis through augmenting Nrf2 and suppressing NF-κB. These activities remain to be further substantiated in animals and humans. The possible concerted actions of EGCG suggest the importance of further studies on the prevention and treatment of COVID-19 in humans. These results also call for epidemiological studies on potential preventive effects of green tea drinking on COVID-19.

Randomized Phase II Trial of Polyphenon E versus Placebo in Patients at High Risk of Recurrent Colonic Neoplasia.

Polyphenon E (Poly E) is a green tea polyphenol preparation whose most active component is epigallocatechin gallate (EGCG). We studied the cancer preventive efficacy and safety of Poly E in subjects with rectal aberrant crypt foci (ACF), which represent putative precursors of colorectal cancers. Eligible subjects had prior colorectal advanced adenomas or cancers, and had ≥5 rectal ACF at a preregistration chromoendoscopy. Subjects (N = 39) were randomized to 6 months of oral Poly E (780 mg EGCG) daily or placebo. Baseline characteristics were similar by treatment arm (all P >0.41); 32 of 39 (82%) subjects completed 6 months of treatment. The primary endpoint was percent reduction in rectal ACF at chromoendoscopy comparing before and after treatment. Among 32 subjects (15 Poly E, 17 placebo), percent change in rectal ACF number (baseline vs. 6 months) did not differ significantly between study arms (3.7% difference of means; P = 0.28); total ACF burden was also similar (-2.3% difference of means; P = 0.83). Adenoma recurrence rates at 6 months were similar by arm (P > 0.35). Total drug received did not differ significantly by study arm; 31 (79%) subjects received ≥70% of prescribed Poly E. Poly E was well tolerated and adverse events (AE) did not differ significantly by arm. One subject on placebo had two grade 3 AEs; one subject had grade 2 hepatic transaminase elevations attributed to treatment. In conclusion, Poly E for 6 months did not significantly reduce rectal ACF number relative to placebo. Poly E was well tolerated and without significant toxicity at the dose studied. PREVENTION RELEVANCE: We report a chemoprevention trial of polyphenon E in subjects at high risk of colorectal cancer. The results show that polyphenon E was well tolerated, but did not significantly reduce the number of rectal aberrant crypt foci, a surrogate endpoint biomarker of colorectal cancer.

Farnesyl dimethyl chromanol targets colon cancer stem cells and prevents colorectal cancer metastasis.

The activation and growth of tumour-initiating cells with stem-like properties in distant organs characterize colorectal cancer (CRC) growth and metastasis. Thus, inhibition of colon cancer stem cell (CCSC) growth holds promise for CRC growth and metastasis prevention. We and others have shown that farnesyl dimethyl chromanol (FDMC) inhibits cancer cell growth and induces apoptosis in vitro and in vivo. We provide the first demonstration that FDMC inhibits CCSC viability, survival, self-renewal (spheroid formation), pluripotent transcription factors (Nanog, Oct4, and Sox2) expression, organoids formation, and Wnt/ß-catenin signalling, as evidenced by comparisons with vehicle-treated controls. In addition, FDMC inhibits CCSC migration, invasion, inflammation (NF-kB), angiogenesis (vascular endothelial growth factor, VEGF), and metastasis (MMP9), which are critical tumour metastasis processes. Moreover, FDMC induced apoptosis (TUNEL, Annexin V, cleaved caspase 3, and cleaved PARP) in CCSCs and CCSC-derived spheroids and organoids. Finally, in an orthotopic (cecum-injected CCSCs) xenograft metastasis model, we show that FDMC significantly retards CCSC-derived tumour growth (Ki-67); inhibits inflammation (NF-kB), angiogenesis (VEGF and CD31), and ß-catenin signalling; and induces apoptosis (cleaved PARP) in tumour tissues and inhibits liver metastasis. In summary, our results demonstrate that FDMC inhibits the CCSC metastatic phenotype and thereby supports investigating its ability to prevent CRC metastases.

The relationship between host circadian rhythms and intestinal microbiota: A new cue to improve health by tea polyphenols.

Under the control of the host circadian rhythms, intestinal microbiota undergoes dietary-dependent diurnal fluctuations in composition and function. In addition, microbiome plays a critical role in maintaining the host circadian rhythms and metabolic homeostasis. The interactions between host circadian rhythms and intestinal microbiota suggest that intervention with prebiotics or probiotic is a possible way to alleviate circadian rhythm misalignment and related metabolic diseases. This review discusses the circadian rhythm oscillations of gut flora, relationship between host circadian rhythms and microbiome and related effects on metabolism. The influence on circadian rhythms by the interactions between tea polyphenols (TP) and intestinal microbiota is highlighted.

Research on esophageal cancer: With personal perspectives from studies in China and Kenya.

The most common form of esophageal cancer (EC), esophageal squamous cell carcinoma (ESCC), is prevalent in many unindustrialized societies, among people with lower socioeconomic status and those who frequently use tobacco and alcohol. In some areas, ESCC mortality ranked top among all cancer. In this review, we begin with discussions of the extensive research on EC in Linxian in northern China that started 60 years ago and the recent studies in Kenya from our personal perspectives. Based on the results obtained from these studies and information from the literature, we summarize our current understanding about the risk factors for ESCC including lifestyle factors (smoking, alcohol, consumption of food and beverages at high temperature and other unhealthy habits), poor diet and nutritional insufficiencies and genetic susceptibility. Elimination or minimization of these environmental risk factors, as well as early detection and treatment of precancerous lesions, would be effective means for the prevention of ESCC. Current knowledge of molecular alterations in ESCC (gene mutations, hypermethylation and amplification or overexpression), as well as treatment of ESCC and the potential of targeted therapy, are also discussed. Finally, we propose effective approaches for the prevention of ESCC by adapting a healthy lifestyle, including a healthy diet that would also prevent other diseases. Community outreach, public education and international collaboration are important for achieving this public health goal.

Yellow Tea Stimulates Thermogenesis in Mice through Heterogeneous Browning of Adipose Tissues.

SCOPE: Large-leaf yellow tea (YT) exhibits interesting beneficial metabolic effects in previous studies. Here, the authors elucidated the actions of YT on thermogenesis, energy metabolism, and adipocyte metabolic conversion. METHODS AND RESULTS: Five-week-old male C57BL/6 mice are fed low-fat diet, high-fat diet (HFD), and HFD supplemented with 0.5% or 2.5% YT. After treatment for 10 or 14 weeks, YT enhances energy expenditure, O2 consumption and CO2 production. YT strongly boosts thermogenic program in brown adipose tissue (BAT) and subcutaneous adipose tissue (SAT), while only weakly in epididymal adipose tissue (EAT). These are accompanied by higher body temperature, increased mitochondrial copy numbers, and upregulation of thermogenic genes (Ucp1, Pgc1α, etc.) and proteins. The classic brown adipocyte markers (Eva1, Zic1) are induced only in BAT, while beige adipocyte markers (Tbx1, Tmem26) are boosted only in SAT. Furthermore, subcutaneous-originated preadipocytes are induced by YT in vitro to differentiate to brown-like adipocytes - a browning effect. CONCLUSION: Dietary YT induces adaptive thermogenesis through increasing mitochondrial biogenesis in EAT, inducing beigeing in SAT and enhancing browning in the BAT.

The Hypoglycemic Effect of Berberine and Berberrubine Involves Modulation of Intestinal Farnesoid X Receptor Signaling Pathway and Inhibition of Hepatic Gluconeogenesis.

Our previous study suggests that berberine (BBR) lowers lipids by modulating bile acids and activating intestinal farnesoid X receptor (FXR). However, to what extent this pathway contributes to the hypoglycemic effect of BBR has not been determined. In this study, the glucose-lowering effects of BBR and its primary metabolites, berberrubine (M1) and demethyleneberberine, in a high-fat diet-induced obese mouse model were studied, and their modulation of the global metabolic profile of mouse livers and systemic bile acids was determined. The results revealed that BBR (150 mg/kg) and M1 (50 mg/kg) decreased mouse serum glucose levels by 23.15% and 48.14%, respectively. Both BBR and M1 markedly modulated the hepatic expression of genes involved in gluconeogenesis and metabolism of amino acids, fatty acids, and purine. BBR showed a stronger modulatory effect on systemic bile acids than its metabolites. Moreover, molecular docking and gene expression analysis in vivo and in vitro suggest that BBR and M1 are FXR agonists. The mRNA levels of gluconeogenesis genes in the liver, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were significantly decreased by BBR and M1. In summary, BBR and M1 modulate systemic bile acids and activate the intestinal FXR signaling pathway, which reduces hepatic gluconeogenesis by inhibiting the gene expression of gluconeogenesis genes, achieving a hypoglycemic effect. BBR and M1 may function as new, natural, and intestinal-specific FXR agonists with a potential clinical application to treat hyperglycemia and obesity. SIGNIFICANCE STATEMENT: This investigation revealed that BBR and its metabolite, berberrubine, significantly lowered blood glucose, mainly through activating intestinal farnesoid X receptor signaling pathway, either directly by themselves or indirectly by modulating the composition of systemic bile acids, thus inhibiting the expression of gluconeogenic genes in the liver and, finally, reducing hepatic gluconeogenesis and lowering blood glucose. The results will help elucidate the mechanism of BBR and provide a reference for mechanism interpretation of other natural products with low bioavailability.

Plasma, Prostate and Urine Levels of Tocopherols and Metabolites in Men after Supplementation with a γ-Tocopherol-Rich Vitamin E Mixture.

The vitamin E forms γ- and δ-tocopherols (T) inhibit carcinogenesis in animal models; nevertheless, their cancer preventive activities in humans are uncertain. As an initial step to address this issue, we conducted a pilot phase 0 trial to determine the levels of tocopherols and their metabolites in prostate cancer patients undergoing radical prostatectomy. The patients were randomized to no supplementation or two capsules of a γ-T-rich vitamin E mixture daily for 7 or 14 day prior to prostatectomy. Blood and urine samples were collected before supplementation and on the day of surgery, along with prostate tissue, for analysis of tocopherols and their metabolites. Estimated blood loss during surgery was not significantly different across treatment arms and there were no reported adverse events. Prostate tissue levels of γ-T and δ-T were increased after 14 day of supplementation. Their side-chain degradation metabolites (CEHCs and CMBHCs) were significantly elevated in plasma, prostate and urine samples after supplementation for 7 or 14 day. In conclusion, supplementation with γ-T-rich vitamin E increased the prostate levels of γ-T and δ-T. The use of pure γ-T, δ-T or tocopherol mixtures with higher ratio of γ-T or δ-T to α-T is recommended for future studies.

Colitis-induced IL11 promotes colon carcinogenesis.

Colitis increases the risk of colorectal cancer; however, the mechanism of the association between colitis and cancer remains largely unknown. To identify colitis-associated cancer promoting factors, we investigated gene expression changes caused by dextran sulfate sodium (DSS)-induced colitis in mice. By analyzing gene expression profiles, we found that IL11 was upregulated in DSS-induced colitis tissue and 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP)/DSS-induced colon tumours in mice as well as in human colorectal cancer. By characterizing the activation/phosphorylation of STAT3 (pSTAT3), we found that pSTAT3 was induced transiently in colitis, but maintained at higher levels from hyper-proliferative dysplastic lesions to tumours. Using the IL11 receptor (IL11Rα1) knockout mice, we found that pSTAT3 in the newly regenerated crypt epithelial cells in colitis is abolished in IL11Rα1+/- and -/- mice, suggesting that colitis-induced IL11 activates STAT3 in colon crypt epithelial cells. Moreover, colitis-promoted colon carcinogenesis was significantly reduced in IL11Rα1+/- and -/- mice. To determine the roles of the IL11 in colitis, we found that the inhibition of IL11 signalling by recombinant IL11 antagonist mutein during colitis was sufficient to attenuate colitis-promoted carcinogenesis. Together, our results demonstrated that colitis-induced IL11 plays critical roles in creating cancer promoting microenvironment to facilitate the development of colon cancer from dormant premalignant cells.