Objective:High-fat diet is one of the main risk factors that disrupt the balance of gut microbiota,which eventually will induce colorectal cancer(CRC).Evodiamine(EVO)is a wildly used multifunctional traditional Chines...Objective:High-fat diet is one of the main risk factors that disrupt the balance of gut microbiota,which eventually will induce colorectal cancer(CRC).Evodiamine(EVO)is a wildly used multifunctional traditional Chinese medicine extract.In this study,we investigated the role of gut microbiota in high-fat dietpropelled CRC and the potential of EVO for CRC chemoprevention.Methods:Gut microbiota,serum D-lactic acid and endotoxin from 38 patients with colon cancer and 18 healthy subjects were detected by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay(ELISA).In addition,body mass index,phospho-signal transducer and activator of transcription 3(p-STAT3)expression in cancer tissues and paracancerous tissues were detected by immunohistochemistry.A mouse intestinal inflammatory tumor model was established by azomethane/sodium dextran sulfate,followed by treatment with EVO and 5-aminosalicylic acid(ASA).Gut microbiota and inflammatory factors were detected by quantitative polymerase chain reaction,while serum D-lactic acid and endotoxin were detected by ELISA.Furthermore,cell proliferation,cell apoptosis,and interleukin(IL)-6/STAT3/P65 pathway were evaluated by 5-ethynyl-20-deoxyuridine,terminal-deoxynucleotidyl transferase-mediated nick-end labeling,and Western blot assays.Results:In patients with colon cancer,the numbers of Enterococcus faecalis and Escherichia coli were increased,while those of Bifidobacterium,Campylobacter and Lactobacillus were decreased.Serum endotoxin and D-lactic acid levels and p-STAT3 levels were significantly increased.In the mouse model,both EVO and ASA inhibited tumor formation,decreased the proliferation of tumor cells,and induced apoptosis of tumor cells.Compared with the control group,the numbers of E.faecalis and E.coli were decreased,while Bifidobacterium,Campylobacter and Lactobacillus numbers were increased.In the EVO group,serum endotoxin and D-lactic acid levels and inflammatory factors were significantly decreased.Further,the IL6/STAT3/P65 signaling pathway was inhibited in the EVO group.Conclusion:EVO may inhibit the occurrence of colon cancer by regulating gut microbiota and inhibiting intestinal inflammation.The potential mechanism involves inhibition of the IL6/STAT3/P65 signaling pathway,revealing its potential therapeutic significance in clinical applications.展开更多
BACKGROUND Although expression of interleukin(IL)-34 is upregulated in active ulcerative colitis(UC),the molecular function and underlying mechanism are largely unclear.AIM To investigate the function of IL-34 in acut...BACKGROUND Although expression of interleukin(IL)-34 is upregulated in active ulcerative colitis(UC),the molecular function and underlying mechanism are largely unclear.AIM To investigate the function of IL-34 in acute colitis,in a wound healing model and in colitis-associated cancer in IL-34-deficient mice.METHODS Colitis was induced by administration of dextran sodium sulfate(DSS),and carcinogenesis was induced by azoxymethane(AOM).Whether the impact of IL-34 on colitis was dependent on macrophages was validated by depletion of macrophages in a murine model.The association between IL-34 expression and epithelial proliferation was studied in patients with active UC.RESULTS IL-34 deficiency aggravated murine colitis in acute colitis and in wound healing phase.The effect of IL-34 on experimental colitis was not dependent on macrophage differentiation and polarization.IL-34-deficient mice developed more tumors than wild-type mice following administration of AOM and DSS.No significant difference was shown in degree of cellular differentiation in tumors between wild-type and IL-34-deficient mice.IL-34 was dramatically increased in the active UC patients as previously reported.More importantly,expression of IL-34 was positively correlated with epithelial cell proliferation in patients with UC.CONCLUSION IL-34 deficiency exacerbates colonic inflammation and accelerates colitis-associated carcinogenesis in mice.It might be served as a potential therapeutic target in UC.展开更多
BACKGROUND Colitis-associated cancer(CAC)accounts for 2%-3%of colorectal cancer(CRC)cases preceded by inflammatory bowel diseases(IBD)such as Crohn's disease and ulcerative colitis.Intestinal microbiota has been r...BACKGROUND Colitis-associated cancer(CAC)accounts for 2%-3%of colorectal cancer(CRC)cases preceded by inflammatory bowel diseases(IBD)such as Crohn's disease and ulcerative colitis.Intestinal microbiota has been reported to play a central role in the pathogenesis of IBD and CAC.Recently,numerous prebiotics and probiotics have being investigated as antitumor agents due to their capacity to modulate inflammatory responses.Previous studies have indicated that lactic acid bacteria could be successfully used in managing sporadic CRC,however little is known about their role in CAC.AIM To investigate the effect of the probiotic Lactobacillus bulgaricus(L.bulgaricus)during the development of an experimental model of colitis associated colon cancer(CAC).METHODS C57BL/6 mice received an intraperitoneal injection of azoxymethane(10 mg/kg),followed by three cycles of sodium dextran sulphate diluted in water(5%w/v).Probiotic group received daily L.bulgaricus.Intestinal inflammation was determined by scoring clinical signs.Cytokines levels were determined from colon and/or tumor samples by ELISA BD OptEIATM kits.The level of significance was set at P<0.05.Graphs were generated and statistical analysis performed using the software GraphPad Prism 6.0.RESULTS L.bulgaricus treatment inhibited of total tumor volume and mean size of tumors.In addition,the probiotic also attenuated the clinical signs of intestinal inflammation inducing a decrease in intestinal and tumor levels of IL-6,TNF-α,IL-17,IL-23 and IL-1β.CONCLUSION Our results suggest a potential chemopreventive effect of probiotic on CAC.L.bulgaricus regulates the inflammatory response and preventing CAC.展开更多
BACKGROUND Phosphatidylinositol-3-kinases(PI3K)is a well-known route in inflammationrelated cancer.Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis(UC)and colorectal ca...BACKGROUND Phosphatidylinositol-3-kinases(PI3K)is a well-known route in inflammationrelated cancer.Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis(UC)and colorectal cancer(CRC)with colitisassociated cancer(CAC).PI3K/AKT pathway has been recommended as a potential additional therapeutic option for CRC due to its substantial role in modifying cellular processes.Buparlisib is a pan-class I PI3K inhibitor previously shown to reduce tumor growth.AIM To investigate the regulation of rs10889677 and the role of buparlisib in the PI3K signaling pathway in CAC pathogenesis.METHODS Genomic DNA from 32 colonic samples,including CAC(n=7),UC(n=10)and CRC(n=15),was sequenced for the rs10889677 mutation.The mutant and wildtype fragments were amplified and cloned in the pmirGLO vector.The luciferase activity of cloned vectors was assessed after transfection into the HT29 cell line.CAC mice were induced by a mixture of a single azoxymethane injection and three cycles of dextran sulphate sodium,then buparlisib was administered after 14 d.The excised colon was subjected to immunohistochemistry for Ki67 and Cleaved-caspase-3 markers and quantitative real-time polymerase chain reaction analysis for Pdk1 and Sgk2.RESULTS Luciferase activity decreased by 2.07-fold in the rs10889677 mutant,confirming the hypothesis that the variant disrupted miRNA binding sites,which led to an increase in IL23R expression and the activation of the PI3K signaling pathway.Furthermore,CAC-induced mice had a significantly higher disease activity index(P<0.05).Buparlisib treatment significantly decreased mean weight loss in CAC-induced mice(P<0.05),reduced the percentage of proliferating cells by 5%,and increased the number of apoptotic cells.The treatment also caused a downward trend of Pdk1 expression and significantly decreased Sgk2 expression.CONCLUSION Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway,and buparlisib had the ability to prevent PI3K-non-AKT activation in the pathophysiology of CAC.展开更多
Surgical therapy for ulcerative colitis(UC) depends on the medical therapy administered for the patient's condition. UC is a benign disease. However, it has been reported that the rare cases of cancer in UC patien...Surgical therapy for ulcerative colitis(UC) depends on the medical therapy administered for the patient's condition. UC is a benign disease. However, it has been reported that the rare cases of cancer in UC patients are increasing, and such cases have a worse prognosis. Recently, surgical therapy has greatly changed, there has been quite an increase in the number of UC patients with high-grade dysplasia and/or cancer. These lesions are known as colitis-associated cancer(CAC). The relationship between inflammation and tumorigenesis is well-established, and in the last decade, a great deal of supporting evidence has been obtained from genetic, pharmacological, and epidemiological studies. Inflammatory bowel disease, especially UC, is an important risk factor for the development of colon cancer. We should determine the risk factors for UC patients with cancer based on a large body of data, and we should attempt to prevent the increase in the number of such patients using these newly identified risk factors in the near future. Actively introducing the surgical treatment in addition to medical treatment should be considered. Several physicians should analyze UC from their unique perspectives in order to establish new clinically relevant diagnostic and treatment methods in the future. This article discusses CAC, including its etiology, mechanism, diagnosis, and treatment in UC patients.展开更多
BACKGROUND Inflammation is a well-established enabling factor for cancer development and provides a framework for the high prevalence of colon cancer in inflammatory bowel disease.In accordance,chronic inflammation ha...BACKGROUND Inflammation is a well-established enabling factor for cancer development and provides a framework for the high prevalence of colon cancer in inflammatory bowel disease.In accordance,chronic inflammation has recently been implicated in the development of cancer stem cells(CSCs).However,the mechanism whereby anti-inflammatory drugs act in the prevention of colitis-associated cancer(CAC)is only partially understood.AIM To evaluate the role of diacerein(DAR),an anti-inflammatory drug that mainly acts through the inhibition of interleukin(IL)-1βexpression in the development of CSCs and CAC.METHODS The effects of DAR on colon inflammation in mice with CAC were evaluated by inflammatory index,reverse real-time transcription polymerase chain reaction and western blot.Cytokine levels were measured by enzyme-linked immunosorbent assay.Cells assays evaluated the effects of DAR on CSCs.Immunohistochemistry and apoptosis assays were also used to evaluate the effects of DAR on tumorigenesis associated with inflammation.RESULTS DAR treatment reduced colon inflammation as well as the number and size of tumors in azoxymethane plus dextran sulphate sodium-treated animals.Accordingly,DAR treatment was associated with reduced intracellular signals of inflammation(inhibitor of nuclear factor kappa B kinase and c-Jun N-terminal kinase phosphorylation)in the colon.In addition,DAR treatment was associated with a decrease in colon CSC formation,suggesting that besides reducing colonic inflammation,DAR has a direct effect on the inhibition of colon carcinogenesis.CONCLUSION Together,these data indicate that DAR-mediated IL-1βsuppression attenuates inflammation-induced colon cancer and CSC formation,highlighting DAR as a potential candidate for the chemoprevention of CAC.展开更多
In inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD), the duration and severity of inflammation are responsible for the development of colorectal cancer. Inflammatory cytokine...In inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD), the duration and severity of inflammation are responsible for the development of colorectal cancer. Inflammatory cytokines such as interleukin (IL)-8 and tumor necrotic factor (TNF)-a, which are released by epithelial and immune cells, are involved in the pathogenesis of colitis-associated cancer. Current treatments for advanced colorectal cancers focus primarily on targeting epidermal growth factor receptor (EGFR) signaling. IL-8 (a G-protein coupled receptor (GPCR) agonist), which is involved in neutrophil recruitment and activation in persistent active colitis, also promotes cleavage of theproheparin-binding epidermal growth factor—like growth factor (proHB-EGF) through a disintegrin and metalloproteinase (ADAM), so that the resulting soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, where HB-EGF-CTF binds the nuclear promyelocytic leukemia zinc finger (PLZF) protein, resulting in the nuclear export of the PLZF transcriptional repressor and thereby affecting cell proliferation. Screening for potent chemical inhibitors of the interactions between HB-EGF-CTF and PLZF identified telmisartan (and related compounds in corporating a biphenyl tetrazole moiety) as inhibitors of cell proliferation. Here we focus on the inhibitory effects of these compounds on cell proliferation, demonstrating the potential for targeting the nuclear translocation of HB-EGF-CTF in the treatment of colitis-associated cancer.展开更多
Colitis-associated colorectal cancer(CAC),a serious complication of ulcerative colitis(UC),is associated with a poor prognosis.The vitamin D receptor(VDR)is recognized for its protective role in UC and CAC through the...Colitis-associated colorectal cancer(CAC),a serious complication of ulcerative colitis(UC),is associated with a poor prognosis.The vitamin D receptor(VDR)is recognized for its protective role in UC and CAC through the maintenance of intestinal barrier integrity and the regulation of inflammation.This study demonstrates a significant reduction in m^(6)A-related genes,particularly methyltransferase like 14(METTL14),in UC and CAC patients and identifies an association between METTL14 and VDR.In the azoxymethane(AOM)/dextran sodium sulfate(DSS)-induced mousemodel,vitamin D treatment increases METTL14 expression and reduces tumorburden,while Vdr-knockout mice exhibit lower METTL14 levels and increased tumorigenesis.In vitro,the VDR agonist calcipotriol upregulates METTL14 in NCM460 cells,with this effect attenuated by VDR knockdown.VDRknockdown inDLD-1colon cancer cellsdecreases METTL14 expressionand promotes proliferation,which is reversed by METTL14 overexpression.Mechanistic studies reveal that VDR regulates METTL14 expression via promoter binding,modulating key target genes such as SOX4,DROSH,and PHLPP2.This study highlights the role of the VDR-METTL14 axis as a protective mechanism in CAC and suggests its potential as a therapeutic target for preventing and treating CAC.展开更多
Objectives:Colorectal cancer(CRC)is one of the most common cancers all over the world.The progression of CRC is associated with inflammation and disruptions in intestinal flora.3-O-Acetyl-11-keto-β-boswellic acid(AKB...Objectives:Colorectal cancer(CRC)is one of the most common cancers all over the world.The progression of CRC is associated with inflammation and disruptions in intestinal flora.3-O-Acetyl-11-keto-β-boswellic acid(AKBA)has been noted for its potent anti-inflammatory properties.However,the effect of AKBA on colon cancer caused by inflammation and its mechanism are not unclear.The study is to explore the effect of AKBA on CRC and its mechanism.Materials and Methods:Cell proliferation,(5-ethynyl-2′-deoxyuridine,EdU)-DNA synthesis assay and colony formation were used to assess the effect of AKBA on the proliferation of CRC cells.Flow cytometry was employed to analyze the cell cycle and apoptosis rate of cells treated with AKBA.RNA sequencing was done to explore the underlying mechanisms of AKBA.Western blot was used to assess the expression of key proteins in the nuclear factor kappa-B(NF-κB)signaling pathway after the treatment of AKBA.Real-time quantitative PCR(RT-qPCR),enzyme-linked immunosorbent assay(ELISA),and Meso Scale Discovery(MSD)assays were employed to check the anti-inflammation effects of AKBA on Lipopolysaccharide(LPS)-induced RAW264.7 cells and LPS-induced mouse model.Additionally,the Azoxymethane/Dextran sulfate sodium(AOM/DSS)-induced colitis-associated CRC model was used to evaluate the anti-CRC effect of AKBA.Gut microbiota profiling of fecal samples from CRC mice,both with and without AKBA treatment,was conducted through metagenomic sequencing analysis.Results:Our results showed that AKBA reduced the proliferation of HCT116 and SW620 cells,increased apoptosis of cells,and arrested the cell cycle at the G2/M phase.Results from RNA-seq showed that AKBA inhibited CRC by inhibiting the NF-κB signaling pathway and reducing cellular inflammation.Furthermore,AKBA reduced the levels of inflammatory cytokines,including tumor necrosis factor-α(TNF-α),Interferon-γ(IFN-γ),Interleukin-IL-12p70(IL-12p70),Interleukin-1β(IL-1β),and tumor necrosis factor-α(TNF-α)in both the spleen and serum of LPS-induced acute inflammation mice.Additionally,AKBA inhibited the development of AOM/DSS-induced colitis-associated colon cancer in mice and positively influenced gut microbiota.Conclusion:This study highlights the inhibitory effect of AKBA on colitis-associated CRC and reveals a novel aspect of its role in the remodeling of gut microbiota.These findings suggest that AKBA may be used as a potential therapeutic agent for CRC.展开更多
Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether m...Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether mitochondrial transcription factor A(TFAM),a key regulator of mitochondrial DNA transcription and replication,is involved in the initiation and progression of colitis-associated cancer(CAC).Methods:TFAM expression was examined in tissue samples of inflammatory bowel diseases(IBD)and CAC by immunohistochemistry.Intestinal epithelial cell(IEC)-specific TFAM-knockout mice(TFAM^(△IEC))and colorectal cancer(CRC)cells with TFAM knockdown or overexpression were used to evaluate the role of TFAMin colitis and the initiation and progression ofCAC.The underlying mechanisms of TFAMwere also explored by analyzingmitochondrial respiration function and biogenesis.Results:The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity.The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3(STAT3)/miR-23b-dependent manner.In addition,TFAM knockout impaired IECturnover to promote dextran sulfate sodium(DSS)-induced colitis inmice.Of note,TFAMknockout increased the susceptibility of mice to azoxymethane/DSSinduced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis.By contrast,TFAM expression was upregulated in CAC tissues and contributed to cell growth.Furthermore,it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells.Mechanistically,TFAMpromoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.Conclusions:TFAM plays a dual role in the initiation and progression of CAC,providing a novel understanding of CAC pathogenesis.展开更多
Intestinal macrophages are essential players in intestinal inflammation and intestinal immune homeostasis.Intestinal macrophages have the ability to polarize into two distinct phenotypes based on various environmental...Intestinal macrophages are essential players in intestinal inflammation and intestinal immune homeostasis.Intestinal macrophages have the ability to polarize into two distinct phenotypes based on various environmental signals.These phenotypes include the typically activated pro-inflammatory M1 phenotype and the alternatively activated anti-inflammatory M2 phenotype.Under normal circumstances,intestinal macrophages prevent inflammatory damage to the gut.However,when genetic and environmental factors influence the polarization of intestinal macrophages,it can lead to an imbalance in M1/M2 macrophage activation and subsequently an imbalance in the control of intestinal inflammation.It transforms physiological inflammation into pathological intestinal damage.In patients with ulcerative colitis-associated cancer(UC-CRC),intestinal inflammatory disorders are closely associated with intestinal M1/M2 macrophage polarization imbalance.Consequently,restoring the polarization equilibrium of M1/M2 macrophages might be an evidence of traditional Chinese medicine in the treatment of UC-CRC,the pivotal role o effective measure to prevent and treat UC-CRC.This paper aims to examine the clinicalf macrophage polarization in UC-CRC pathogenesis,and the potential mechanisms of traditional Chinese medicine in regulating macrophage polarization to treat UC-CRC.Our goal is to provide novel insights into the clinical practice,basic research,and drug development of UC-CRC.展开更多
The association between ulcerative colitis(UC) and colorectal cancer(CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC(UC-CRC). UC-CRC patients are y...The association between ulcerative colitis(UC) and colorectal cancer(CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC(UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, lowgrade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC.展开更多
Colorectal cancer(CRC)is the third most lethal cancer and leading cause of cancer mortality worldwide.A key driver of CRC development is colon inflammatory responses especially in patients with inflammatory bowl disea...Colorectal cancer(CRC)is the third most lethal cancer and leading cause of cancer mortality worldwide.A key driver of CRC development is colon inflammatory responses especially in patients with inflammatory bowl disease(IBD).It has been proved that Panax notoginseng saponins(PNS)have anti-inflammatory,anti-oxidant and anti-tumor effects.The chemopreventive and immunomodulatory functions of PNS on colitis-associated colorectal cancer(CAC)have not been evaluated.This present study was designed to study the potential protective effects of PNS on AOM/DSS-induced CAC mice to explore the possible mechanism of PNS against CAC.Our study showed that PNS significantly alleviated colitis severity and prevented the occurrence of CAC.Functional assays revealed that PNS relieved immunosuppression of Treg cells in the CAC microenvironment by inhibiting the expression of IDO 1 mediated directly by signal transducer and activator of transcription 1(STAT1)rather than phosphorylated STAT1.Ultimately,Rhl,one of the PNS metabolites,exhibited the best inhibitory effect on IDO1 enzyme activity.Our study showed that PNS exerted significant chemopreventive function and immunomodulatory properties on CAC.It could reduce macrophages accumulation and Treg cells differentiation to reshape the immune microenvironment of CAC.These findings provided a promising approach for CAC intervention.展开更多
Objective:The goal of this study was to get preliminary insight on the intra-tumor heterogeneity in colitisassociated cancer(CAC)and to reveal a potential evolutionary trajectory from ulcerative colitis(UC)to CAC at t...Objective:The goal of this study was to get preliminary insight on the intra-tumor heterogeneity in colitisassociated cancer(CAC)and to reveal a potential evolutionary trajectory from ulcerative colitis(UC)to CAC at the single-cell level.Methods:Fresh samples of tumor tissues and adjacent UC tissues from a CAC patient with pT3N1M0 stage cancer were examined by single-cell RNA sequencing(scRNA-seq).Data from The Cancer Genome Atlas(TCGA)and The Human Protein Atlas were used to confirm the different expression levels in normal and tumor tissues and to determine their relationships with patient prognosis.Results:Ultimately,4,777 single-cell transcriptomes(1,220 genes per cell)were examined,of which 2,250(47%)and 2,527(53%)originated from tumor and adjacent UC tissues,respectively.We defined the composition of cancer-associated stromal cells and identified six cell clusters,including myeloid,T and B cells,fibroblasts,endothelial and epithelial cells.Notable pathways and transcription factors involved in these cell clusters were analyzed and described.Moreover,the precise cellular composition and developmental trajectory from UC to UCassociated colon cancer were graphed,and it was predicted that CD74,CLCA1,and DPEP1 played a potential role in disease progression.Conclusions:scRNA-seq technology revealed intra-tumor cell heterogeneity in UC-associated colon cancer,and might provide a promising direction to identify novel potential therapeutic targets in the evolution from UC to CAC.展开更多
Colitis-associated colorectal cancer(CAC)is defined as a specific cluster of colorectal cancers that develop as a result of prolonged colitis in patients with inflammatory bowel disease(IBD).Patients with IBD,includin...Colitis-associated colorectal cancer(CAC)is defined as a specific cluster of colorectal cancers that develop as a result of prolonged colitis in patients with inflammatory bowel disease(IBD).Patients with IBD,including ulcerative colitis and Crohn’s disease,are known to have an increased risk of developing CAC.Although the incidence of CAC has significantly decreased over the past few decades,individuals with CAC have increased mortality compared to individuals with sporadic colorectal cancer,and the incidence of CAC increases with duration.Chronic inflammation is generally recognized as a major contributor to the pathogenesis of CAC.CAC has been shown to progress from colitis to dysplasia and finally to carcinoma.Accumulating evidence suggests that multiple immune-mediated pathways,DNA damage pathways,and pathogens are involved in the pathogenesis of CAC.Over the past decade,there has been an increasing effort to develop clinical approaches that could help improve outcomes for CAC patients.Colonoscopic surveillance plays an important role in reducing the risk of advanced and interval cancers.It is generally recommended that CAC patients undergo endoscopic removal or colectomy.This review summarizes the current understanding of CAC,particularly its epidemiology,mechanisms,and management.It focuses on the mechanisms that contribute to the development of CAC,covering advances in genomics,immunology,and the microbiome;presents evidence for management strategies,including endoscopy and colectomy;and discusses new strategies to interfere with the process and development of CAC.These scientific findings will pave the way for the management of CAC in the near future.展开更多
Colorectal cancer （CRC） is one of the leading causes of cancer-related deaths, and inflammatory bowel diseases and dysregulated cell proliferation play important roles in colorectal carcinogenesis. Therefore, inhibi...Colorectal cancer （CRC） is one of the leading causes of cancer-related deaths, and inflammatory bowel diseases and dysregulated cell proliferation play important roles in colorectal carcinogenesis. Therefore, inhibition of inflammatory signaling and cell proliferation is used as a major strategy for chemoprevention of CRC. In the present study, it was found that IC5, a dithiocarbamate derivative, could inhibit the proliferation of LoVo human colon cancer cells in a concentration-dependent manner, with an IC50 of 22 gM. The anti-proliferation effect of IC5 was accompanied by a significant cell cycle arrest in G2/M phase. Further study revealed that IC5 significantly inhibited NF-~B signaling in LoVo cells, suggesting that IC5 could inhibit inflammatory responses. We then evaluated the in vivo efficacy of IC5 to inhibit colitis-associated colorectal carcinogenesis using an azoxymethane （AOM）/dextran sodium sulfate （DSS） mouse model. AOM/DSS treatment resulted in a CRC incidence of 58.3%, while the incidences were decreased to 37.5% and 25% in mice orally administered with 50 and 100 mg/kg IC5, respectively. In addition, IC5 also reduced the plasma levels of alanine aminotransferase and asparatate aminotransferase. Taken together, these results suggested that IC5 could prevent colitis-associated colorectal carcinogenesis, and more attention should be paid to it as a cancer chemopreventive agent in further investigation.展开更多
Colitis-associated colorectal cancer(CA-CRC) is the cause of death in 10%-15% of inflammatory bowel disease(IBD) patients. CA-CRC results from the accumulation of mutations in intestinal epithelial cells and progresse...Colitis-associated colorectal cancer(CA-CRC) is the cause of death in 10%-15% of inflammatory bowel disease(IBD) patients. CA-CRC results from the accumulation of mutations in intestinal epithelial cells and progresses through a well-characterized inflammation to dysplasia to carcinoma sequence. Quantitative estimates of overall CA-CRC risks are highly variable ranging from 2% to 40% depending on IBD severity, duration and location, with IBD duration being the most significant risk factor associated with CA-CRC development. Recently, studies have identified IBD patients with similar patterns of colonic inflammation, but that differ with respect to CA-CRC development, suggesting a role for additional non-inflammatory risk factors in CA-CRC development. One suggestion is that select IBD patients carry polymorphisms in various low penetrance disease susceptibility genes, which predispose them to CA-CRC development, although these loci have proven difficult to identify in human genomewide association studies. Mouse models of CA-CRC have provided a viable alternative for the discovery, validation and study of individual genes in CA-CRC pathology. In this review, we summarize the current CA-CRC literature with a strong focus on genetic predisposition and highlight an emerging role for mouse models in the search for CA-CRC risk alleles.展开更多
It has long been appreciated that there is a direct relationship between the intensity and duration of inflammatory bowel diseases (IBD) and increasing intestinal cancer risk but which elements of the inflammatory res...It has long been appreciated that there is a direct relationship between the intensity and duration of inflammatory bowel diseases (IBD) and increasing intestinal cancer risk but which elements of the inflammatory response are responsible have not been identified. Anti-TNF drugs have been successful at treating IBD but considering the presumed anti-tumor activity of TNF, it is important to understand whether the treatment impacts on the patients’ intestinal cancer risk. We modeled this relationship by “treating mice lacking TNF receptors with a colon cancer causing combination of azoxymethane followed by repeated dextran sulphate sodium exposures (AOM + DSS regime). TNF receptor type1 gene deficient (TNFR1-/-) and TNFR2-/- mice experienced similar clinical illnesses and colonic inflammation as C57BL/6 wildtype controls during the AOM + DSS regime. Despite the inflammation, TNFR1-/- mice developed significantly fewer colon tumors than the other strains. The reduced tumor incidence was a product of the combined lack of receptor expression on hematopoietic and nonhematopoietic cells, shown using bone marrow cell chimeras of wildtype and TNFR1-/- mice. As oxidative damage is a potent contributing factor to tumorigenesis and inflammatory leukocytes make copious amounts of reactive oxygen radicals, we measured oxidative damage in the animals’ colons. TNFR1-/- mice showed less damage compared to the other strains. We subsequently examined mice deficient in their leukocyte NADPH oxidative pathway (Nox2-/-) for their cancer incidence using the AOM + DSS regime. Nox2-/- mice became inflamed but had fewer tumors than wildtype mice. We conclude that TNF promotes colon cancer including through promoting oxidative processes utilizing TNFR1 in leukocytes. Moreover, the C57BL/6 strain can be used to dissociate mechanisms of colon inflammation from tumorigenic processes. We interpret our results to mean that IBD patients on TNF antagonist therapies will potentially benefit with reduced colon cancer risk even if they do not respond with reduced inflammation.展开更多
Gut microbiota dysbiosis is a risk factor for colorectal cancer(CRC) in inflammatory bowel disease(IBD).In this study, the effects of Panax notoginseng saponins(PNS) on colitis-associated CRC progression were evaluate...Gut microbiota dysbiosis is a risk factor for colorectal cancer(CRC) in inflammatory bowel disease(IBD).In this study, the effects of Panax notoginseng saponins(PNS) on colitis-associated CRC progression were evaluated on an azoxymethane(AOM)/dextran sulfate sodium(DSS) mouse model.In vivo, PNS significantly relieved AOM/DSS-induced colon tumorigenesis and development by reducing the disease activity index(DAI) scores and colon tumor load.The 16S rRNA data of fecal samples showed that the microbiome community was obviously destructed, while PNS could recover the richness and diversity of gut microbiota.Especially, PNS could increase the abundance of Akkermansia spp.which was significantly decreased in model group and negatively correlated with the progression of CRC.Moreover, ginsenoside compound K(GC-K) was evaluated on the effects of human CRC cells,which was the main bio-transformed metabolite of PNS by gut microbiota.Our data showed that PNS played important role in the prevention of the progression of CRC, due to their regulation on the microbiome balance and microbial bio-converted product with antiCRC activity.展开更多
Patients with extensive ulcerative colitis(UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical value in managing...Patients with extensive ulcerative colitis(UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical value in managing cancer risk in these UC patients. Using a wide range of molecular techniques- including cutting-edge OMICS technologies- recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer.展开更多
基金supported by Wenzhou Science and Technology Bureau Project(to Zhu Liqing,No.Y20190088)。
文摘Objective:High-fat diet is one of the main risk factors that disrupt the balance of gut microbiota,which eventually will induce colorectal cancer(CRC).Evodiamine(EVO)is a wildly used multifunctional traditional Chinese medicine extract.In this study,we investigated the role of gut microbiota in high-fat dietpropelled CRC and the potential of EVO for CRC chemoprevention.Methods:Gut microbiota,serum D-lactic acid and endotoxin from 38 patients with colon cancer and 18 healthy subjects were detected by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay(ELISA).In addition,body mass index,phospho-signal transducer and activator of transcription 3(p-STAT3)expression in cancer tissues and paracancerous tissues were detected by immunohistochemistry.A mouse intestinal inflammatory tumor model was established by azomethane/sodium dextran sulfate,followed by treatment with EVO and 5-aminosalicylic acid(ASA).Gut microbiota and inflammatory factors were detected by quantitative polymerase chain reaction,while serum D-lactic acid and endotoxin were detected by ELISA.Furthermore,cell proliferation,cell apoptosis,and interleukin(IL)-6/STAT3/P65 pathway were evaluated by 5-ethynyl-20-deoxyuridine,terminal-deoxynucleotidyl transferase-mediated nick-end labeling,and Western blot assays.Results:In patients with colon cancer,the numbers of Enterococcus faecalis and Escherichia coli were increased,while those of Bifidobacterium,Campylobacter and Lactobacillus were decreased.Serum endotoxin and D-lactic acid levels and p-STAT3 levels were significantly increased.In the mouse model,both EVO and ASA inhibited tumor formation,decreased the proliferation of tumor cells,and induced apoptosis of tumor cells.Compared with the control group,the numbers of E.faecalis and E.coli were decreased,while Bifidobacterium,Campylobacter and Lactobacillus numbers were increased.In the EVO group,serum endotoxin and D-lactic acid levels and inflammatory factors were significantly decreased.Further,the IL6/STAT3/P65 signaling pathway was inhibited in the EVO group.Conclusion:EVO may inhibit the occurrence of colon cancer by regulating gut microbiota and inhibiting intestinal inflammation.The potential mechanism involves inhibition of the IL6/STAT3/P65 signaling pathway,revealing its potential therapeutic significance in clinical applications.
基金the Science and Technology Bureau,No.MS22018007Six Peak Talents in Jiangsu Province,No.YY-177+4 种基金Project of Jiangsu Province Youth Medical Talent Development,No.QNRC2016400 and No.QNRC2016697Project of Nantong Youth Medical Talent Development,No.05Youth Fund of the National Natural Science Foundation of China,No.82000497Youth Fund of the Natural Science Foundation of Jiangsu Province,No.BK20200965Scientific Research Fund of Nantong Health Commission,No.MB2020037.
文摘BACKGROUND Although expression of interleukin(IL)-34 is upregulated in active ulcerative colitis(UC),the molecular function and underlying mechanism are largely unclear.AIM To investigate the function of IL-34 in acute colitis,in a wound healing model and in colitis-associated cancer in IL-34-deficient mice.METHODS Colitis was induced by administration of dextran sodium sulfate(DSS),and carcinogenesis was induced by azoxymethane(AOM).Whether the impact of IL-34 on colitis was dependent on macrophages was validated by depletion of macrophages in a murine model.The association between IL-34 expression and epithelial proliferation was studied in patients with active UC.RESULTS IL-34 deficiency aggravated murine colitis in acute colitis and in wound healing phase.The effect of IL-34 on experimental colitis was not dependent on macrophage differentiation and polarization.IL-34-deficient mice developed more tumors than wild-type mice following administration of AOM and DSS.No significant difference was shown in degree of cellular differentiation in tumors between wild-type and IL-34-deficient mice.IL-34 was dramatically increased in the active UC patients as previously reported.More importantly,expression of IL-34 was positively correlated with epithelial cell proliferation in patients with UC.CONCLUSION IL-34 deficiency exacerbates colonic inflammation and accelerates colitis-associated carcinogenesis in mice.It might be served as a potential therapeutic target in UC.
基金Supported by Brazilian National Council for Scientific and Technological Development(CNPq),No.140152/2013-0.
文摘BACKGROUND Colitis-associated cancer(CAC)accounts for 2%-3%of colorectal cancer(CRC)cases preceded by inflammatory bowel diseases(IBD)such as Crohn's disease and ulcerative colitis.Intestinal microbiota has been reported to play a central role in the pathogenesis of IBD and CAC.Recently,numerous prebiotics and probiotics have being investigated as antitumor agents due to their capacity to modulate inflammatory responses.Previous studies have indicated that lactic acid bacteria could be successfully used in managing sporadic CRC,however little is known about their role in CAC.AIM To investigate the effect of the probiotic Lactobacillus bulgaricus(L.bulgaricus)during the development of an experimental model of colitis associated colon cancer(CAC).METHODS C57BL/6 mice received an intraperitoneal injection of azoxymethane(10 mg/kg),followed by three cycles of sodium dextran sulphate diluted in water(5%w/v).Probiotic group received daily L.bulgaricus.Intestinal inflammation was determined by scoring clinical signs.Cytokines levels were determined from colon and/or tumor samples by ELISA BD OptEIATM kits.The level of significance was set at P<0.05.Graphs were generated and statistical analysis performed using the software GraphPad Prism 6.0.RESULTS L.bulgaricus treatment inhibited of total tumor volume and mean size of tumors.In addition,the probiotic also attenuated the clinical signs of intestinal inflammation inducing a decrease in intestinal and tumor levels of IL-6,TNF-α,IL-17,IL-23 and IL-1β.CONCLUSION Our results suggest a potential chemopreventive effect of probiotic on CAC.L.bulgaricus regulates the inflammatory response and preventing CAC.
基金The Fundamental Research Grant Scheme,Ministry of Higher Education,Malaysia,No.FRGS/1/2018/SKK06/UKM/02/4.
文摘BACKGROUND Phosphatidylinositol-3-kinases(PI3K)is a well-known route in inflammationrelated cancer.Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis(UC)and colorectal cancer(CRC)with colitisassociated cancer(CAC).PI3K/AKT pathway has been recommended as a potential additional therapeutic option for CRC due to its substantial role in modifying cellular processes.Buparlisib is a pan-class I PI3K inhibitor previously shown to reduce tumor growth.AIM To investigate the regulation of rs10889677 and the role of buparlisib in the PI3K signaling pathway in CAC pathogenesis.METHODS Genomic DNA from 32 colonic samples,including CAC(n=7),UC(n=10)and CRC(n=15),was sequenced for the rs10889677 mutation.The mutant and wildtype fragments were amplified and cloned in the pmirGLO vector.The luciferase activity of cloned vectors was assessed after transfection into the HT29 cell line.CAC mice were induced by a mixture of a single azoxymethane injection and three cycles of dextran sulphate sodium,then buparlisib was administered after 14 d.The excised colon was subjected to immunohistochemistry for Ki67 and Cleaved-caspase-3 markers and quantitative real-time polymerase chain reaction analysis for Pdk1 and Sgk2.RESULTS Luciferase activity decreased by 2.07-fold in the rs10889677 mutant,confirming the hypothesis that the variant disrupted miRNA binding sites,which led to an increase in IL23R expression and the activation of the PI3K signaling pathway.Furthermore,CAC-induced mice had a significantly higher disease activity index(P<0.05).Buparlisib treatment significantly decreased mean weight loss in CAC-induced mice(P<0.05),reduced the percentage of proliferating cells by 5%,and increased the number of apoptotic cells.The treatment also caused a downward trend of Pdk1 expression and significantly decreased Sgk2 expression.CONCLUSION Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway,and buparlisib had the ability to prevent PI3K-non-AKT activation in the pathophysiology of CAC.
文摘Surgical therapy for ulcerative colitis(UC) depends on the medical therapy administered for the patient's condition. UC is a benign disease. However, it has been reported that the rare cases of cancer in UC patients are increasing, and such cases have a worse prognosis. Recently, surgical therapy has greatly changed, there has been quite an increase in the number of UC patients with high-grade dysplasia and/or cancer. These lesions are known as colitis-associated cancer(CAC). The relationship between inflammation and tumorigenesis is well-established, and in the last decade, a great deal of supporting evidence has been obtained from genetic, pharmacological, and epidemiological studies. Inflammatory bowel disease, especially UC, is an important risk factor for the development of colon cancer. We should determine the risk factors for UC patients with cancer based on a large body of data, and we should attempt to prevent the increase in the number of such patients using these newly identified risk factors in the near future. Actively introducing the surgical treatment in addition to medical treatment should be considered. Several physicians should analyze UC from their unique perspectives in order to establish new clinically relevant diagnostic and treatment methods in the future. This article discusses CAC, including its etiology, mechanism, diagnosis, and treatment in UC patients.
基金Supported by the São Paulo Research Foundation,No.07607-8/2013and the National Research Council,No.150127/2016-2 and No.306821/2010-9.
文摘BACKGROUND Inflammation is a well-established enabling factor for cancer development and provides a framework for the high prevalence of colon cancer in inflammatory bowel disease.In accordance,chronic inflammation has recently been implicated in the development of cancer stem cells(CSCs).However,the mechanism whereby anti-inflammatory drugs act in the prevention of colitis-associated cancer(CAC)is only partially understood.AIM To evaluate the role of diacerein(DAR),an anti-inflammatory drug that mainly acts through the inhibition of interleukin(IL)-1βexpression in the development of CSCs and CAC.METHODS The effects of DAR on colon inflammation in mice with CAC were evaluated by inflammatory index,reverse real-time transcription polymerase chain reaction and western blot.Cytokine levels were measured by enzyme-linked immunosorbent assay.Cells assays evaluated the effects of DAR on CSCs.Immunohistochemistry and apoptosis assays were also used to evaluate the effects of DAR on tumorigenesis associated with inflammation.RESULTS DAR treatment reduced colon inflammation as well as the number and size of tumors in azoxymethane plus dextran sulphate sodium-treated animals.Accordingly,DAR treatment was associated with reduced intracellular signals of inflammation(inhibitor of nuclear factor kappa B kinase and c-Jun N-terminal kinase phosphorylation)in the colon.In addition,DAR treatment was associated with a decrease in colon CSC formation,suggesting that besides reducing colonic inflammation,DAR has a direct effect on the inhibition of colon carcinogenesis.CONCLUSION Together,these data indicate that DAR-mediated IL-1βsuppression attenuates inflammation-induced colon cancer and CSC formation,highlighting DAR as a potential candidate for the chemoprevention of CAC.
文摘In inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD), the duration and severity of inflammation are responsible for the development of colorectal cancer. Inflammatory cytokines such as interleukin (IL)-8 and tumor necrotic factor (TNF)-a, which are released by epithelial and immune cells, are involved in the pathogenesis of colitis-associated cancer. Current treatments for advanced colorectal cancers focus primarily on targeting epidermal growth factor receptor (EGFR) signaling. IL-8 (a G-protein coupled receptor (GPCR) agonist), which is involved in neutrophil recruitment and activation in persistent active colitis, also promotes cleavage of theproheparin-binding epidermal growth factor—like growth factor (proHB-EGF) through a disintegrin and metalloproteinase (ADAM), so that the resulting soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, where HB-EGF-CTF binds the nuclear promyelocytic leukemia zinc finger (PLZF) protein, resulting in the nuclear export of the PLZF transcriptional repressor and thereby affecting cell proliferation. Screening for potent chemical inhibitors of the interactions between HB-EGF-CTF and PLZF identified telmisartan (and related compounds in corporating a biphenyl tetrazole moiety) as inhibitors of cell proliferation. Here we focus on the inhibitory effects of these compounds on cell proliferation, demonstrating the potential for targeting the nuclear translocation of HB-EGF-CTF in the treatment of colitis-associated cancer.
基金funded by National High-Level Hospital Clinical Research Funding (2022-PUMCH-A-203)CAMS Innovation Fund for Medical Sciences (2021-I2M-1-001)+4 种基金Health Research & Special Projects Grant of China (201002020 and 201502005)The Integrated Entrusted Project of Research Funding at Peking Union Medical College Hospital (ZC201903347)the National Natural Science Foundation of China (81970495)Capital Health Development Scientific Research Fund (2022-2-4014)Peking Union Medical College Hospital Research Funding for Postdoc (kyfyjj202315)
文摘Colitis-associated colorectal cancer(CAC),a serious complication of ulcerative colitis(UC),is associated with a poor prognosis.The vitamin D receptor(VDR)is recognized for its protective role in UC and CAC through the maintenance of intestinal barrier integrity and the regulation of inflammation.This study demonstrates a significant reduction in m^(6)A-related genes,particularly methyltransferase like 14(METTL14),in UC and CAC patients and identifies an association between METTL14 and VDR.In the azoxymethane(AOM)/dextran sodium sulfate(DSS)-induced mousemodel,vitamin D treatment increases METTL14 expression and reduces tumorburden,while Vdr-knockout mice exhibit lower METTL14 levels and increased tumorigenesis.In vitro,the VDR agonist calcipotriol upregulates METTL14 in NCM460 cells,with this effect attenuated by VDR knockdown.VDRknockdown inDLD-1colon cancer cellsdecreases METTL14 expressionand promotes proliferation,which is reversed by METTL14 overexpression.Mechanistic studies reveal that VDR regulates METTL14 expression via promoter binding,modulating key target genes such as SOX4,DROSH,and PHLPP2.This study highlights the role of the VDR-METTL14 axis as a protective mechanism in CAC and suggests its potential as a therapeutic target for preventing and treating CAC.
基金financially supported by Beijing Natural Science Foundation[7252202,25JL008,China]from Beijing Natural Science Foundation CommitteeThis work was also supported by CAMS Innovation Fund for Medical Sciences[2021-I2M-1-029,2023-12M-2-006,China]and[2021-I2M-1-028,China]from Chinese Academy of Medical Science&Peking Union Medical College(CAMS&PUMC)+1 种基金National Natural Science Foundation of China[81703536 and 22278443,China]from Natural Science Foundation CommitteeInternational Cooperation Project of Qinghai Province[2020-HZ-803,China]from Science and Technology Department of Qinghai Province.
文摘Objectives:Colorectal cancer(CRC)is one of the most common cancers all over the world.The progression of CRC is associated with inflammation and disruptions in intestinal flora.3-O-Acetyl-11-keto-β-boswellic acid(AKBA)has been noted for its potent anti-inflammatory properties.However,the effect of AKBA on colon cancer caused by inflammation and its mechanism are not unclear.The study is to explore the effect of AKBA on CRC and its mechanism.Materials and Methods:Cell proliferation,(5-ethynyl-2′-deoxyuridine,EdU)-DNA synthesis assay and colony formation were used to assess the effect of AKBA on the proliferation of CRC cells.Flow cytometry was employed to analyze the cell cycle and apoptosis rate of cells treated with AKBA.RNA sequencing was done to explore the underlying mechanisms of AKBA.Western blot was used to assess the expression of key proteins in the nuclear factor kappa-B(NF-κB)signaling pathway after the treatment of AKBA.Real-time quantitative PCR(RT-qPCR),enzyme-linked immunosorbent assay(ELISA),and Meso Scale Discovery(MSD)assays were employed to check the anti-inflammation effects of AKBA on Lipopolysaccharide(LPS)-induced RAW264.7 cells and LPS-induced mouse model.Additionally,the Azoxymethane/Dextran sulfate sodium(AOM/DSS)-induced colitis-associated CRC model was used to evaluate the anti-CRC effect of AKBA.Gut microbiota profiling of fecal samples from CRC mice,both with and without AKBA treatment,was conducted through metagenomic sequencing analysis.Results:Our results showed that AKBA reduced the proliferation of HCT116 and SW620 cells,increased apoptosis of cells,and arrested the cell cycle at the G2/M phase.Results from RNA-seq showed that AKBA inhibited CRC by inhibiting the NF-κB signaling pathway and reducing cellular inflammation.Furthermore,AKBA reduced the levels of inflammatory cytokines,including tumor necrosis factor-α(TNF-α),Interferon-γ(IFN-γ),Interleukin-IL-12p70(IL-12p70),Interleukin-1β(IL-1β),and tumor necrosis factor-α(TNF-α)in both the spleen and serum of LPS-induced acute inflammation mice.Additionally,AKBA inhibited the development of AOM/DSS-induced colitis-associated colon cancer in mice and positively influenced gut microbiota.Conclusion:This study highlights the inhibitory effect of AKBA on colitis-associated CRC and reveals a novel aspect of its role in the remodeling of gut microbiota.These findings suggest that AKBA may be used as a potential therapeutic agent for CRC.
基金National Natural Science Foundation of China,Grant/Award Numbers:82072722,81830070,81772935,81672340StateKey Laboratory ofCancer Biology Project,Grant/Award Number:CBSKL2019ZZ26。
文摘Background:Mitochondria are key regulators in cell proliferation and apoptosis.Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis.This study aimed to investigate whether mitochondrial transcription factor A(TFAM),a key regulator of mitochondrial DNA transcription and replication,is involved in the initiation and progression of colitis-associated cancer(CAC).Methods:TFAM expression was examined in tissue samples of inflammatory bowel diseases(IBD)and CAC by immunohistochemistry.Intestinal epithelial cell(IEC)-specific TFAM-knockout mice(TFAM^(△IEC))and colorectal cancer(CRC)cells with TFAM knockdown or overexpression were used to evaluate the role of TFAMin colitis and the initiation and progression ofCAC.The underlying mechanisms of TFAMwere also explored by analyzingmitochondrial respiration function and biogenesis.Results:The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity.The downregulation of TFAM in IECs was induced by interleukin-6 in a signal transducer and activator of transcription 3(STAT3)/miR-23b-dependent manner.In addition,TFAM knockout impaired IECturnover to promote dextran sulfate sodium(DSS)-induced colitis inmice.Of note,TFAMknockout increased the susceptibility of mice to azoxymethane/DSSinduced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis-associated tumorigenesis.By contrast,TFAM expression was upregulated in CAC tissues and contributed to cell growth.Furthermore,it was demonstrated that β-catenin induced the upregulation of TFAM through c-Myc in CRC cells.Mechanistically,TFAMpromoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity.Conclusions:TFAM plays a dual role in the initiation and progression of CAC,providing a novel understanding of CAC pathogenesis.
基金This work was supported by the National Natural Science Foundation of China(No.82274600,No.81774451 and No.82104501)the Natural Science Foundation of Guangdong Province(No.2017A030313827)+1 种基金The Basic and Applied Basic Research Project of Guangzhou Municipal Science and Technology Bureau(No.202102080485)Science and Technology Innovation Special Topic of Maoming City(No.2022S014).
文摘Intestinal macrophages are essential players in intestinal inflammation and intestinal immune homeostasis.Intestinal macrophages have the ability to polarize into two distinct phenotypes based on various environmental signals.These phenotypes include the typically activated pro-inflammatory M1 phenotype and the alternatively activated anti-inflammatory M2 phenotype.Under normal circumstances,intestinal macrophages prevent inflammatory damage to the gut.However,when genetic and environmental factors influence the polarization of intestinal macrophages,it can lead to an imbalance in M1/M2 macrophage activation and subsequently an imbalance in the control of intestinal inflammation.It transforms physiological inflammation into pathological intestinal damage.In patients with ulcerative colitis-associated cancer(UC-CRC),intestinal inflammatory disorders are closely associated with intestinal M1/M2 macrophage polarization imbalance.Consequently,restoring the polarization equilibrium of M1/M2 macrophages might be an evidence of traditional Chinese medicine in the treatment of UC-CRC,the pivotal role o effective measure to prevent and treat UC-CRC.This paper aims to examine the clinicalf macrophage polarization in UC-CRC pathogenesis,and the potential mechanisms of traditional Chinese medicine in regulating macrophage polarization to treat UC-CRC.Our goal is to provide novel insights into the clinical practice,basic research,and drug development of UC-CRC.
文摘The association between ulcerative colitis(UC) and colorectal cancer(CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC(UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, lowgrade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC.
基金This work was supported by the National Natural Science Foundation of China(Nos.81872903 and 82173956)the“Double First-Class”University project of China Pharmaceutical University(CPU2018GY03)Fundamental Research Funds for the Central Universities of China Pharmaceutical University(2016ZZD003).
文摘Colorectal cancer(CRC)is the third most lethal cancer and leading cause of cancer mortality worldwide.A key driver of CRC development is colon inflammatory responses especially in patients with inflammatory bowl disease(IBD).It has been proved that Panax notoginseng saponins(PNS)have anti-inflammatory,anti-oxidant and anti-tumor effects.The chemopreventive and immunomodulatory functions of PNS on colitis-associated colorectal cancer(CAC)have not been evaluated.This present study was designed to study the potential protective effects of PNS on AOM/DSS-induced CAC mice to explore the possible mechanism of PNS against CAC.Our study showed that PNS significantly alleviated colitis severity and prevented the occurrence of CAC.Functional assays revealed that PNS relieved immunosuppression of Treg cells in the CAC microenvironment by inhibiting the expression of IDO 1 mediated directly by signal transducer and activator of transcription 1(STAT1)rather than phosphorylated STAT1.Ultimately,Rhl,one of the PNS metabolites,exhibited the best inhibitory effect on IDO1 enzyme activity.Our study showed that PNS exerted significant chemopreventive function and immunomodulatory properties on CAC.It could reduce macrophages accumulation and Treg cells differentiation to reshape the immune microenvironment of CAC.These findings provided a promising approach for CAC intervention.
基金supported by National Key Research and Development Program of China(No.2017YFC1308800)Industry-University-Research Innovation Fund in Ministry of Education of the People’s Republic of China(No.2018A01013)。
文摘Objective:The goal of this study was to get preliminary insight on the intra-tumor heterogeneity in colitisassociated cancer(CAC)and to reveal a potential evolutionary trajectory from ulcerative colitis(UC)to CAC at the single-cell level.Methods:Fresh samples of tumor tissues and adjacent UC tissues from a CAC patient with pT3N1M0 stage cancer were examined by single-cell RNA sequencing(scRNA-seq).Data from The Cancer Genome Atlas(TCGA)and The Human Protein Atlas were used to confirm the different expression levels in normal and tumor tissues and to determine their relationships with patient prognosis.Results:Ultimately,4,777 single-cell transcriptomes(1,220 genes per cell)were examined,of which 2,250(47%)and 2,527(53%)originated from tumor and adjacent UC tissues,respectively.We defined the composition of cancer-associated stromal cells and identified six cell clusters,including myeloid,T and B cells,fibroblasts,endothelial and epithelial cells.Notable pathways and transcription factors involved in these cell clusters were analyzed and described.Moreover,the precise cellular composition and developmental trajectory from UC to UCassociated colon cancer were graphed,and it was predicted that CD74,CLCA1,and DPEP1 played a potential role in disease progression.Conclusions:scRNA-seq technology revealed intra-tumor cell heterogeneity in UC-associated colon cancer,and might provide a promising direction to identify novel potential therapeutic targets in the evolution from UC to CAC.
基金Supported by the National Key Research and Development Program,No.2022YFC2504003Young Scholar Independent Innovation Science Fund of Chinese PLA General Hospital,No.22QNCZ020Medical Science and Technology Young Scholar Fostering Fund,No.21QNPY109.
文摘Colitis-associated colorectal cancer(CAC)is defined as a specific cluster of colorectal cancers that develop as a result of prolonged colitis in patients with inflammatory bowel disease(IBD).Patients with IBD,including ulcerative colitis and Crohn’s disease,are known to have an increased risk of developing CAC.Although the incidence of CAC has significantly decreased over the past few decades,individuals with CAC have increased mortality compared to individuals with sporadic colorectal cancer,and the incidence of CAC increases with duration.Chronic inflammation is generally recognized as a major contributor to the pathogenesis of CAC.CAC has been shown to progress from colitis to dysplasia and finally to carcinoma.Accumulating evidence suggests that multiple immune-mediated pathways,DNA damage pathways,and pathogens are involved in the pathogenesis of CAC.Over the past decade,there has been an increasing effort to develop clinical approaches that could help improve outcomes for CAC patients.Colonoscopic surveillance plays an important role in reducing the risk of advanced and interval cancers.It is generally recommended that CAC patients undergo endoscopic removal or colectomy.This review summarizes the current understanding of CAC,particularly its epidemiology,mechanisms,and management.It focuses on the mechanisms that contribute to the development of CAC,covering advances in genomics,immunology,and the microbiome;presents evidence for management strategies,including endoscopy and colectomy;and discusses new strategies to interfere with the process and development of CAC.These scientific findings will pave the way for the management of CAC in the near future.
基金National Natural Science Foundation(Grant No.81272468 and 21001011)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,Ministry of Education
文摘Colorectal cancer （CRC） is one of the leading causes of cancer-related deaths, and inflammatory bowel diseases and dysregulated cell proliferation play important roles in colorectal carcinogenesis. Therefore, inhibition of inflammatory signaling and cell proliferation is used as a major strategy for chemoprevention of CRC. In the present study, it was found that IC5, a dithiocarbamate derivative, could inhibit the proliferation of LoVo human colon cancer cells in a concentration-dependent manner, with an IC50 of 22 gM. The anti-proliferation effect of IC5 was accompanied by a significant cell cycle arrest in G2/M phase. Further study revealed that IC5 significantly inhibited NF-~B signaling in LoVo cells, suggesting that IC5 could inhibit inflammatory responses. We then evaluated the in vivo efficacy of IC5 to inhibit colitis-associated colorectal carcinogenesis using an azoxymethane （AOM）/dextran sodium sulfate （DSS） mouse model. AOM/DSS treatment resulted in a CRC incidence of 58.3%, while the incidences were decreased to 37.5% and 25% in mice orally administered with 50 and 100 mg/kg IC5, respectively. In addition, IC5 also reduced the plasma levels of alanine aminotransferase and asparatate aminotransferase. Taken together, these results suggested that IC5 could prevent colitis-associated colorectal carcinogenesis, and more attention should be paid to it as a cancer chemopreventive agent in further investigation.
基金Supported by The Cancer Research Society,No.19490(to Beauchemin N and Gros P).Van Der Kraak L is the recipient of a Canadian Institute of Health Research Doctoral Award(PA-Digestive Health)and a Mc Gill Integrated Cancer Research Training Program studentship
文摘Colitis-associated colorectal cancer(CA-CRC) is the cause of death in 10%-15% of inflammatory bowel disease(IBD) patients. CA-CRC results from the accumulation of mutations in intestinal epithelial cells and progresses through a well-characterized inflammation to dysplasia to carcinoma sequence. Quantitative estimates of overall CA-CRC risks are highly variable ranging from 2% to 40% depending on IBD severity, duration and location, with IBD duration being the most significant risk factor associated with CA-CRC development. Recently, studies have identified IBD patients with similar patterns of colonic inflammation, but that differ with respect to CA-CRC development, suggesting a role for additional non-inflammatory risk factors in CA-CRC development. One suggestion is that select IBD patients carry polymorphisms in various low penetrance disease susceptibility genes, which predispose them to CA-CRC development, although these loci have proven difficult to identify in human genomewide association studies. Mouse models of CA-CRC have provided a viable alternative for the discovery, validation and study of individual genes in CA-CRC pathology. In this review, we summarize the current CA-CRC literature with a strong focus on genetic predisposition and highlight an emerging role for mouse models in the search for CA-CRC risk alleles.
文摘It has long been appreciated that there is a direct relationship between the intensity and duration of inflammatory bowel diseases (IBD) and increasing intestinal cancer risk but which elements of the inflammatory response are responsible have not been identified. Anti-TNF drugs have been successful at treating IBD but considering the presumed anti-tumor activity of TNF, it is important to understand whether the treatment impacts on the patients’ intestinal cancer risk. We modeled this relationship by “treating mice lacking TNF receptors with a colon cancer causing combination of azoxymethane followed by repeated dextran sulphate sodium exposures (AOM + DSS regime). TNF receptor type1 gene deficient (TNFR1-/-) and TNFR2-/- mice experienced similar clinical illnesses and colonic inflammation as C57BL/6 wildtype controls during the AOM + DSS regime. Despite the inflammation, TNFR1-/- mice developed significantly fewer colon tumors than the other strains. The reduced tumor incidence was a product of the combined lack of receptor expression on hematopoietic and nonhematopoietic cells, shown using bone marrow cell chimeras of wildtype and TNFR1-/- mice. As oxidative damage is a potent contributing factor to tumorigenesis and inflammatory leukocytes make copious amounts of reactive oxygen radicals, we measured oxidative damage in the animals’ colons. TNFR1-/- mice showed less damage compared to the other strains. We subsequently examined mice deficient in their leukocyte NADPH oxidative pathway (Nox2-/-) for their cancer incidence using the AOM + DSS regime. Nox2-/- mice became inflamed but had fewer tumors than wildtype mice. We conclude that TNF promotes colon cancer including through promoting oxidative processes utilizing TNFR1 in leukocytes. Moreover, the C57BL/6 strain can be used to dissociate mechanisms of colon inflammation from tumorigenic processes. We interpret our results to mean that IBD patients on TNF antagonist therapies will potentially benefit with reduced colon cancer risk even if they do not respond with reduced inflammation.
基金supported by the National Natural Scientific Foundation of China(No.81903784)Key Research and Development Plan of Hunan Province(No.2018sk2129)Hunan Provincial Natural Science Foundation of China(No.2020JJ4878)。
文摘Gut microbiota dysbiosis is a risk factor for colorectal cancer(CRC) in inflammatory bowel disease(IBD).In this study, the effects of Panax notoginseng saponins(PNS) on colitis-associated CRC progression were evaluated on an azoxymethane(AOM)/dextran sulfate sodium(DSS) mouse model.In vivo, PNS significantly relieved AOM/DSS-induced colon tumorigenesis and development by reducing the disease activity index(DAI) scores and colon tumor load.The 16S rRNA data of fecal samples showed that the microbiome community was obviously destructed, while PNS could recover the richness and diversity of gut microbiota.Especially, PNS could increase the abundance of Akkermansia spp.which was significantly decreased in model group and negatively correlated with the progression of CRC.Moreover, ginsenoside compound K(GC-K) was evaluated on the effects of human CRC cells,which was the main bio-transformed metabolite of PNS by gut microbiota.Our data showed that PNS played important role in the prevention of the progression of CRC, due to their regulation on the microbiome balance and microbial bio-converted product with antiCRC activity.
文摘Patients with extensive ulcerative colitis(UC) of more than eight years duration have an increased risk of colorectal cancer. Molecular biomarkers for dysplasia and cancer could have a great clinical value in managing cancer risk in these UC patients. Using a wide range of molecular techniques- including cutting-edge OMICS technologies- recent studies have identified clinically relevant biomarker candidates from a variety of biosamples, including colonic biopsies, blood, stool, and urine. While the challenge remains to validate these candidate biomarkers in multi-center studies and with larger patient cohorts, it is certain that accurate biomarkers of colitis-associated neoplasia would improve clinical management of neoplastic risk in UC patients. This review highlights the ongoing avenues of research in biomarker development for colitis-associated colorectal cancer.
