Carcinogenesis is a multilevel process characterized by genetic and epigenetic alterations,thus contributing to uncontrolled proliferation that eventually leads to cancer.The process of carcinogenesis involves an intr...Carcinogenesis is a multilevel process characterized by genetic and epigenetic alterations,thus contributing to uncontrolled proliferation that eventually leads to cancer.The process of carcinogenesis involves an intricate dis-orchestration in the expression of both,coding and non-coding sequences and is also dependent on the reprogramming of energy metabolism as both direct and indirect consequence of oncogenic mutations.Dysregulated mitochondrial energetics is an important hallmark of cancer,where cancer cells switch to the glycolytic pathway as an alternate source of energy to support the continuous energy supply needed for their indefinite growth.Even though functional mitochondria are indispensable for cancer cells,cancer cells exhibit different bioenergetics transitions based on the development status of cells undergoing carcinogenesis.Although the role of coding sequences in regulating energy metabolism shift is well studied,the role of non-coding sequences in modulating energy metabolism is still unclear.MicroRNAs(miRNAs),usually present in the nucleus and cytoplasm,have now been reported to localize in the mitochondria also known as,mitochondrial miRNAs(MitomiRs),which can originate either from the nuclear or mitochondrial genome.MitomiRs are reported to be associated with both oncogenic and tumor-suppressive functions.MitomiRs can target metabolic pathway-related protein-coding genes to alter cellular metabolism and promote carcinogenesis.Several mitomiRs like miR-1,miR-133,miR-128,and miR-21 have been reported to be involved in normal physiology,survival,and pathology.Since energy metabolism is one of the most important hallmarks of carcinogenesis and its underlying mechanism involves dysregulation of mitochondrial metabolism,we have tried to collate the importance of mitomiRs in the process of cancer energy metabolism and carcinogenesis.展开更多
Spices are defined as any aromatic condiment of plant origin used to alter the flavor and aroma of foods. Besides flavor and aroma, many spices have antioxidant activity, mainly related to the presence in cloves of ph...Spices are defined as any aromatic condiment of plant origin used to alter the flavor and aroma of foods. Besides flavor and aroma, many spices have antioxidant activity, mainly related to the presence in cloves of phenolic compounds, such as flavonoids, terpenoids and eugenol. In turn, the most common uses of gum arabic are in the form of powder for addition to soft drink syrups, cuisine and baked goods, specifically to stabilize the texture of products, increase the viscosity of liquids and promote the leavening of baked products (e.g., cakes). Both eugenol, extracted from cloves, and gum arabic, extracted from the hardened sap of two species of the Acacia tree, are dietary constituents routinely consumed virtually throughout the world. Both of them are also widely used medicinally to inhibit oxidative stress and genotoxicity. The prevention arm of the study included groups: Ia, IIa, IIIa, Iva, V, VI, VII, VIII. Once a week for 20 weeks, the controls received saline s.c. while the experimental groups received DMH at 20 mg/kg s.c. During the same period and for an additional 9 weeks, the animals received either water, 10% GA, EUG, or 10% GA + EUG by gavage. The treatment arm of the study included groups Ib, IIb, IIIb e IVb, IX, X, XI, XII). Once a week for 20 weeks, the controls received saline s.c. while the experimental groups received DMH at 20 mg/kg s.c. During the subsequent 9 weeks, the animals received either water, 10% GA, EUG or 10% GA + EUG by gavage. The novelty of this study is the investigation of their use alone and together for the prevention and treatment of experimental colorectal carcinogenesis induced by dimethylhydrazine. Our results show that the combined use of 10% gum arabic and eugenol was effective, with antioxidant action in the colon, as well as reducing oxidative stress in all colon segments and preventing and treating genotoxicity in all colon segments. Furthermore, their joint administration reduced the number of aberrant crypts and the number of aberrant crypt foci (ACF) in the distal segment and entire colon, as well as the number of ACF with at least 5 crypts in the entire colon. Thus, our results also demonstrate the synergistic effects of 10% gum arabic together with eugenol (from cloves), with antioxidant, antigenotoxic and anticarcinogenic actions (prevention and treatment) at the doses and durations studied, in the colon of rats submitted to colorectal carcinogenesis induced by dimethylhydrazine.展开更多
The effects of Aspirin on tumor chemoprevention and inhibition have been debated and researched in recent years and its effects on colorectal cancer are quite clear.For breast cancer,however,conclusions are inconsiste...The effects of Aspirin on tumor chemoprevention and inhibition have been debated and researched in recent years and its effects on colorectal cancer are quite clear.For breast cancer,however,conclusions are inconsistent and the anti-tumor mechanism of Aspirin is not clear yet.In our study,we used DMBA-induced mammary gland carcinogenesis model to assess the chemoprevention effect of Aspirin on mammary precancerous lesions.After SD rats were treated with Aspirin,the total numbers of precancerous lesion in experimental groups were 16（40 mg/kg Aspirin） and 13（20 mg/kg Aspirin）,while the number in control group was 35.In vitro,we found that Aspirin inhibited cell proliferation in human breast cancer cell line MCF-7 by SRB assay with no apparent cytotoxity under the doses of 10,8,6,4 and 2 mM,the inhibitory rates were 86.96%,54.56%,24.83%,14.24% and 4.49%,respectively.In mechanism research,the results of gene microarray assay demonstrated that 4 mM and 2 mM Aspirin were effective in changing gene expression profile in MCF-7 cells.The expression of cell cycle regulator,cyclin A,was significantly down-regulated under the same doses,while the down-regulation of Cdk2 was only remarkable at 4 mM.Our findings reveal that Aspirin is effective in tumor inhibition during initial phase in rats.In MCF-7 cells,Aspirin reduces cell proliferation without significant cytotoxity and its possible mechanism involves altering tumor-related gene expression and regulating cell cycle process.展开更多
AIM To investigate the effects of VSL#3 on tumor formation, and fecal and intestinal mucosal microbiota in azoxymethane/dextran sulfate sodium(AOM/DSS) induced mice model. METHODS C57 BL/6 mice were administered AOM/D...AIM To investigate the effects of VSL#3 on tumor formation, and fecal and intestinal mucosal microbiota in azoxymethane/dextran sulfate sodium(AOM/DSS) induced mice model. METHODS C57 BL/6 mice were administered AOM/DSS to develop the ulcerative colitis(UC) carcinogenesis model. Mice were treated with 5-ASA(75 mg/kg/d), VSL#3(1.5 × 109 CFU/d), or 5-ASA combined with VSL#3 by gavage from the day of AOM injection for three months(five days/week). The tumor load was compared in each group, and tumor necrosis factor(TNF-α) and interleukin(IL)-6 levels were evaluated in colon tissue. The stool and intestinal mucosa samples were collected to analyze the differences in the intestinal microbiota by 16 s rDNA sequencing method.RESULTS VSL#3 significantly reduced the tumor load in AOM/DSS-induced mice model and decreased the level of TNF-α and IL-6 in colon tissue. The model group had a lower level of Lactobacillus and higher level of Oscillibacter and Lachnoclostridium in fecal microbiota than the control group. After the intervention with 5-ASA and VSL#3, Bacillus and Lactococcus were increased, while Lachnoclostridium and Oscillibacter were reduced. 5-ASA combined with VSL#3 increased the Lactobacillus and decreased the Oscillibacter. The intestinal mucosal microbiota analysis showed a lower level of Bifidobacterium and Ruminococcaceae_UCG-014 and higher level of Al oprevotel a in the model group as compared to the control group. After supplementation with VSL#3, Bifidobacterium was increased. 5-ASA combined with VSL#3 increased the level of both Lachnoclostridium and Bifidobacterium. CONCLUSION VSL#3 can prevent UC-associated carcinogenesis in mice, reduce the colonic mucosal inflammation levels, and rebalance the fecal and mucosal intestinal microbiota.展开更多
To investigate the roles of maspin and kai1 expression in tumorigenesis and progression of gastric cancer. Methods Maspin and kai1 expressions were detected in normal gastric mucosa (n = 182), gastric dysplasia (n = 6...To investigate the roles of maspin and kai1 expression in tumorigenesis and progression of gastric cancer. Methods Maspin and kai1 expressions were detected in normal gastric mucosa (n = 182), gastric dysplasia (n = 69), and gastric cancer (n = 113) by immunohisto-chemistry. Their expressions were compared with clinicopathological parameters of tumors. Relationship between maspin and kai1 expression was also concerned in gastric cancer. Results The positive rates of maspin expression were 79.8% (145/182), 75.4% (52/69), and 50.4% (57/113) in normal gastric mucosa, gastric dysplasia, and gastric cancer, while those of kai1 expression were 81.9% (149/182), 65.2% (49/69), and 58.4% (66/113) in corresponding tissues respectively. Gastric cancer less frequently expressed maspin than the normal gastric mucosa and gastric dysplasia (P < 0.05), while dysplasia and cancer showed less frequent expression of kai1 than normal mucosa (P < 0.05). Maspin expression showed negative association with invasive depth, metastasis, Lauren’s and histological classifications (P < 0.05), but not with tumor size, Borrmann’s classification, growth pattern or TNM staging (P > 0.05). Kai1 expression was negatively correlated with invasive depth, metastasis, growth pattern, Lauren’s and histo-logical classifications (P < 0.05), but not with tumor size, Borrmann’s classification or TNM staging (P > 0.05). Maspin and kai1 were collaboratively expressed in gastric cancer (P < 0.05). Conclusions Down-regulated expressions of maspin and kai1 play an important role in gastric carcinogenesis. Abnormal expression of maspin and kai1 might have inhibitory effects on invasion and metastasis of gastric cancer and act as an effe-ctive and objective marker to indicate the pathobiological behaviors of gastric cancer.展开更多
Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogeneoverexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanis...Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogeneoverexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a varietyof methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play impor-tant roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpGisland methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesisand its relevance of clinical implications.展开更多
AIM:To investigate the expression of interleukin (IL)-22 and its related proteins in biopsy specimens from patients with ulcerative colitis (UC) and UC-related carcinogenesis. METHODS:Biopsy specimens were obtained fr...AIM:To investigate the expression of interleukin (IL)-22 and its related proteins in biopsy specimens from patients with ulcerative colitis (UC) and UC-related carcinogenesis. METHODS:Biopsy specimens were obtained from patients with inactive (n = 10), mild-to-moderately active (n = 30), severely active (n = 34), initial (n = 30), and chronic UC (n = 44), as well as UC patients with dysplasia (n = 10). Specimens from patients without colonic abnormalities (n = 20) served as controls. Chronic colitis in experimental mice was induced by 2.5% dextran sodium sulfate. The expression levels of IL-22, IL-23, IL-22R1 and phosphorylated STAT3 (p- STAT3) were determined by immunohistochemistry. Bcl-2, cyclin D1 and survivin expression was detected by Western blotting. RESULTS:Patients with active UC had significantly more IL-22, IL-23, IL-22R1 and p-STAT3-positive cells than the patients with inactive UC and normal controls. Furthermore, IL-22 and related proteins were closely related to the severity of the colitis. The expression of IL-22 and IL-22R1 in the tissue of initial UC was stronger than in that of chronic UC, whereas the expression of p-STAT3 was significantly increased in chronic UC tissues. In dysplasia tissues, the expression level of IL-22 and related proteins was higher compared with controls. Mouse colitis model showed that expression of IL-22, IL-22R1 and IL-23 was increased with time, p-STAT3 and the downstream gene were also remarkably upregulated.CONCLUSION:IL-22/STAT3 signaling pathway may be related to UC and UC-induced carcinogenesis and IL-22 can be used as a biomarker in judging the severity of UC.展开更多
There appears to be the strong association between Helicobacter pylori （H pylori） and gastric cancer. We reviewed the latest evidences about the effects of H pylori infection on gastric carcinogenesis, classified in...There appears to be the strong association between Helicobacter pylori （H pylori） and gastric cancer. We reviewed the latest evidences about the effects of H pylori infection on gastric carcinogenesis, classified into epidemiology, dynamics of gastric mucosal changes, DNA damages, virulence factors, host factors, and source of gastric malignancy. Through the considerable progress made in research into virulence factors resulting from differences between Hpylori strains, such as cagA positivity, as well as into host factors, such as gene polymorphisms, a diverse spectrum of H pyloriassociated diseases, including gastric cancer, is beginning to lend itself to elucidation. The impact of the novel hypothesis advanced by Houghton et al proposing bonemarrow derived stem cells （BMDC） as a potential source of gastric malignancy on evolving research remains to be seen with interest. Further progress in research into H pylori eradication as a viable prophylaxis of gastric cancer, as well as into the mechanisms of gastric carcinogenesis, is to be eagerly awaited for the current year and beyond.展开更多
Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory...Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.展开更多
Epigenetic alterations contribute significantly to the development and progression of gastric cancer,one of the leading causes of cancer death worldwide.Epigenetics refers to the number of modifications of the chromat...Epigenetic alterations contribute significantly to the development and progression of gastric cancer,one of the leading causes of cancer death worldwide.Epigenetics refers to the number of modifications of the chromatin structure that affect gene expression without altering the primary sequence of DNA,and these changes lead to transcriptional activation or silencing of the gene.Over the years,the study of epigenetic processes has increased,and novel therapeutic approaches that target DNA methylation and histone modifications have emerged.A greater understanding of epigenetics and the therapeutic potential of manipulating these processes is necessary for gastric cancer treatment.Here,we review recent research on the effects of aberrant DNA and histone methylation on the onset and progression of gastric tumors and the development of compounds that target enzymes that regulate the epigenome.展开更多
AIM: Although polysaccharides from Phellinus mushrooms are a well-known material with anti-tumor properties, there is no information about the effect of polysaccharides from Phellinus gilvus (PG) on tumor. The modulat...AIM: Although polysaccharides from Phellinus mushrooms are a well-known material with anti-tumor properties, there is no information about the effect of polysaccharides from Phellinus gilvus (PG) on tumor. The modulating effect of polysaccharides isolated from PG on the benzo(a)pyrene (BaP)-induced forestomach carcinogenesis in ICR female mice was investigated in this study.METHODS: A forestomach carcinogenesis model was established in 40 ICR female mice receiving oral administration of BaP for 4 wk. The mice were randomly assigned to 4 groups (10 each). The mice in each group were treated with sterile water or PG for 4 and 8 wk (SW4,PGW4, SW8, and PGW8 groups). Eight or 12 wk after the first dose of BaP, forestomachs were removed for histopathological and RT-PCR analysis.RESULTS: In histopathological changes and RT-PCR analysis, sterile water-treated mice showed significant hyperplasia of the gastric mucosa with a significantly increased expression of mutant p53 mRNA compared to mice treated with PG for 8 wk.CONCLUSION: Polysaccharides isolated from PG may inhibit BaP-induced forestomach carcinogenesis in mice bydown-regulating mutant p53 expression.展开更多
Ulcerative colitis(UC)is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial.UC-associated carcinogenesis presents a different sequence of tumorigenic event...Ulcerative colitis(UC)is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial.UC-associated carcinogenesis presents a different sequence of tumorigenic events compared to those that contribute to the development of sporadic colorectal cancer.In fact,in UC,the early events are represented by oxidative DNA damage and DNA methylation that can produce an inhibition of oncosuppressor genes,mutation of p53,aneuploidy,and microsatellite instability.Hypermethylation of tumor suppressor and DNA mismatch repair gene promoter regions is an epigenetic mechanism of gene silencing that contribute to tumorigenesis and may represent the first step in inflammatory carcinogenesis.Moreover,p53 is frequently mutated in the early stages of UC-associated cancer.Aneuploidy is an independentrisk factor for forthcoming carcinogenesis in UC.Epithelial cell-T-cell cross-talk mediated by CD80 is a key factor in controlling the progression from low to high grade dysplasia in UC-associated carcinogenesis.展开更多
AIM:To characterize the immune responses including local and systemic immunity induced by infection with H pylori,especially with CagA+ H pylori strains and the underlying immunopathogenesis. METHODS:A total of 711 pa...AIM:To characterize the immune responses including local and systemic immunity induced by infection with H pylori,especially with CagA+ H pylori strains and the underlying immunopathogenesis. METHODS:A total of 711 patients with different gastric lesions were recruited to determine the presence of H pylori infection and cytotoxin associated protein A (CagA),the presence of T helper (Th) cells and regulatory T (Treg) cells in peripheral blood mononuclear cells (PBMCs),expression of plasma cytokines,and RNA and protein expression of IFN-γ and IL-4 in gastric biopsies and PBMCs were determined by rapid urease test,urea 14C breath test,immunoblotting test,flow cytometry ,real time RT-PCR and immunohistochemistry. RESULTS:Of the patients,629 (88.47%) were infected with H pylori ; 506 (71.16%) with CagA+ and 123 (17.30%) with CagA- strains. Among patients infected with CagA+ H pylori strains,Th1-mediated cellular immunity was associated with earlier stages of gastric carcinogenesis,while Th2-mediated humoral immunity dominated the advanced stages and was negatively associated with an abundance of Treg cells. However,there was no such tendency in Th1/Th2 polarization in patients infected with CagA- H pylori strains and those without H pylori infection. CONCLUSION:Polarization of Th cell immune responses occurs in patients with CagA+ H pyloriinfection,which is associated with the stage and severity of gastric pathology during the progression of gastric carcinogenesis. This finding provides further evidence for a causal role of CagA+ H pylori infection in the immunopathogenesis of gastric cancer.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
Inflammation is a primary defense process against various extracellular stimuli,such as viruses,pathogens,foods,and environmental pollutants.When cells respond to stimuli for short periods of time,it results in acute ...Inflammation is a primary defense process against various extracellular stimuli,such as viruses,pathogens,foods,and environmental pollutants.When cells respond to stimuli for short periods of time,it results in acute or physiological inflammation.However,if the stimulation is sustained for longer time or a pathological state occurs,it is known as chronic or pathological inflammation.Several studies have shown that tumorigenesis in the gastrointestinal (GI) tract is closely associated with chronic inflammation,for which abnormal cellular alterations that accompany chronic inflammation such as oxidative stresses,gene mutations,epigenetic changes,and inflammatory cytokines,are shared with carcinogenic processes,which forms a critical cross-link between chronic inflammation and carcinogenesis.Transforming growth factor (TGF)-β is a multi-potent cytokine that plays an important role in regulation of cell growth,apoptosis and differentiation.Most importantly,TGF-β is a strong anti-inflammatory cytokine that regulates the development of effector cells.TGF-β has a suppressive effect on carcinogenesis under normal conditions by inhibiting abnormal cell growth,but on the other hand,many GI cancers originate from uncontrolled cell growth and differentiation by genetic loss of TGF-β signaling molecules or perturbation of TGF-β adaptors.Once a tumor has developed,TGF-β exerts a promoting effect on the tumor itself and stromal cells to enhance cell growth,alter the responsiveness of tumor cells to stimulate invasion and metastasis,and inhibited immune surveillance.Therefore,novel development of therapeutic agents to inhibit TGF-β-induced progression of tumor and to retain its growth inhibitory activities,in addition to anti-inflammatory actions,could be useful in oncology.In this review,we discuss the role of TGF-β in inflammation and carcinogenesis of the GI tract related to abnormal TGF-β signaling.展开更多
Hepatocellular carcinoma(HCC) is now the second leading cause of cancer-related deaths globally and many patients have incurable disease. HCC predominantly occurs in the setting of liver cirrhosis and is a paradigm fo...Hepatocellular carcinoma(HCC) is now the second leading cause of cancer-related deaths globally and many patients have incurable disease. HCC predominantly occurs in the setting of liver cirrhosis and is a paradigm for inflammation-induced cancer. The causes of chronic liver disease promote the development of transformed or premalignant hepatocytes and predisposes to the development of HCC. For HCC to grow and progress it is now clear that it requires an immunosuppressive niche within the fibrogenic microenvironment of cirrhosis. The rationale for targeting this immunosuppression is supported by responses seen in recent trials with checkpoint inhibitors. With the impact of immunotherapy, HCC progression may be delayed and long term durable responses may be seen. This makes the management of the underlying liver cirrhosis in HCC even more crucial as studies demonstrate that measures of liver function are a major prognostic factor in HCC. In this review, we discuss the development of cancer in the setting of liver inflammation and fibrosis, reviewing the microenvironment that leads to this tumourigenic climate and the implications this has for patient management.展开更多
To study the role of cyclinD 1 and CDK4 in malignant transformation of human fetal lung diploid fibroblast cell line （2BS） induced by silica. Methods Recombination vectors with sense and antisense pXJ41-cyclinD1 and...To study the role of cyclinD 1 and CDK4 in malignant transformation of human fetal lung diploid fibroblast cell line （2BS） induced by silica. Methods Recombination vectors with sense and antisense pXJ41-cyclinD1 and pXJ41-CDK4 were constructed, and then transfected into the malignant transformed cells induced by silica, respectively. At the same time, pXJ41-neo was used as the control. Results During the progress of the malignant transformation of 2BS cells induced by silica, cyclinD 1 and CDK4 were overexpressed. Antisense RNA suppressed cyclinD 1 and CDK4 gene expression in the antisense pXJ41-cyclinD1 and pXJ41-CDK4 transfected cells. Antisense RNA led to cell cycle arrest, resulting in lengthened G1 phase （the percentages of cells in the G1 phase changed from 45.1% to 52.7% and 58.0% for cyclinD1 and CDK4 transfected cells, respectively）, and eventually attenuated the increase of the proliferation of malignant transformed cells induced by silica. Compared with malignant transformed cells induced by silica, cells transfected with antisense pXJ41-cyclinD1 and pXJ41-CDK4 showed obviously reduced growth rates. On the 8th day, the suppression rates were 58.69 and 77.43% （the growth rate of malignant transformed cells induced by silica was 100%）, doubling time changed from 21.0 h to 31.4 h and 21.0 h to 42.7 h, respectively, the growth capacities on soft agar of cells transfected by antisense pXJ41-cyclinD1 and pXJ41-CDK4 decreased obviously. Conclusion CyclinD 1 and CDK4 play an important role in maintaining transformed phenotype of the cancer cells.展开更多
AIM:To investigate the causal relationship between hypoadiponectinemia and colorectal carcinogenesis in in vivo experimental model,and to determine the con-tribution of adiponectin defi ciency to colorectal cancer dev...AIM:To investigate the causal relationship between hypoadiponectinemia and colorectal carcinogenesis in in vivo experimental model,and to determine the con-tribution of adiponectin defi ciency to colorectal cancer development and proliferation.METHODS:We examined the influence of adiponectin defi ciency on colorectal carcinogenesis induced by the administration of azoxymethane(AOM)(7.5 mg/kg,in-traperitoneal injection once a week for 8 wk),by using adiponectin-knockout(KO) mice.RESULTS:At 53 wk after the fi rst AOM treatment,KOmice developed larger and histologically more progres-sive colorectal tumors with greater frequency com-pared with wild-type(WT) mice,although the tumor incidence was not different between WT and KO mice.KO mice showed increased cell proliferation of colorec-tal tumor cells,which correlated with the expression levels of cyclooxygenase-2(COX-2) in the colorectal tumors.In addition,KO mice showed higher incidence and frequency of liver tumors after AOM treatment.Thirteen percent of WT mice developed liver tumors,and these WT mice had only a single tumor.In contrast,50% of KO mice developed liver tumors,and 58% of these KO mice had multiple tumors.CONCLUSION:Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by AOM in mice.This study strongly suggests that hypoadiponectinemia could be involved in the pathogenesis for colorectal cancer and liver tumor in human subjects.展开更多
文摘Carcinogenesis is a multilevel process characterized by genetic and epigenetic alterations,thus contributing to uncontrolled proliferation that eventually leads to cancer.The process of carcinogenesis involves an intricate dis-orchestration in the expression of both,coding and non-coding sequences and is also dependent on the reprogramming of energy metabolism as both direct and indirect consequence of oncogenic mutations.Dysregulated mitochondrial energetics is an important hallmark of cancer,where cancer cells switch to the glycolytic pathway as an alternate source of energy to support the continuous energy supply needed for their indefinite growth.Even though functional mitochondria are indispensable for cancer cells,cancer cells exhibit different bioenergetics transitions based on the development status of cells undergoing carcinogenesis.Although the role of coding sequences in regulating energy metabolism shift is well studied,the role of non-coding sequences in modulating energy metabolism is still unclear.MicroRNAs(miRNAs),usually present in the nucleus and cytoplasm,have now been reported to localize in the mitochondria also known as,mitochondrial miRNAs(MitomiRs),which can originate either from the nuclear or mitochondrial genome.MitomiRs are reported to be associated with both oncogenic and tumor-suppressive functions.MitomiRs can target metabolic pathway-related protein-coding genes to alter cellular metabolism and promote carcinogenesis.Several mitomiRs like miR-1,miR-133,miR-128,and miR-21 have been reported to be involved in normal physiology,survival,and pathology.Since energy metabolism is one of the most important hallmarks of carcinogenesis and its underlying mechanism involves dysregulation of mitochondrial metabolism,we have tried to collate the importance of mitomiRs in the process of cancer energy metabolism and carcinogenesis.
文摘Spices are defined as any aromatic condiment of plant origin used to alter the flavor and aroma of foods. Besides flavor and aroma, many spices have antioxidant activity, mainly related to the presence in cloves of phenolic compounds, such as flavonoids, terpenoids and eugenol. In turn, the most common uses of gum arabic are in the form of powder for addition to soft drink syrups, cuisine and baked goods, specifically to stabilize the texture of products, increase the viscosity of liquids and promote the leavening of baked products (e.g., cakes). Both eugenol, extracted from cloves, and gum arabic, extracted from the hardened sap of two species of the Acacia tree, are dietary constituents routinely consumed virtually throughout the world. Both of them are also widely used medicinally to inhibit oxidative stress and genotoxicity. The prevention arm of the study included groups: Ia, IIa, IIIa, Iva, V, VI, VII, VIII. Once a week for 20 weeks, the controls received saline s.c. while the experimental groups received DMH at 20 mg/kg s.c. During the same period and for an additional 9 weeks, the animals received either water, 10% GA, EUG, or 10% GA + EUG by gavage. The treatment arm of the study included groups Ib, IIb, IIIb e IVb, IX, X, XI, XII). Once a week for 20 weeks, the controls received saline s.c. while the experimental groups received DMH at 20 mg/kg s.c. During the subsequent 9 weeks, the animals received either water, 10% GA, EUG or 10% GA + EUG by gavage. The novelty of this study is the investigation of their use alone and together for the prevention and treatment of experimental colorectal carcinogenesis induced by dimethylhydrazine. Our results show that the combined use of 10% gum arabic and eugenol was effective, with antioxidant action in the colon, as well as reducing oxidative stress in all colon segments and preventing and treating genotoxicity in all colon segments. Furthermore, their joint administration reduced the number of aberrant crypts and the number of aberrant crypt foci (ACF) in the distal segment and entire colon, as well as the number of ACF with at least 5 crypts in the entire colon. Thus, our results also demonstrate the synergistic effects of 10% gum arabic together with eugenol (from cloves), with antioxidant, antigenotoxic and anticarcinogenic actions (prevention and treatment) at the doses and durations studied, in the colon of rats submitted to colorectal carcinogenesis induced by dimethylhydrazine.
基金The Comprehensive Center for Drug Discovery and Development,Peking University(Grant No.2009ZX09301-010)
文摘The effects of Aspirin on tumor chemoprevention and inhibition have been debated and researched in recent years and its effects on colorectal cancer are quite clear.For breast cancer,however,conclusions are inconsistent and the anti-tumor mechanism of Aspirin is not clear yet.In our study,we used DMBA-induced mammary gland carcinogenesis model to assess the chemoprevention effect of Aspirin on mammary precancerous lesions.After SD rats were treated with Aspirin,the total numbers of precancerous lesion in experimental groups were 16（40 mg/kg Aspirin） and 13（20 mg/kg Aspirin）,while the number in control group was 35.In vitro,we found that Aspirin inhibited cell proliferation in human breast cancer cell line MCF-7 by SRB assay with no apparent cytotoxity under the doses of 10,8,6,4 and 2 mM,the inhibitory rates were 86.96%,54.56%,24.83%,14.24% and 4.49%,respectively.In mechanism research,the results of gene microarray assay demonstrated that 4 mM and 2 mM Aspirin were effective in changing gene expression profile in MCF-7 cells.The expression of cell cycle regulator,cyclin A,was significantly down-regulated under the same doses,while the down-regulation of Cdk2 was only remarkable at 4 mM.Our findings reveal that Aspirin is effective in tumor inhibition during initial phase in rats.In MCF-7 cells,Aspirin reduces cell proliferation without significant cytotoxity and its possible mechanism involves altering tumor-related gene expression and regulating cell cycle process.
基金Supported by the National Natural Science Foundation of China,No.81370500 and No.81770559
文摘AIM To investigate the effects of VSL#3 on tumor formation, and fecal and intestinal mucosal microbiota in azoxymethane/dextran sulfate sodium(AOM/DSS) induced mice model. METHODS C57 BL/6 mice were administered AOM/DSS to develop the ulcerative colitis(UC) carcinogenesis model. Mice were treated with 5-ASA(75 mg/kg/d), VSL#3(1.5 × 109 CFU/d), or 5-ASA combined with VSL#3 by gavage from the day of AOM injection for three months(five days/week). The tumor load was compared in each group, and tumor necrosis factor(TNF-α) and interleukin(IL)-6 levels were evaluated in colon tissue. The stool and intestinal mucosa samples were collected to analyze the differences in the intestinal microbiota by 16 s rDNA sequencing method.RESULTS VSL#3 significantly reduced the tumor load in AOM/DSS-induced mice model and decreased the level of TNF-α and IL-6 in colon tissue. The model group had a lower level of Lactobacillus and higher level of Oscillibacter and Lachnoclostridium in fecal microbiota than the control group. After the intervention with 5-ASA and VSL#3, Bacillus and Lactococcus were increased, while Lachnoclostridium and Oscillibacter were reduced. 5-ASA combined with VSL#3 increased the Lactobacillus and decreased the Oscillibacter. The intestinal mucosal microbiota analysis showed a lower level of Bifidobacterium and Ruminococcaceae_UCG-014 and higher level of Al oprevotel a in the model group as compared to the control group. After supplementation with VSL#3, Bifidobacterium was increased. 5-ASA combined with VSL#3 increased the level of both Lachnoclostridium and Bifidobacterium. CONCLUSION VSL#3 can prevent UC-associated carcinogenesis in mice, reduce the colonic mucosal inflammation levels, and rebalance the fecal and mucosal intestinal microbiota.
文摘To investigate the roles of maspin and kai1 expression in tumorigenesis and progression of gastric cancer. Methods Maspin and kai1 expressions were detected in normal gastric mucosa (n = 182), gastric dysplasia (n = 69), and gastric cancer (n = 113) by immunohisto-chemistry. Their expressions were compared with clinicopathological parameters of tumors. Relationship between maspin and kai1 expression was also concerned in gastric cancer. Results The positive rates of maspin expression were 79.8% (145/182), 75.4% (52/69), and 50.4% (57/113) in normal gastric mucosa, gastric dysplasia, and gastric cancer, while those of kai1 expression were 81.9% (149/182), 65.2% (49/69), and 58.4% (66/113) in corresponding tissues respectively. Gastric cancer less frequently expressed maspin than the normal gastric mucosa and gastric dysplasia (P < 0.05), while dysplasia and cancer showed less frequent expression of kai1 than normal mucosa (P < 0.05). Maspin expression showed negative association with invasive depth, metastasis, Lauren’s and histological classifications (P < 0.05), but not with tumor size, Borrmann’s classification, growth pattern or TNM staging (P > 0.05). Kai1 expression was negatively correlated with invasive depth, metastasis, growth pattern, Lauren’s and histo-logical classifications (P < 0.05), but not with tumor size, Borrmann’s classification or TNM staging (P > 0.05). Maspin and kai1 were collaboratively expressed in gastric cancer (P < 0.05). Conclusions Down-regulated expressions of maspin and kai1 play an important role in gastric carcinogenesis. Abnormal expression of maspin and kai1 might have inhibitory effects on invasion and metastasis of gastric cancer and act as an effe-ctive and objective marker to indicate the pathobiological behaviors of gastric cancer.
文摘Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogeneoverexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a varietyof methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play impor-tant roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpGisland methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesisand its relevance of clinical implications.
基金Supported by National Natural Science Foundation of China,No.81072692Natural Science Foundation of Jiangsu Higher Education Institutions of China,No.10KJB320007
文摘AIM:To investigate the expression of interleukin (IL)-22 and its related proteins in biopsy specimens from patients with ulcerative colitis (UC) and UC-related carcinogenesis. METHODS:Biopsy specimens were obtained from patients with inactive (n = 10), mild-to-moderately active (n = 30), severely active (n = 34), initial (n = 30), and chronic UC (n = 44), as well as UC patients with dysplasia (n = 10). Specimens from patients without colonic abnormalities (n = 20) served as controls. Chronic colitis in experimental mice was induced by 2.5% dextran sodium sulfate. The expression levels of IL-22, IL-23, IL-22R1 and phosphorylated STAT3 (p- STAT3) were determined by immunohistochemistry. Bcl-2, cyclin D1 and survivin expression was detected by Western blotting. RESULTS:Patients with active UC had significantly more IL-22, IL-23, IL-22R1 and p-STAT3-positive cells than the patients with inactive UC and normal controls. Furthermore, IL-22 and related proteins were closely related to the severity of the colitis. The expression of IL-22 and IL-22R1 in the tissue of initial UC was stronger than in that of chronic UC, whereas the expression of p-STAT3 was significantly increased in chronic UC tissues. In dysplasia tissues, the expression level of IL-22 and related proteins was higher compared with controls. Mouse colitis model showed that expression of IL-22, IL-22R1 and IL-23 was increased with time, p-STAT3 and the downstream gene were also remarkably upregulated.CONCLUSION:IL-22/STAT3 signaling pathway may be related to UC and UC-induced carcinogenesis and IL-22 can be used as a biomarker in judging the severity of UC.
基金Supported by a Grant-in Aid for Cancer Research from the Japanese Ministry of Health and Welfare. No. 08457170
文摘There appears to be the strong association between Helicobacter pylori （H pylori） and gastric cancer. We reviewed the latest evidences about the effects of H pylori infection on gastric carcinogenesis, classified into epidemiology, dynamics of gastric mucosal changes, DNA damages, virulence factors, host factors, and source of gastric malignancy. Through the considerable progress made in research into virulence factors resulting from differences between Hpylori strains, such as cagA positivity, as well as into host factors, such as gene polymorphisms, a diverse spectrum of H pyloriassociated diseases, including gastric cancer, is beginning to lend itself to elucidation. The impact of the novel hypothesis advanced by Houghton et al proposing bonemarrow derived stem cells （BMDC） as a potential source of gastric malignancy on evolving research remains to be seen with interest. Further progress in research into H pylori eradication as a viable prophylaxis of gastric cancer, as well as into the mechanisms of gastric carcinogenesis, is to be eagerly awaited for the current year and beyond.
基金Supported by grant from United States National Institute of Health(NIH),No.P01 CA87969(to SE Hankinson),No.UM1 CA167552,and No.P01 CA55075(to WC Willett),No.R01 CA137178(to AT Chan),No.P50 CA127003(to CS Fuchs),No.R01 CA151993(to S Ogino)Bennett Family Fund for Targeted Therapies ResearchEntertainment Industry Foundation through National Colorectal Cancer Research Alliance
文摘Toll-like receptors (TLRs) are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins, and signal expression of major histocompatibility complex proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These protein receptors are characterized by their ability to respond to invading pathogens promptly by recognizing particular TLR ligands, including flagellin and lipopolysaccharide of bacteria, nucleic acids derived from viruses, and zymosan of fungi. There are 2 major TLR pathways; one is mediated by myeloid differentiation factor 88 (MYD88) adaptor proteins, and the other is independent of MYD88. The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) and all the TLRs, except TLR3, have been shown to activate this pathway. TLR3 and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling. TLRs play a vital role in activating immune responses. TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis, and are highly likely to be involved in the activation of a number of pathways following cancer therapy. Colorectal cancer (CRC) is one of the most common cancers, and accounts for almost half a million deaths annually worldwide. Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum. The key molecules involved in inflammation-driven carcinogenesis include TLRs. As sensors of cell death and tissue remodeling, TLRs may have a universal role in cancer; stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years. TLRs 3/4/7/8/9 are all validated targets for cancer therapy, and a number of companies are developing agonists and vaccine adjuvants. On the other hand, antagonists may favor inhibition of signaling responsible for autoimmune responses. In this paper, we review TLR signaling in CRC from carcinogenesis to cancer therapy.
基金Supported by Sao Paulo State Research Foundation (FAPESP),No. 2009/07145-9 and 2010/11174-1National Counsel of Technological and Scientific Development (CNPq)Coordination for the Improvement of Higher Level Personnel (CAPES)
文摘Epigenetic alterations contribute significantly to the development and progression of gastric cancer,one of the leading causes of cancer death worldwide.Epigenetics refers to the number of modifications of the chromatin structure that affect gene expression without altering the primary sequence of DNA,and these changes lead to transcriptional activation or silencing of the gene.Over the years,the study of epigenetic processes has increased,and novel therapeutic approaches that target DNA methylation and histone modifications have emerged.A greater understanding of epigenetics and the therapeutic potential of manipulating these processes is necessary for gastric cancer treatment.Here,we review recent research on the effects of aberrant DNA and histone methylation on the onset and progression of gastric tumors and the development of compounds that target enzymes that regulate the epigenome.
基金Supported by grant R08-2003-000-10120-0 from the Basic Research Program of the Korea Science & Engineering Foundation
文摘AIM: Although polysaccharides from Phellinus mushrooms are a well-known material with anti-tumor properties, there is no information about the effect of polysaccharides from Phellinus gilvus (PG) on tumor. The modulating effect of polysaccharides isolated from PG on the benzo(a)pyrene (BaP)-induced forestomach carcinogenesis in ICR female mice was investigated in this study.METHODS: A forestomach carcinogenesis model was established in 40 ICR female mice receiving oral administration of BaP for 4 wk. The mice were randomly assigned to 4 groups (10 each). The mice in each group were treated with sterile water or PG for 4 and 8 wk (SW4,PGW4, SW8, and PGW8 groups). Eight or 12 wk after the first dose of BaP, forestomachs were removed for histopathological and RT-PCR analysis.RESULTS: In histopathological changes and RT-PCR analysis, sterile water-treated mice showed significant hyperplasia of the gastric mucosa with a significantly increased expression of mutant p53 mRNA compared to mice treated with PG for 8 wk.CONCLUSION: Polysaccharides isolated from PG may inhibit BaP-induced forestomach carcinogenesis in mice bydown-regulating mutant p53 expression.
文摘Ulcerative colitis(UC)is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial.UC-associated carcinogenesis presents a different sequence of tumorigenic events compared to those that contribute to the development of sporadic colorectal cancer.In fact,in UC,the early events are represented by oxidative DNA damage and DNA methylation that can produce an inhibition of oncosuppressor genes,mutation of p53,aneuploidy,and microsatellite instability.Hypermethylation of tumor suppressor and DNA mismatch repair gene promoter regions is an epigenetic mechanism of gene silencing that contribute to tumorigenesis and may represent the first step in inflammatory carcinogenesis.Moreover,p53 is frequently mutated in the early stages of UC-associated cancer.Aneuploidy is an independentrisk factor for forthcoming carcinogenesis in UC.Epithelial cell-T-cell cross-talk mediated by CD80 is a key factor in controlling the progression from low to high grade dysplasia in UC-associated carcinogenesis.
基金Development Foundation from Nanjing Board of Health of Jiangsu Province,China,No.ZKX05008
文摘AIM:To characterize the immune responses including local and systemic immunity induced by infection with H pylori,especially with CagA+ H pylori strains and the underlying immunopathogenesis. METHODS:A total of 711 patients with different gastric lesions were recruited to determine the presence of H pylori infection and cytotoxin associated protein A (CagA),the presence of T helper (Th) cells and regulatory T (Treg) cells in peripheral blood mononuclear cells (PBMCs),expression of plasma cytokines,and RNA and protein expression of IFN-γ and IL-4 in gastric biopsies and PBMCs were determined by rapid urease test,urea 14C breath test,immunoblotting test,flow cytometry ,real time RT-PCR and immunohistochemistry. RESULTS:Of the patients,629 (88.47%) were infected with H pylori ; 506 (71.16%) with CagA+ and 123 (17.30%) with CagA- strains. Among patients infected with CagA+ H pylori strains,Th1-mediated cellular immunity was associated with earlier stages of gastric carcinogenesis,while Th2-mediated humoral immunity dominated the advanced stages and was negatively associated with an abundance of Treg cells. However,there was no such tendency in Th1/Th2 polarization in patients infected with CagA- H pylori strains and those without H pylori infection. CONCLUSION:Polarization of Th cell immune responses occurs in patients with CagA+ H pyloriinfection,which is associated with the stage and severity of gastric pathology during the progression of gastric carcinogenesis. This finding provides further evidence for a causal role of CagA+ H pylori infection in the immunopathogenesis of gastric cancer.
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 Korea Science and Engineering Foundation (KOSEF)grant funded by the Korea government (MOST),No.20090081756
文摘Inflammation is a primary defense process against various extracellular stimuli,such as viruses,pathogens,foods,and environmental pollutants.When cells respond to stimuli for short periods of time,it results in acute or physiological inflammation.However,if the stimulation is sustained for longer time or a pathological state occurs,it is known as chronic or pathological inflammation.Several studies have shown that tumorigenesis in the gastrointestinal (GI) tract is closely associated with chronic inflammation,for which abnormal cellular alterations that accompany chronic inflammation such as oxidative stresses,gene mutations,epigenetic changes,and inflammatory cytokines,are shared with carcinogenic processes,which forms a critical cross-link between chronic inflammation and carcinogenesis.Transforming growth factor (TGF)-β is a multi-potent cytokine that plays an important role in regulation of cell growth,apoptosis and differentiation.Most importantly,TGF-β is a strong anti-inflammatory cytokine that regulates the development of effector cells.TGF-β has a suppressive effect on carcinogenesis under normal conditions by inhibiting abnormal cell growth,but on the other hand,many GI cancers originate from uncontrolled cell growth and differentiation by genetic loss of TGF-β signaling molecules or perturbation of TGF-β adaptors.Once a tumor has developed,TGF-β exerts a promoting effect on the tumor itself and stromal cells to enhance cell growth,alter the responsiveness of tumor cells to stimulate invasion and metastasis,and inhibited immune surveillance.Therefore,novel development of therapeutic agents to inhibit TGF-β-induced progression of tumor and to retain its growth inhibitory activities,in addition to anti-inflammatory actions,could be useful in oncology.In this review,we discuss the role of TGF-β in inflammation and carcinogenesis of the GI tract related to abnormal TGF-β signaling.
文摘Hepatocellular carcinoma(HCC) is now the second leading cause of cancer-related deaths globally and many patients have incurable disease. HCC predominantly occurs in the setting of liver cirrhosis and is a paradigm for inflammation-induced cancer. The causes of chronic liver disease promote the development of transformed or premalignant hepatocytes and predisposes to the development of HCC. For HCC to grow and progress it is now clear that it requires an immunosuppressive niche within the fibrogenic microenvironment of cirrhosis. The rationale for targeting this immunosuppression is supported by responses seen in recent trials with checkpoint inhibitors. With the impact of immunotherapy, HCC progression may be delayed and long term durable responses may be seen. This makes the management of the underlying liver cirrhosis in HCC even more crucial as studies demonstrate that measures of liver function are a major prognostic factor in HCC. In this review, we discuss the development of cancer in the setting of liver inflammation and fibrosis, reviewing the microenvironment that leads to this tumourigenic climate and the implications this has for patient management.
基金This work was supported by grants from National Natural Science Foundation of China (30028019) and 973 National Key BasicResearch and Development Program (2002 CB 512906).
文摘To study the role of cyclinD 1 and CDK4 in malignant transformation of human fetal lung diploid fibroblast cell line （2BS） induced by silica. Methods Recombination vectors with sense and antisense pXJ41-cyclinD1 and pXJ41-CDK4 were constructed, and then transfected into the malignant transformed cells induced by silica, respectively. At the same time, pXJ41-neo was used as the control. Results During the progress of the malignant transformation of 2BS cells induced by silica, cyclinD 1 and CDK4 were overexpressed. Antisense RNA suppressed cyclinD 1 and CDK4 gene expression in the antisense pXJ41-cyclinD1 and pXJ41-CDK4 transfected cells. Antisense RNA led to cell cycle arrest, resulting in lengthened G1 phase （the percentages of cells in the G1 phase changed from 45.1% to 52.7% and 58.0% for cyclinD1 and CDK4 transfected cells, respectively）, and eventually attenuated the increase of the proliferation of malignant transformed cells induced by silica. Compared with malignant transformed cells induced by silica, cells transfected with antisense pXJ41-cyclinD1 and pXJ41-CDK4 showed obviously reduced growth rates. On the 8th day, the suppression rates were 58.69 and 77.43% （the growth rate of malignant transformed cells induced by silica was 100%）, doubling time changed from 21.0 h to 31.4 h and 21.0 h to 42.7 h, respectively, the growth capacities on soft agar of cells transfected by antisense pXJ41-cyclinD1 and pXJ41-CDK4 decreased obviously. Conclusion CyclinD 1 and CDK4 play an important role in maintaining transformed phenotype of the cancer cells.
基金Supported by A grant from Foundation for Promotion of Cancer Research in Japan
文摘AIM:To investigate the causal relationship between hypoadiponectinemia and colorectal carcinogenesis in in vivo experimental model,and to determine the con-tribution of adiponectin defi ciency to colorectal cancer development and proliferation.METHODS:We examined the influence of adiponectin defi ciency on colorectal carcinogenesis induced by the administration of azoxymethane(AOM)(7.5 mg/kg,in-traperitoneal injection once a week for 8 wk),by using adiponectin-knockout(KO) mice.RESULTS:At 53 wk after the fi rst AOM treatment,KOmice developed larger and histologically more progres-sive colorectal tumors with greater frequency com-pared with wild-type(WT) mice,although the tumor incidence was not different between WT and KO mice.KO mice showed increased cell proliferation of colorec-tal tumor cells,which correlated with the expression levels of cyclooxygenase-2(COX-2) in the colorectal tumors.In addition,KO mice showed higher incidence and frequency of liver tumors after AOM treatment.Thirteen percent of WT mice developed liver tumors,and these WT mice had only a single tumor.In contrast,50% of KO mice developed liver tumors,and 58% of these KO mice had multiple tumors.CONCLUSION:Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by AOM in mice.This study strongly suggests that hypoadiponectinemia could be involved in the pathogenesis for colorectal cancer and liver tumor in human subjects.
