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A Protective Role by Interleukin-17F in Colon Tumorigenesis  [PDF]
Zan Tong, Xuexian O. Yang, Huichao Yan, Weihuang Liu, Xiaoyin Niu, Yun Shi, Wenfeng Fang, Bing Xiong, Yu Wan, Chen Dong
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034959
Abstract: Interleukin-17F (IL-17F), produced by Th17 cells and other immune cells, is a member of IL-17 cytokine family with highest homology to IL-17A. IL-17F has been shown to have multiple functions in inflammatory responses. While IL-17A plays important roles in cancer development, the function of IL-17F in tumorigenesis has not yet been elucidated. In the current study, we found that IL-17F is expressed in normal human colonic epithelial cells, but this expression is greatly decreased in colon cancer tissues. To examine the roles of IL-17F in colon cancer, we have used IL-17F over-expressing colon cancer cell lines and IL-17F-deficient mice. Our data showed decreased tumor growth of IL-17F-transfected HCT116 cells comparing to mock transfectants when transplanted in nude mice. Conversely, there were increased colonic tumor numbers and tumor areas in Il-17f?/? mice than those from wild-type controls after colon cancer induction. These results indicate that IL-17F plays an inhibitory role in colon tumorigenesis in vivo. In IL-17F over-expressing tumors, there was no significant change in leukocyte infiltration; instead, we found decreased VEGF levels and CD31+ cells. While the VEGF levels were increased in the colon tissues of Il-17f?/? mice with colon cancer. Together, our findings demonstrate a protective role for IL-17F in colon cancer development, possibly via inhibiting tumor angiogenesis.
Upregulated CD133 expression in tumorigenesis of colon cancer cells  [cached]
Zhi-Li Yang,Qi Zheng,Jun Yan,Ye Pan
World Journal of Gastroenterology , 2011,
Abstract: AIM: To analyze the upregulated CD133 expression in tumorigenesis of primary colon cancer cells.METHODS: Upregulated CD133 expression in tumorigenesis of colorectal cancer cell lines (Lovo, Colo205, Caco-2, HCT116 and SW620) was analyzed by flow cytometry. Human colon cancer tissue samples were stained with anti-human CD133. SW620 cells were sorted according to the CD133 expression level measured by fluorescence-activated cell sorting. Spheroids of colorectal cancer cells were cultured with the hanging drop. Expression of CD133 and Lgr5 in spheroids of colorectal cancer cells and monolayer culture was detected by RT-qPCR. Spheroids of colorectal cancer cells were analyzed using anti-human CD133 with immunohistochemical staining.RESULTS: CD133 antigen was expressed in colorectal cancer cell lines (Lovo, Colo205, Caco-2, HCT116 and SW620) as well as in primary and metastatic human colon cancer tissues. However, the CD133 was differently expressed in these cell lines and tissues. The expression levels of CD133 and Lgr5 were significantly higher in spheroids of parental, CD133hi and CD133- cells than in their monolayer culture at the mRNA level (P < 0.05). Immunohistochemical staining of spheroids of CD133- cells showed that CD133 was highly expressed in colorectal cancer cell lines.CONCLUSION: Upregulated CD133 expression plays a role in tumorigenesis colorectal cancer cells, which may promote the expression of other critical genes that can drive tumorigenesis.
ICAD Deficiency in Human Colon Cancer and Predisposition to Colon Tumorigenesis: Linkage to Apoptosis Resistance and Genomic Instability  [PDF]
Youssef Errami, Hassan Brim, Karine Oumouna-Benachour, Mustapha Oumouna, Amarjit S. Naura, Hogyoung Kim, Jihang Ju, Christian J. Davis, Jong G. Kim, Hassan Ashktorab, Kenneth Fallon, Ming Xu, Jianhua Zhang, Luis Del Valle, A. Hamid Boulares
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057871
Abstract: We previously showed that DNA fragmentation factor, which comprises a caspase-3-activated DNase (CAD) and its inhibitor (ICAD), may influence the rate of cell death by generating PARP-1-activating DNA breaks. Here we tested the hypothesis that ICAD-deficient colon epithelial cells exhibiting resistance to death stimuli may accumulate additional genetic modifications, leading to a tumorigenic phenotype. We show that ICAD deficiency may be associated with colon malignancy in humans. Indeed, an examination of ICAD expression using immunohistochemistry in an array of both colon cancer and normal tissues revealed that ICAD expression levels were severely compromised in the cancerous tissues. Upon DNA damage caused by a low dose of irradiation, ICAD cells acquire a tumorigenic phenotype. Colon epithelial cells derived from ICAD mice showed a significant resistance to death induced by the colon carcinogen dimethylhydrazine in vitro and in mice. Such resistance was associated with a decrease in PARP-1 activation. In an animal model of dimethylhydrazine-induced colon tumorigenesis, ICAD?/? mice developed significantly higher numbers of tumors with markedly larger sizes than the wild-type counterparts. Interestingly, the phenotype of the ICAD?/? mice was not associated with a significant increase in the precancerous aberrant crypt foci suggesting a potential link to tumor progression rather than initiation. More importantly, ICAD deficiency was associated with severe genomic instability as assessed by array comparative genomic hybridization. Such genomic instability consisted most prominently of amplifications but with sizable deletions as compared to the wild-type counterparts affecting several cancer-related genes including RAF-1, GSN, LMO3, and Fzd6 independently of p53. Altogether, our results present a viable case for the involvement of ICAD deficiency in colon carcinogenesis and show that apoptosis and genomic instability may comprise the means by which such deficiency may contribute to the process of increasing susceptibility to carcinogen-induced tumorigenesis.
The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth  [PDF]
Ron Firestein, Gil Blander, Shaday Michan, Philipp Oberdoerffer, Shuji Ogino, Jennifer Campbell, Anupama Bhimavarapu, Sandra Luikenhuis, Rafael de Cabo, Charles Fuchs, William C. Hahn, Leonard P. Guarente, David A. Sinclair
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002020
Abstract: Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD+-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a β-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates β-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of β-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of β?catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in β?catenin-driven malignancies.
American ginseng suppresses Western diet-promoted tumorigenesis in model of inflammation-associated colon cancer: role of EGFR
Urszula Dougherty, Reba Mustafi, Yunwei Wang, Mark W Musch, Chong-Zhi Wang, Vani J Konda, Anirudh Kulkarni, John Hart, Glyn Dawson, Karen E Kim, Chun-Su Yuan, Eugene B Chang, Marc Bissonnette
BMC Complementary and Alternative Medicine , 2011, DOI: 10.1186/1472-6882-11-111
Abstract: Mice were initiated with azoxymethane (AOM) and, two weeks later fed a Western diet (WD, 20% fat) alone, or WD supplemented with 250-ppm ginseng. After 1 wk, mice received 2.5% dextran sulfate sodium (DSS) for 5 days and were sacrificed 12 wks after AOM. Tumors were harvested and cell proliferation measured by Ki67 staining and apoptosis by TUNEL assay. Levels of EGF-related signaling molecules and apoptosis regulators were determined by Western blotting. Anti-tumor effects of intraperitoneal compound K were examined using a tumor xenograft model and compound K absorption measured following oral ginseng gavage by UPLC-mass spectrometry. Effects of dietary ginseng on microbial diversity were measured by analysis of bacterial 16S rRNA.Ginseng significantly inhibited colonic inflammation and tumorigenesis and concomitantly reduced proliferation and increased apoptosis. The EGFR cascade was up-regulated in colonic tumors and ginseng significantly reduced EGFR and ErbB2 activation and Cox-2 expression. Dietary ginseng altered colonic microbial diversity, and bacterial suppression with metronidazole reduced serum compound K following ginseng gavage. Furthermore, compound K significantly inhibited tumor xenograft growth.Ginseng inhibited colonic inflammation and tumorigenesis promoted by Western diet. We speculate that the ginseng metabolite compound K contributes to the chemopreventive effects of this agent in colonic tumorigenesis.Colon cancer arises from activating mutations in oncogenes and inactivating mutations in tumor suppressor genes. While hereditary forms of this disease arise from germline mutations such as loss of function mutations in the adenomatous polyposis coli (apc) gene, most colon cancers are sporadic and involve somatic mutations in apc or other genes. Environmental especially dietary factors are believed to contribute substantially to the risk of colon cancer development [1,2]. In this regard Western diets that are rich in Western style fats have bee
Dark Aberrant Crypt Foci with activated Wnt pathway are related to tumorigenesis in the colon of AOM-treated rat
Qing Lu, Bo Jiang, Chen Lin, Tao Shan
Journal of Experimental & Clinical Cancer Research , 2008, DOI: 10.1186/1756-9966-27-26
Abstract: Sixty wistar rats were sacrificed at different time points after exposure to azoxymethane and the colons were stained with methylene blue for stereomicroscopic analysis.We found two types of early lesions: classic ACF and dark ACF. Dark ACF were characterized by dark blue staining, mildly enlarged or small compressed crypts that are not elevated from the surrounding epithelium. Large dark ACF and nascent tumors displayed the same surface morphology. Furthermore, dark ACF grew significantly faster than classic ACF and showed dysplasia without hyperplasia. In contrast, classic ACF showed hyperplasia without dysplasia. Dark ACF has significant higher expression rate of β-catenin (100%) and MMP-7 (81.82%) compared with the expression of β-catenin and MMP-7 in classic ACF (4.84% and 7.87%, respectively).Our data indicated that dark ACF is closely related to tumorigenesis while classic ACF is not. Furthermore, Wnt signal pathway was activated during the early period of dark ACF.Aberrant crypt foci (ACF) were first described by Bird and Good. The lesion of ACF is composed of the enlarged crypts that are slightly elevated above the surrounding mucosa and the densely stained crypts with methylene blue [1]. ACF are considered as putative preneoplastic lesions of the colon in both humans and experimental animals [2,3].Although ACF may share some morphologic, genetic, and biochemical features with colonic tumors [4-7], conflicting evidence has also been reported. For example, mutations in the K-ras gene are relatively common in human ACF, but are only detected at a relatively late stage of colon cancer [8-11]. In rat models, although hundreds of ACF are induced per animal by azoxymethane (AOM), and K-ras mutations are frequently observed in those ACF, only a few colon tumors are observed per animal [12-14]. In azoxymethane/dimethylhydrazine-treated rats and in patients with sporadic colorectal cancer, the number of tumors is minuscule compared with the large number of ACF [15],
Dietary exposure to soy or whey proteins alters colonic global gene expression profiles during rat colon tumorigenesis
Rijin Xiao, Thomas M Badger, Frank A Simmen
Molecular Cancer , 2005, DOI: 10.1186/1476-4598-4-1
Abstract: Male Sprague Dawley rats, fed one of the three purified diets, were studied at 40 weeks after AOM injection and when tumors had developed in some animals of each group. Total RNA, purified from non-tumor tissue within the proximal half of each colon, was used to prepare biotinylated probes, which were hybridized to Affymetrix RG_U34A rat microarrays containing probes sets for 8799 rat genes. Microarray data were analyzed using DMT (Affymetrix), SAM (Stanford) and pair-wise comparisons. Differentially expressed genes (SPI and/or WPH vs. CAS) were found. We identified 31 induced and 49 repressed genes in the proximal colons of the SPI-fed group and 44 induced and 119 repressed genes in the proximal colons of the WPH-fed group, relative to CAS. Hierarchical clustering identified the co-induction or co-repression of multiple genes by SPI and WPH. The differential expression of I-FABP (2.92-, 3.97-fold down-regulated in SPI and WPH fed rats; P = 0.023, P = 0.01, respectively), cyclin D1 (1.61-, 2.42-fold down-regulated in SPI and WPH fed rats; P = 0.033, P = 0.001, respectively), and the c-neu proto-oncogene (2.46-, 4.10-fold down-regulated in SPI and WPH fed rats; P < 0.001, P < 0.001, respectively) mRNAs were confirmed by real-time quantitative RT-PCR. SPI and WPH affected colonic neuro-endocrine gene expression: peptide YY (PYY) and glucagon mRNAs were down-regulated in WPH fed rats, whereas somatostatin mRNA and corresponding circulating protein levels, were enhanced by SPI and WPH.The identification of transcripts co- or differentially-regulated by SPI and WPH diets suggests common as well as unique anti-tumorigenesis mechanisms of action which may involve growth factor, neuroendocrine and immune system genes. SPI and WPH induction of somatostatin, a known anti-proliferative agent for colon cancer cells, would inhibit tumorigenesis.Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer-related mortality in the U.S. [1,2]. Estim
Tissue-Specific Effects of Reduced β-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium  [PDF]
Ying Feng?,Naoya Sakamoto?,Rong Wu?,Jie-yu Liu?,Alexandra Wiese?,Maranne E. Green?,Megan Green?,Aytekin Akyol?,Badal C. Roy?,Yali Zhai
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005638
Abstract: Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the β-catenin protein pool that functions as a co-activator of T cell factor (TCF)-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding β-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models. Concurrent somatic inactivation of one Ctnnb1 allele, dramatically inhibited Apc mutation-induced colon polyposis and greatly extended Apc-mutant mouse survival. Ctnnb1 hemizygous dose markedly inhibited increases in β-catenin levels in the cytoplasm and nucleus following Apc inactivation in colon epithelium, with attenuated expression of key β-catenin/TCF-regulated target genes, including those encoding the EphB2/B3 receptors, the stem cell marker Lgr5, and Myc, leading to maintenance of crypt compartmentalization and restriction of stem and proliferating cells to the crypt base. A critical threshold for β-catenin levels in TCF-regulated transcription was uncovered for Apc mutation-induced effects in colon epithelium, along with evidence of a feed-forward role for β-catenin in Ctnnb1 gene expression and CTNNB1 transcription. The active β-catenin protein pool was highly sensitive to CTNNB1 transcript levels in colon cancer cells. In mouse ovarian endometrioid adenocarcinomas (OEAs) arising from Apc- and Pten-inactivation, while Ctnnb1 hemizygous dose affected β-catenin levels and some β-catenin/TCF target genes, Myc induction was retained and OEAs arose in a fashion akin to that seen with intact Ctnnb1 gene dose. Our findings indicate Ctnnb1 gene dose exerts tissue-specific differences in Apc mutation-instigated tumorigenesis. Differential expression of selected β-catenin/TCF-regulated genes, such as Myc, likely underlies context-dependent effects of Ctnnb1 gene dosage in tumorigenesis.
Protection Against Azoxymethane-Induced Mouse Colon Tumorigenesis by Wheat Bran and Black Tea  [PDF]
Abdel-Moneim M. Abdel-Galil
Pakistan Journal of Biological Sciences , 2002,
Abstract: Black tea (BT) and wheat bran (WB) were evaluated for their ability to modulate azoxymethane (AOM) - induced colon tumors in SWA mice. Female SWA mice, 6 weeks of age, were allocated in two separate experiments. Two dose levels of BT (4 and 8 mg tea solids/ml in drinking fluid) and WB (10 and 20% in basal diet) were administered during either the initiation and postinitiation (experiment 1) or postinitiation (experiment 2) stages of colon carcinogenesis. In experiment 1, the oral administration of 4mg BT insignificantly reduced the incidence and multiplicity of colon adenomas and adenocarcinomas ; whereas, 8mg BT significantly reduced the incidence and multiplicity of colon adenomas. Supplementing the diet with 10 or 20% WB significantly (P< 0.05) reduced, in a dose-dependent manner, the incidence, multiplicity and volume of adenomas and adenocarcinomas as compared to AOM alone group. Administration of 4 or 8 mg BT inhibited the number of colon adenomas per mouse by 8 and 28% and the number of colon carcinomas per mouse by 10 or 19%, respectively. Oral administration of 10 or 20% WB significantly inhibited the number of adenomas per mouse by 67 and 71% and the number of carcinomas per mouse by 48 and 56%, respectively (experiment 1). Administration of 4 or 8mg BT during the postinitiation phase (experiment 2) did not significantly alter the incidence and multiplicity of colon tumors (adenomas or adenocarcinomas). On the other hand, supplementing diet with 10 or 20 % WB significantly (P> 0.05) reduced the incidence, multiplicity and volume of tumors/mouse. Low and high doses of BT insignificantly inhibited the number of adenomas per mouse by 8 and 10 % and the number of adenocarcinomas per mouse by 8 and 12%, respectively. In contrast, 10 or 20 % WB markedly inhibited the number of adenomas per mouse by 32 and 49 % and the number of carcinomas per mouse by 27 and 39 %, respectively. In this protocol, supplementing diets with WB provided a significant protection against AOM-induced colon tumors when applied during either the initiation and postinitiation or the postinitiation stages, whereas, BT was slightly effective in modulating colon carcinogenesis under the same experimental conditions.
Intestinal Iron Homeostasis and Colon Tumorigenesis  [PDF]
Xiang Xue,Yatrik M. Shah
Nutrients , 2013, DOI: 10.3390/nu5072333
Abstract: Colorectal cancer (CRC) is the third most common cause of cancer-related deaths in industrialized countries. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Iron is an essential nutrient for cell growth. Iron overload caused by hereditary mutations or excess dietary iron uptake has been identified as a risk factor for CRC. Intestinal iron is tightly controlled by iron transporters that are responsible for iron uptake, distribution, and export. Dysregulation of intestinal iron transporters are observed in CRC and lead to iron accumulation in tumors. Intratumoral iron results in oxidative stress, lipid peroxidation, protein modification and DNA damage with consequent promotion of oncogene activation. In addition, excess iron in intestinal tumors may lead to increase in tumor-elicited inflammation and tumor growth. Limiting intratumoral iron through specifically chelating excess intestinal iron or modulating activities of iron transporter may be an attractive therapeutic target for CRC.
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