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The nuclear receptor is an emerging therapeutic target in various human diseases. Vitamin D receptor (VDR), a nuclear receptor,
mediates the biological functions of vitamin D. Classically, vitamin D is recognized as an essential contributor to mineral
and bone homeostasis. Increasing evidence demonstrates that vitamin D is involved in inflammatory responses. Persistent intestinal
inflammation is associated with colon cancer. This review focuses on vitamin D and VDR in inflammatory bowel diseases and
colon cancer. We place emphasis on the regulatory roles of vitamin D/VDR in inflammation, enteric bacteria, and tumorigenesis.
We summarize the signaling pathways regulated by VDR in intestinal homeostasis. Finally, we discuss the potential application
of the insights gleaned from these findings to personalized therapies in chronic inflammation and colon cancer. 相似文献
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Seung Won Kim Ki Cheong Park Soung Min Jeon Tak Bum Ohn Tae Il Kim Won Ho Kim Jae Hee Cheon 《Cellular oncology (Dordrecht)》2013,36(2):169-178
Background
Although it has been well established that galectin-4 is selectively expressed by intestinal epithelial cells, the role of galectin-4 in colorectal cancer (CRC) development is, as yet, poorly understood. Here, we aimed to explore the role of galectin-4 in CRC development, both in vitro and in vivo.Methods
Galectin-4 expression was investigated in tissue specimens from patients with adenoma, carcinoma and ulcerative colitis (UC) using immunohistochemistry. Colorectal cancer-derived HT-29 cells, in which galectin-4 expression was knocked down, were established using shRNA. mRNA and protein expression levels of galectin-4 and several downstream cancer-related genes were analyzed using RT-PCR, qPCR array, Western blotting, and immunofluorescence assays. To investigate the effect of galectin-4 expression abrogation on tumorigenesis in vivo, xenograft assays were performed.Results
Immunohistochemistry analyses showed high expression levels of galectin-4 in normal colon mucosa tissues. Conversely, the expression levels of galectin-4 were significantly lower in CRC samples and its precursor lesions with dysplasia or inflammation. We found that shRNA-mediated galectin-4 silencing increases cell proliferation and, concomitantly, activates NF-κB and STAT3 signaling along with IL-6 up-regulation. In addition, we found that shRNA-mediated galectin-4 silencing promotes the expression of NF-κB target genes and other cancer-related genes and, concomitantly, enhances the in vivo growth of xenografts.Conclusions
We show that abrogation of galectin-4 expression promotes cancer cell proliferation and, for the first time, provide evidence that down-regulation of galectin-4 elicits tumor promotion in vitro and in vivo through activation of IL-6/NF-κB/STAT3 signaling. 相似文献6.
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Intestinal injury or chronic inflammation induce cytokines that promote crypt regeneration and mucosal repair. If excessive or prolonged, such mechanisms may increase colon cancer risk. Factors that terminate or limit cytokine action in intestinal epithelial cells (IEC) may protect against crypt hyperplasia and neoplasia. We hypothesized that suppressor of cytokine signaling-3 (SOCS3) is such a factor. Mice with Vilin-promoter/Cre-recombinase (VC)-mediated IEC-specific SOCS3 gene disruption (VC/HO), WT/HO littermates with floxed but intact SOCS3 genes and VC/WT mice were studied. Colon was examined after acute dextran sodium sulfate (DSS)-induced mucosal injury or after azoxymethane (AOM) and chronic DSS. Signaling pathways were examined in colon, cultured IEC or colon cancer cell lines. VC/HO mice showed no basal phenotype. After acute DSS, VC/HO exhibited enhanced crypt proliferation and crypt hyperplasia and reduced transforming growth factor (TGF) beta expression in colon. Inflammation and mucosal damage were similar across genotypes. Following AOM/DSS, VC/HO mice had increased size, number and load of colonic tumors and increased STAT3 and nuclear factor-kappa B (NF-kappaB) activation in colon. In vitro, SOCS3 overexpression reduced proliferation, IL-6-mediated STAT3 activation and tumor necrosis factor (TNF) alpha-mediated NF-kappaB activation. We conclude that cytokine induction of SOCS3 normally provides an intrinsic mechanism to limit injury-induced crypt hyperproliferation and inflammation-associated colon cancer by regulating both STAT3 and NF-kappaB pathways. 相似文献
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Chalcones and its derivatives are reported to exhibit anti-cancer effects in several cancer cell lines, including colon cancer cells. However, the in vivo anticancer effects and associated mechanisms of chalcones against intestinal tumorigenesis currently remain unclear. The aim of the present study was to investigate the chemopreventive effect of a chalcone derivative, 4′-hydroxychalcone (4-HC), in a transgenic adenomatous polyposis coli multiple intestinal neoplasia mouse model (ApcMin) of spontaneous intestinal adenomas. ApcMin mice were fed 4-HC (10 mg/kg/day) or the vehicle control by oral gavage starting at 8 weeks of age, and were sacrificed at 20 weeks. The administration of 4-HC significantly decreased the number of colon adenomas by 45% and the size of colon adenomas by 35% compared with the respective controls. Similarly, the number of adenomas in the distal small intestine (DSI) and proximal small intestine also decreased by 35 and 33%, respectively, in 4-HC-treated mice, and adenoma size in the DSI decreased by 39% compared with the respective controls. Treatment with 4-HC strongly decreased proliferation in colon and DSI adenomas, as detected by immunofluorescence staining with the proliferation marker protein Ki-67, and promoted apoptosis in colon adenomas, as detected by TUNEL immunofluorescence staining. In addition, decreased mRNA expression of β-catenin target genes, including c-Myc, Axin2 and CD44, in colon adenomas of 4-HC-treated animals demonstrated the involvement of the Wnt/β-catenin signaling pathway in the initiation and progression of colon neoplasms. Treatment with 4-HC also decreased the protein levels of β-catenin in colon adenomas, as demonstrated by immunofluorescence staining. The results suggested that 4-HC may be a promising candidate for the chemoprevention of intestinal tumorigenesis, and further investigations are required to evaluate its clinical utility. 相似文献
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Gankyrin induces STAT3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma 下载免费PDF全文
Toshiharu Sakurai Norihisa Yada Satoru Hagiwara Tadaaki Arizumi Kosuke Minaga Ken Kamata Mamoru Takenaka Yasunori Minami Tomohiro Watanabe Naoshi Nishida Masatoshi Kudo 《Cancer science》2017,108(10):1996-2003
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Michaela Lang Maximilian Baumgartner Aleksandra Rożalska Adrian Frick Alessandra Riva Michael Jarek David Berry Christoph Gasche 《International journal of cancer. Journal international du cancer》2020,147(8):2316-2326
Colorectal cancer is a multifactorial disease involving inherited DNA mutations, environmental factors, gut inflammation and intestinal microbiota. Certain germline mutations within the DNA mismatch repair system are associated with Lynch syndrome tumors including right-sided colorectal cancer with mucinous phenotype and presence of an inflammatory infiltrate. Such tumors are more often associated with bacterial biofilms, which may contribute to disease onset and progression. Inflammatory bowel diseases are also associated with colorectal cancer and intestinal dysbiosis. Herein we addressed the question, whether inflammation can aggravate colorectal cancer development under mismatch repair deficiency. MSH2loxP/loxP Vill-cre mice were crossed into the IL-10−/− background to study the importance of inflammation and mucosal bacteria as a driver of tumorigenesis in a Lynch syndrome mouse model. An increase in large bowel tumorigenesis was found in double knockout mice both under conventional housing and under specific pathogen-free conditions. This increase was mostly due to the development of proximal tumors, a hotspot for tumorigenesis in Lynch syndrome, and was associated with a higher degree of inflammation. Additionally, bacterial invasion into the mucus of tumor crypts was observed in the proximal tumors. Inflammation shifted fecal and mucosal microbiota composition and was associated with enrichment in Escherichia-Shigella as well as Akkermansia, Bacteroides and Parabacteroides genera in fecal samples. Tumor-bearing double knockout mice showed a similar enrichment for Escherichia-Shigella and Parabacteroides. Lactobacilli, Lachnospiraceae and Muribaculaceae family members were depleted upon inflammation. In summary, chronic inflammation aggravates colonic tumorigenesis under mismatch repair deficiency and is associated with a shift in microbiota composition. 相似文献
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Ghrelin administration suppresses inflammation‐associated colorectal carcinogenesis in mice 下载免费PDF全文
Makiko Kawaguchi Ai Kanemaru Tsuyoshi Fukushima Koji Yamamoto Hiroyuki Tanaka Yukihiro Haruyama Hiroshi Itoh Nobuhiro Matsumoto Kenji Kangawa Masamitsu Nakazato Hiroaki Kataoka 《Cancer science》2015,106(9):1130-1136
Ghrelin is a 28-amino-acid peptide that stimulates the release of pituitary growth hormone. Because of its orexigenic effects, ghrelin is being developed as a therapeutic option for postoperative support and treatment of anorexia-cachexia syndrome of cancer patients. However, ghrelin has a multiplicity of physiological functions, and it also affects cell proliferation. Therefore, the effects of ghrelin administration on carcinogenesis and cancer progression in patients susceptible to cancer should be clarified. In this study, we examined the effects of ghrelin on cancer promotion in vivo using murine intestinal carcinogenesis models. Intestinal tumorigenesis was examined to determine the effects of either exogenous ghrelin administration or ghrelin deficiency following deletion of the Ghrl gene. Two murine intestinal tumorigenesis models were used. The first was the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced inflammation-associated colon carcinogenesis model and the second was the ApcMin/+ genetic cancer susceptibility model. In AOM/DSS-treated mice, administration of ghrelin significantly suppressed tumor formation in the colon. In contrast, ghrelin administration did not affect the number of intestinal tumors formed in ApcMin/+ mice. The absence of endogenous ghrelin did not affect the incidence of intestinal tumors in either AOM/DSS-treated mice or ApcMin/+ mice, though tumor size tended to be larger in Ghrl−/− colons in the AOM/DSS model. No tumor-promoting effect was observed by ghrelin administration in either tumorigenesis model. In summary, this study provides in vivo experimental evidence for the usefulness of ghrelin administration in the chemoprevention of inflammation-associated colorectal carcinogenesis and may suggest its safety in patients under colitis-associated cancer susceptibility conditions. 相似文献
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Bogi Pratomo WibowoHandono KalimHusnul KhotimahHidayat SujutiReza Ardi Wibowo 《Asian Pacific journal of cancer prevention》2023,24(1):163-170
Objective: Colorectal cancer (CRC) is one of the main causes of morbidity and mortality due to cancer. The purpose of this in-silico study was to examine the relationship of chronic infection mechanisms caused by Salmonella Anti virulence agent A (AvrA) to gene mutations in the carcinogenic process of CRC. Methods: Gene expression data on the mouse colon was obtained from the GSE22215 dataset | Gene Expression Omnibus (GEO). Adjusted p-value was calculated using Benjamini & Hochberg False Discovery Rate (FDR<0.01). Gene expression in colon adenocarcicoma tumors was obtained from The Cancer Genome Atlas’s (TCGA) Genomic Data Commons (GDC) dataset containing 458 colon tumor samples. Result: Expressions of MLH1, MSH2, EPCAM, APC, and PMS2 in cases of colon adenocarcinoma tumor showed a correlation with genes that underwent changes due to Salmonella AvrA infection. Among the gens of interest, EPCAM was the gene that had the highest correlation compared to other genes (MLH1, MSH2, APC, and PMS2) (n= 514, Gene r-p value < 0.01 =22355). There were 514 genes that had a correlation with cases of AvrA infection. Tumor Necrosis Factor (TNF), which is a gene that is upregulated in AvrA infection and correlates negatively with EPCAM, had the highest BC value compared to other gens (p= 0.0000768). Survival probability showed that EPCAM was highly expressed and it can increase survival time. In addition to TNF, our study indicated that IL1B (p= 0.000419), S100A8 (p= 2.02E-05), S100A9 (p=0.000419) correlated with the gene of interest. Conclusion: Late Salmonella AvrA infection affects the expression of genes involved in inflammation in colorectal cancer samples. 相似文献
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Young Ho Yun Min Kyung Lim Young-Joo Won Sang Min Park Yoon Jung Chang Sang Woo Oh Soon Ae Shin 《BMC cancer》2008,8(1):1-17
Background
The Ras-dependent ERK1/2 MAP kinase signaling pathway plays a central role in cell proliferation control and is frequently activated in human colorectal cancer. Small-molecule inhibitors of MEK1/MEK2 are therefore viewed as attractive drug candidates for the targeted therapy of this malignancy. However, the exact contribution of MEK1 and MEK2 to the pathogenesis of colorectal cancer remains to be established.Methods
Wild type and constitutively active forms of MEK1 and MEK2 were ectopically expressed by retroviral gene transfer in the normal intestinal epithelial cell line IEC-6. We studied the impact of MEK1 and MEK2 activation on cellular morphology, cell proliferation, survival, migration, invasiveness, and tumorigenesis in mice. RNA interference was used to test the requirement for MEK1 and MEK2 function in maintaining the proliferation of human colorectal cancer cells.Results
We found that expression of activated MEK1 or MEK2 is sufficient to morphologically transform intestinal epithelial cells, dysregulate cell proliferation and induce the formation of high-grade adenocarcinomas after orthotopic transplantation in mice. A large proportion of these intestinal tumors metastasize to the liver and lung. Mechanistically, activation of MEK1 or MEK2 up-regulates the expression of matrix metalloproteinases, promotes invasiveness and protects cells from undergoing anoikis. Importantly, we show that silencing of MEK2 expression completely suppresses the proliferation of human colon carcinoma cell lines, whereas inactivation of MEK1 has a much weaker effect.Conclusion
MEK1 and MEK2 isoforms have similar transforming properties and are able to induce the formation of metastatic intestinal tumors in mice. Our results suggest that MEK2 plays a more important role than MEK1 in sustaining the proliferation of human colorectal cancer cells. 相似文献17.
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Adi Binder Gallimidi Stuart Fischman Brurya Revach Raanan Bulvik Alina Maliutina Ariel M. Rubinstein Gabriel Nussbaum Michael Elkin 《Oncotarget》2015,6(26):22613-22623
Oral squamous cell carcinoma (OSCC) is a lethal disease whose incidence is increasing. Epidemiologic studies demonstrate an association between periodontitis and oral cancer, and periodontal pathogens are implicated in the pathogenesis of numerous disorders, including rheumatoid arthritis, cardiovascular diseases, diabetes and gastrointestinal malignancies. Nevertheless, a causal role for periodontal pathogens in OSCC has not been shown, partly due to the lack of an appropriate animal model. Here, utilizing a newly-established murine model of periodontitis-associated oral tumorigenesis, we report that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect. Our results indicate that periodontal pathogens P. gingivalis and F. nucleatum stimulate tumorigenesis via direct interaction with oral epithelial cells through Toll-like receptors. Furthermore, oral pathogens stimulate human OSCC proliferation and induce expression of key molecules implicated in tumorigenesis. To the best of our knowledge, these findings represent the first demonstration of a mechanistic role for oral bacteria in chemically induced OSCC tumorigenesis. These results are highly relevant for the design of effective prevention and treatment strategies for OSCC. 相似文献
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