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Frontiers in Oncology 2023Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, highlighting the pressing need to address its development. Inflammation plays a crucial role...
BACKGROUND
Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, highlighting the pressing need to address its development. Inflammation plays a crucial role in augmenting the risk of CRC and actively contributes to all stages of tumorigenesis. Consequently, targeting early inflammatory responses in the intestinal tract to restore homeostasis holds significant potential for preventing and treating CRC. Fibrinogen C domain-containing 1 (FIBCD1), a chitin-binding transmembrane protein predominantly found on human intestinal epithelial cells (IECs), has garnered attention in previous research for its ability to effectively suppress inflammatory responses and promote tissue homeostasis at mucosal barriers.
METHODS
In this study, we investigated the role of FIBCD1 in CRC development using transgenic mice that mimic human expression of FIBCD1 at the intestinal mucosal barrier. To model aspects of CRC, we employed the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. Additionally, we examined the expression pattern of FIBCD1 in surgical specimens obtained from human CRC patients by immunohistochemical methods. By accessing public data repositories, we further evaluated FIBCD1 expression in colon adenocarcinoma and explored survival outcomes associated with FIBCD1 expression.
RESULTS
Here, we demonstrate that FIBCD1 substantially impacts CRC development by significantly reducing intestinal inflammation and suppressing colorectal tumorigenesis in mice. Furthermore, we identify a soluble variant of FIBCD1 that is significantly increased in feces during acute inflammation. Finally, we demonstrate increased expression of FIBCD1 by immunohistochemistry in human CRC specimens at more developed tumor stages. These results are further supported by bioinformatic analyses of publicly available repositories, indicating increased FIBCD1 expression in tumor tissues, where higher expression is associated with unfavorable prognosis.
CONCLUSION
Collectively, these findings suggest that FIBCD1 influences early inflammatory responses in the AOM/DSS model, leading to a reduction in tumor size and burden. The increased expression of FIBCD1 in human CRC samples raises intriguing questions regarding its role in CRC, positioning it as a compelling candidate and novel molecular target for future research.
PubMed: 38090485
DOI: 10.3389/fonc.2023.1280891 -
SAGE Open Medicine 2023Pinostrobin (5-hydroxy-7-methoxyflavanone; PN) is a natural active ingredient with numerous biological activities extensively utilized in tumour chemotherapy. The...
OBJECTIVES
Pinostrobin (5-hydroxy-7-methoxyflavanone; PN) is a natural active ingredient with numerous biological activities extensively utilized in tumour chemotherapy. The present study investigates the chemo-preventive potentials of PN on azoxymethane-mediated colonic aberrant crypt foci in rats.
METHODS
Sprague Dawley rats clustered into five groups, normal control (A) and cancer controls were subcutaneously injected with normal saline and 15 mg/kg azoxymethane, respectively, and nourished on 10% tween 20 and fed on 10% tween 20; reference control (C), injected with 15 mg/kg azoxymethane and injected (intraperitoneal) with 35 mg/kg 5-fluorouracil (5-FU); D and E rat groups received a subcutaneous injection of 15 mg/kg azoxymethane and nourished on 30 and 60 mg/kg of PN, respectively.
RESULTS
The acute toxicity trial showed a lack of any abnormal signs or mortality in rats ingested with 250 and 500 mg/kg of PN. The gross morphology of colon tissues revealed significantly lower total colonic aberrant crypt foci incidence in PN-treated rats than that of cancer controls. Histological examination of colon tissues showed increased aberrant crypt foci availability with bizarrely elongated nuclei, stratified cells and higher depletion of the submucosal glands in cancer controls. PN treatment caused positive modulation of apoptotic (Bax and Bcl-2) proteins and inflammatory cytokines (TNF-α, IL-6 and IL-10). Moreover, rats fed on PN had significantly higher antioxidants (superoxide dismutase) and lower malondialdehyde concentrations in their colon tissue homogenates.
CONCLUSION
The chemoprotective efficiency of PN against azoxymethane-induced aberrant crypt foci is shown by lower aberrant crypt foci values and higher aberrant crypt foci inhibition percentage, possibly through augmentation of genes responsible for apoptotic cascade and inflammations originating from azoxymethane oxidative stress insults.
PubMed: 38078205
DOI: 10.1177/20503121231216585 -
Frontiers in Oncology 2023The chemoattractant receptor, G protein-coupled receptor 15 (GPR15), promotes colon homing of T cells in health and colitis. GPR15 function in colon cancer is largely...
INTRODUCTION
The chemoattractant receptor, G protein-coupled receptor 15 (GPR15), promotes colon homing of T cells in health and colitis. GPR15 function in colon cancer is largely unexplored, motivating our current studies.
METHODS
In human study, immune cells were isolated from tumor tissues and healthy surgical tumor margins (STM), and their proportions as well as expression of GPR15 was analyzed by flow cytometry. In mouse studies, colon cancer was induced in GPR15-deficient (KO) and GPR15-suficient (Het) mice using azoxymethane (AOM) and dextran sulfate sodium (DSS) solution in drinking water. Serial endoscopy was performed in mice to monitor and visualize the distal region of colon. Mice were euthanized 10 weeks after the initial DSS administration, and the colon length and the number of polyps were recorded. Next, we identified the effects of GPR15L on established tumors in the MC38-colorectal cancer (CRC) mouse model. Immune cells were isolated from the mice colons or tumors and assessed by flow cytometry.
RESULTS
Our analysis of human CRC tissue revealed a significant reduction in GPR15 immune cell frequencies in tumors compared to 'tumor-free' surgical margins. Similarly, our data analysis using The Cancer Genome Atlas (TCGA) indicated that lower GPR15 expression is associated with poor survival in human colon cancer. In the AOM/DSS colitis-associated colon cancer model, we observed increased colonic polyps and lower survival in -KO compared to -Het mice. Analysis of immune cell infiltrates in the colonic polyps showed significantly decreased CD8 T cells and increased IL-17 CD4 and IL-17 CD8 T cells in Gpr15-KO than in Het mice. Consistent with a protective role of GPR15, administration of GPR15L to established tumors in the MC38-CRC model increased CD45 cell infiltration, enhanced TNFa expression on CD4+ and CD8+ T cells at the tumor site and dramatically reduced tumor burden.
DISCUSSION
Our findings highlight an important, unidentified role of the GPR15-GPR15L axis in promoting a tumor-suppressive immune microenvironment and unveils a novel, colon-specific therapeutic target for CRC.
PubMed: 38074634
DOI: 10.3389/fonc.2023.1254307 -
Nutrients Dec 2023The edible fungus (ADe) is commonly employed in traditional medicine for intestinal disorders; however, its inhibitory effect on colitis-associated colorectal cancer...
BACKGROUND
The edible fungus (ADe) is commonly employed in traditional medicine for intestinal disorders; however, its inhibitory effect on colitis-associated colorectal cancer (CAC) and the underlying mechanisms remain unexplored. (2) Methods: The inhibitory effect of ADe on CAC was investigated using a mouse model induced by azoxymethane/dextran sulfate sodium.
RESULTS
ADe effectively suppressed the growth and number of intestinal tumors in mice. Intestinal microbiota analyses revealed that ADe treatment increased and while it decreased , , , and . ADe regulated the levels of 2'-deoxyridine, creatinine, 1-palmitoyl lysophosphatidylcholine, and choline in serum. Furthermore, the levels of these metabolites were associated with the abundance of and . ADe up-regulated the free fatty acid receptor 2 and β-Arrestin 2, inhibited the nuclear factor kappa B (NF-κB) pathway, and significantly attenuated the levels of inflammatory cytokines, thereby mitigating the inflammatory in CAC mice.
CONCLUSIONS
The protective effect of ADe in CAC mice is associated with the regulation of intestinal microbiota, which leads to the inhibition of NF-kB pathway and regulation of inflammation.
Topics: Animals; Mice; Colitis; Auricularia; Colitis-Associated Neoplasms; Gastrointestinal Microbiome; Inflammation; NF-kappa B; Dextran Sulfate; Mice, Inbred C57BL; Disease Models, Animal; Colon
PubMed: 38068869
DOI: 10.3390/nu15235011 -
Gut Microbes Dec 2023Aging is a strong risk factor for colorectal cancer (CRC). It is well established that gut microbial dysbiosis can play a role in the etiology of CRC. Although the...
Fecal microbiota transplanted from old mice promotes more colonic inflammation, proliferation, and tumor formation in azoxymethane-treated A/J mice than microbiota originating from young mice.
Aging is a strong risk factor for colorectal cancer (CRC). It is well established that gut microbial dysbiosis can play a role in the etiology of CRC. Although the composition of the gut microbial community changes with age and is reported to become more pro-inflammatory, it is unclear whether such changes are also pro-tumorigenic for the colon. To address this gap, we conducted fecal microbiota transplants (FMT) from young (DY, ~6 wk) and old (DO, ~72 wk) donor mice into young (8 wk) recipient mice that were pre-treated with antibiotics. After initiating tumorigenesis with azoxymethane, recipients were maintained for 19 wk during which time they received monthly FMT boosters. Compared to recipients of young donors (RY), recipients of old donors (RO) had an approximately 3-fold higher prevalence of histologically confirmed colon tumors (15.8 vs 50%, Chi = .03), approximately 2-fold higher proliferating colonocytes as well as significantly elevated colonic IL-6, IL-1β and Tnf-α. Transcriptomics analysis of the colonic mucosa revealed a striking upregulation of mitochondria-related genes in the RO mice, a finding corroborated by increased mitochondrial abundance. Amongst the differences in fecal microbiome observed between DY and DO mice, the genera and were more abundant in DY mice while the genera and were more abundant in DO mice. Amongst recipients, and were higher in RY mice while was higher in RO mice. Differences in fecal microbiota were observed between young and old mice, some of which persisted upon transplant into recipient mice. Recipients of old donors displayed significantly higher colonic proliferation, inflammation and tumor abundance compared to recipients of young donors. These findings support an etiological role for altered gut microbial communities in the increased risk for CRC with increasing age and establishes that such risk can be transmitted between individuals.
Topics: Mice; Animals; Azoxymethane; Gastrointestinal Microbiome; Microbiota; Fecal Microbiota Transplantation; Colonic Neoplasms; Inflammation; Carcinogenesis; Cell Proliferation
PubMed: 38031252
DOI: 10.1080/19490976.2023.2288187 -
Aging Nov 2023Colorectal cancer (CRC) is one of the most common tumors of the digestive tract, with the third-highest incidence and the second-highest mortality rate among all...
Colorectal cancer (CRC) is one of the most common tumors of the digestive tract, with the third-highest incidence and the second-highest mortality rate among all malignant tumors worldwide. However, treatment options for CRC remain limited. As a complementary therapy, acupuncture or electro-acupuncture (EA) has been widely applied in the treatment of various inflammation-related diseases, such as obesity, ulcerative colitis and tumors. Although numerous pre-clinical and clinical studies have investigated the beneficial effects of acupuncture on CRC, the mechanism underlying the therapeutic action of EA is largely unknown. Evidence from previous studies has revealed that SIRT1 participates in CRC progression by activating autophagy-related miRNAs. Using azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colorectal cancer model in mice, we explored whether EA treatment can inhibit inflammation and promote autophagy via the SIRT1/miR-215/Atg14 axis. Our results showed that EA notably alleviated the CRC in mice, by decreasing the tumor number and DAI scores, inflammation, and increasing body weight of mice. Besides, EA increased the expression of SIRT1 and autophagy. Further experiments showed that SIRT1 overexpression downregulated miR-215, and promoted the expression of Atg14, whereas SIRT1 knockdown induced opposite results. In conclusion, EA can ameliorate AOM/DSS-induced CRC through regulating the SIRT1-mediated miR-215/Atg14 axis by suppressing inflammation and promoting autophagy in mice. These findings reveal a potential molecular mechanism underlying the anti-CRC effect of EA indicating that EA is a promising therapeutic candidate for CRC.
Topics: Mice; Animals; Colorectal Neoplasms; Electroacupuncture; Sirtuin 1; Inflammation; MicroRNAs; Autophagy; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38006398
DOI: 10.18632/aging.205236 -
Nutrients Nov 2023Okra flowers are a good source of polysaccharides and flavonoids, with biological activities of anti-inflammatory action and modulation of the gut microbiota....
Okra flowers are a good source of polysaccharides and flavonoids, with biological activities of anti-inflammatory action and modulation of the gut microbiota. Previously, we reported that flavonoid-rich extracts from okra flowers (AFE) presented effective anti-colorectal cancer (CRC) activity in CRC cells as well as xenograft models, but their role in colitis-associated cancer (CAC) is unidentified. In this study, we aimed to evaluate the effects of AFE and APE (polysaccharides extracted from okra flowers) on the CAC symptoms of azoxymethane (AOM)/dextran sodium sulfate (DSS)-intervened mice. The results showed that APE and AFE exert potent efficacy in inhibiting colitis and colorectal tumorigenesis stimulated by AOM/DSS, characterized by decreased colonic shortening, DAI score, and tumor numbers. Compared with the control group, APE/AFE alleviated the microbiota dysbiosis driven by AOM/DSS. In addition, AFE elicited its anticancer activity through regulation of NFκB/IL-6/Stat3, JAK2/Stat3, MAPKs, PI3K/AKT, and Wnt/β-catenin signal transductions in AOM/DSS mice, which was consistent with a vitro model of CT26 cells, while APE treatment exhibited anticancer activity through regulation of Nrf2/IL-6, MAPKs, PI3K/AKT, and Wnt/β-catenin signal transductions in the AOM/DSS mouse model. Collectively, our studies revealed, for the first time, that flavonoids and polysaccharides from okra flowers possess the ability to attenuate colitis and colorectal tumorigenesis, with them having great potential to become promising candidates against CRC.
Topics: Humans; Mice; Animals; Flavonoids; Dextran Sulfate; Abelmoschus; Interleukin-6; Colitis-Associated Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; beta Catenin; Colitis; Azoxymethane; Carcinogenesis; Cell Transformation, Neoplastic; Anticarcinogenic Agents; Disease Models, Animal; Hominidae; Mice, Inbred C57BL; Colorectal Neoplasms
PubMed: 38004214
DOI: 10.3390/nu15224820 -
World Journal of Gastroenterology Oct 2023Phosphatidylinositol-3-kinases (PI3K) is a well-known route in inflammation-related cancer. Recent discovery on PI3K-related genes revealed a potential variant that...
BACKGROUND
Phosphatidylinositol-3-kinases (PI3K) is a well-known route in inflammation-related cancer. Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis (UC) and colorectal cancer (CRC) with colitis-associated cancer (CAC). PI3K/AKT pathway has been recommended as a potential additional therapeutic option for CRC due to its substantial role in modifying cellular processes. Buparlisib is a pan-class I PI3K inhibitor previously shown to reduce tumor growth.
AIM
To investigate the regulation of rs10889677 and the role of buparlisib in the PI3K signaling pathway in CAC pathogenesis.
METHODS
Genomic DNA from 32 colonic samples, including CAC ( = 7), UC ( = 10) and CRC ( = 15), was sequenced for the rs10889677 mutation. The mutant and wildtype fragments were amplified and cloned in the pmirGLO vector. The luciferase activity of cloned vectors was assessed after transfection into the HT29 cell line. CAC mice were induced by a mixture of a single azoxymethane injection and three cycles of dextran sulphate sodium, then buparlisib was administered after 14 d. The excised colon was subjected to immunohistochemistry for Ki67 and Cleaved-caspase-3 markers and quantitative real-time polymerase chain reaction analysis for and .
RESULTS
Luciferase activity decreased by 2.07-fold in the rs10889677 mutant, confirming the hypothesis that the variant disrupted miRNA binding sites, which led to an increase in expression and the activation of the PI3K signaling pathway. Furthermore, CAC-induced mice had a significantly higher disease activity index ( < 0.05). Buparlisib treatment significantly decreased mean weight loss in CAC-induced mice ( < 0.05), reduced the percentage of proliferating cells by 5%, and increased the number of apoptotic cells. The treatment also caused a downward trend of expression and significantly decreased expression.
CONCLUSION
Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway, and buparlisib had the ability to prevent PI3K-non-AKT activation in the pathophysiology of CAC.
Topics: Mice; Animals; Phosphatidylinositol 3-Kinases; Colitis-Associated Neoplasms; Signal Transduction; Inflammation; Colitis, Ulcerative; Colonic Neoplasms; Phosphatidylinositols; Luciferases; Colitis; Aminopyridines; Morpholines
PubMed: 37970476
DOI: 10.3748/wjg.v29.i40.5543 -
Clinical and Translational Medicine Nov 2023Colorectal cancer (CRC) is a complex, multistep disease that arises from the interplay genetic mutations and epigenetic alterations. The histone H3K36...
BACKGOUND
Colorectal cancer (CRC) is a complex, multistep disease that arises from the interplay genetic mutations and epigenetic alterations. The histone H3K36 trimethyltransferase SET domain-containing 2 (SETD2), as an epigenetic signalling molecule, has a 5% mutation rate in CRC. SETD2 expression is decreased in the development of human CRC and mice treated with Azoxymethane /Dextran sodium sulfate (AOM/DSS). Loss of SETD2 promoted CRC development. SMAD Family member 4 (SMAD4) has a 14% mutation rate in CRC, and SMAD4 ablation leads to CRC. The co-mutation of SETD2 and SMAD4 predicted advanced CRC. However, little is known on the potential synergistic effect of SETD2 and SMAD4.
METHODS
CRC tissues from mice and SW620 cells were used as research subjects. Clinical databases of CRC patients were analyzed to investigate the association between SETD2 and SMAD4. SETD2 and SMAD4 double-knockout mice were established to further investigate the role of SETD2 in SMAD4-deficient CRC. The intestinal epithelial cells (IECs) were isolated for RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) to explore the mechanism and the key molecules resulting in CRC. Molecular and cellular experiments were conducted to analyze the role of SETD2 in SMAD4-deficient CRC. Finally, rescue experiments were performed to confirm the molecular mechanism of SETD2 in the development of SMAD4-dificient CRC.
RESULTS
The deletion of SETD2 promotes the malignant progression of SMAD4-deficient CRC. Smad4 ; Setd2 mice developed a more severe CRC phenotype after AOM/DSS induction, with a larger tumour size and a more vigorous epithelial proliferation rate. Further mechanistic findings revealed that the loss of SETD2 resulted in the down-regulation of DUSP7, which is involved in the inhibition of the RAS/ERK signalling pathway. Finally, the ERK1/2 inhibitor SCH772984 significantly attenuated the progression of CRC in Smad4 ;Setd2 mice, and overexpression of DUSP7 significantly inhibited the proliferation rates of SETD2 ; SMAD4 SW620 cells.
CONCLUSIONS
Our results demonstrated that SETD2 inhibits the RAS/ERK signaling pathway by facilitating the transcription of DUSP7 in SMAD4-deficient CRC, which could provide a potential therapeutic target for the treatment of advanced CRC.
Topics: Animals; Humans; Mice; Colorectal Neoplasms; Down-Regulation; Dual-Specificity Phosphatases; Epithelial Cells; Histone-Lysine N-Methyltransferase; Signal Transduction; Smad4 Protein
PubMed: 37962020
DOI: 10.1002/ctm2.1475 -
Cancer Biology & Therapy Dec 2023Despite being the subject of multiple cancer studies, nothing is known about miR-597-5p's role in colitis-associated colorectal cancer (CAC). We intend to explore how...
Despite being the subject of multiple cancer studies, nothing is known about miR-597-5p's role in colitis-associated colorectal cancer (CAC). We intend to explore how miR-597-5p influences the growth and development of CAC. In order to construct a CAC model, mice were stimulated with azoxymethane (AOM)/dextran sulfate sodium (DSS). The in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) was used for the detection of miR-597-5p expression. The protein expression of CXCL5 was determined by western blotting, immunohistochemistry and enzyme-linked immuno sorbent assay (ELISA). The histologic colitis score and hematoxylin and eosin (HE) staining were used to evaluate degree of damage to colonic tissues. The proportion of macrophages detected in colon tumors was also measured using flow cytometry. The transwell test was employed to assess macrophage migration. It was found that the miR-597-5p and its target CXCL5 had a negative correlation. MiR-597-5p expression was decreased, while CXCL5 expression was raised in CAC tissues. In AOM/DSS-induced mice, miR-597-5p deficiency in intestinal epithelial cells resulted in decreasing colon length as well as increasing tumor numbers and histologic colitis score, which was reversed by CXCL5 inhibition. MiR-597-5p deficiency facilitated macrophage recruitment in AOM/DSS-induced mice and promoted macrophage migration in vitro, which were reversed by CXCL5 inhibition. Deficiency of miR-597-5p aggravated macrophage recruitment and tumorigenesis in a mouse CAC model, suggesting that miR-597-5p agonists may have an anti-inflammatory therapeutic effect in inflammatory bowel diseases and reduce the risk of developing CAC.
Topics: Mice; Animals; Colitis; Carcinogenesis; Colonic Neoplasms; Macrophages; MicroRNAs; Dextran Sulfate; Mice, Inbred C57BL; Disease Models, Animal; Colorectal Neoplasms
PubMed: 37942533
DOI: 10.1080/15384047.2023.2274122