scholarly journals Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota—A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia?

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1799 ◽  
Author(s):  
Satu Pekkala ◽  
Anniina Keskitalo ◽  
Emilia Kettunen ◽  
Sanna Lensu ◽  
Noora Nykänen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gut Microbiota ◽  
Tumor Formation ◽  
C2c12 Myotubes ◽  
Muscle Loss ◽  
Receptor Ligands ◽  
Activin Receptor ◽  
Before And After ◽  
Inflammatory Proteins

Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC cells (C26) were inoculated into mice. Activin receptor (ACVR) ligands were blocked, either before tumor formation or before and after, to increase muscle mass and prevent muscle loss. The effects of flagellin on C26-cells were studied in vitro. The occurrence of similar phenomena were studied in murine and human tumors. Cancer modulated the gut microbiota without consistent effects of blocking the ACVR ligands. However, continued treatment for muscle loss modified the association between microbiota and weight loss. Several abundant microbial taxa in cancer were flagellated. Exposure of C26-cells to flagellin increased IL6 and CCL2/MCP-1 mRNA and IL6 excretion. Murine C26 tumors expressed more IL6 and CCL2/MCP-1 mRNA than C26-cells, and human CRC tumors expressed more CCL2/MCP-1 than healthy colon sites. Additionally, flagellin decreased caspase-1 activity and the production of reactive oxygen species, and increased cytotoxicity in C26-cells. Conditioned media from flagellin-treated C26-cells deteriorated C2C12-myotubes and decreased their number. In conclusion, cancer increased flagellated microbes that may promote CRC survival and cachexia by inducing inflammatory proteins such as MCP-1. Cancer-associated gut microbiota could not be rescued by blocking ACVR ligands.

scholarly journals Sevoflurane inhibits malignant progression of colorectal cancer via hsa_circ_0000231-mediated miR-622

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Jingpeng Wang ◽  
Shuyuan Li ◽  
Gaofeng Zhang ◽  
Huihua Han
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Volatile Anesthetic ◽  
Tumor Formation ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas

Abstract Background Sevoflurane (Sev), a commonly used volatile anesthetic, has been reported to inhibit the process of colorectal cancer (CRC). Circular RNAs (circRNAs) are revealed to participate in the pathogenesis of CRC. This study aims to reveal the mechanism of hsa_circ_0000231 in Sev-mediated CRC progression. Methods The expression of hsa_circ_0000231 and microRNA-622 (miR-622) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein level was determined by western blot analysis. Cell proliferation was investigated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell colony formation and DNA content quantitation assays. Cell apoptosis was detected by Annexin V-fluorescein isothiocyanate and propidium iodide double staining and caspase 3 activity assays. Cell migration and invasion were investigated by wound-healing and transwell invasion assays, respectively. The putative relationship between hsa_circ_0000231 and miR-622 was predicted by circular RNA Interactome online database, and identified by dual-luciferase reporter and RNA immunoprecipitation assays. The impacts of hsa_circ_0000231 on Sev-mediated tumor formation in vivo were presented by in vivo assay. Results Hsa_circ_0000231 expression was upregulated, while miR-622 was downregulated in CRC tissues and cells compared with control groups. Sev treatment decreased hsa_circ_0000231 expression, but increased miR-622 expression in CRC cells. Sev treatment suppressed cell proliferation, migration and invasion, and induced cell apoptosis. Hsa_circ_0000231 overexpression restored Sev-mediated CRC progression in vitro. Additionally, hsa_circ_0000231 acted as a sponge of miR-622, and miR-622 inhibitors reversed the impacts of hsa_circ_0000231 silencing on CRC process. Furthermore, Sev treatment inhibited tumor growth by regulating hsa_circ_0000231 in vivo. Conclusion Hsa_circ_0000231 attenuated Sev-aroused repression impacts on CRC development by sponging miR-622. This findings may provide an appropriate anesthetic protocol for CRC sufferers undergoing surgery.

PGM1 Suppresses Colorectal Cancer Cell Migration And Invasion by Regulating PI3K/ AKT Pathway

2021 ◽  
Author(s):  
Zhewen Zheng ◽  
Xue Zhang ◽  
Jian Bai ◽  
Long Long ◽  
Di Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Colony Formation ◽  
Tumor Formation ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Cycle Arrest ◽  
Cancer Pathogenesis

Abstract BackgroundPhosphoglucomutase 1(PGM1) is known for its involvement in cancer pathogenesis. However, its biological role in colorectal cancer (CRC) is unknown. Here, we studied the functions and mechanisms of PGM1 in CRC.Methods We verified PGM-1 as a DEG by a comprehensive strategy of the TCGA-COAD dataset mining and computational biology. Relative levels of PGM-1 in CRC tumors and adjoining peritumoral tissue were identified by qRT-PCR, WB, and IHC staining in a tissue microarray. PGM1 functions were analyzed using CCK8, EdU, colony formation, cell cycle, apoptosis, and Transwell migration and invasion assays. The influence of PGM1 was further investigated using tumor formation in vivo.ResultsPGM1 mRNA and protein were both reduced in CRC and the reduction was related to CRC pathology and overall survival. PGM1 knockdown stimulated both proliferation and colony formation, promoting cell cycle arrest and apoptosis while overexpression has opposite effects in CRC cells both in vivo and in vitro. Furthermore, we lined the actions of PGM1 to the PI3K/ AKT pathway. ConclusionWe verified that PGM1 suppresses CRC through the PI3K/ AKT pathway. These results suggest the potential for targeting PGM1 in CRC therapies.

scholarly journals Impact of Grain Sorghum Polyphenols on Microbiota of Normal Weight and Overweight/Obese Subjects during In Vitro Fecal Fermentation

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 217 ◽  
Author(s):  
Danielle Ashley ◽  
Daya Marasini ◽  
Cindi Brownmiller ◽  
Jung Lee ◽  
Franck Carbonero ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Batch Fermentation ◽  
Short Chain Fatty Acids ◽  
Negative Control ◽  
Normal Weight ◽  
Weight Class ◽  
Gut Health ◽  
Sorghum Bran ◽  
Before And After

The human gut microbiota is considered as a crucial mediator between diet and gut homeostasis and body weight. The unique polyphenolic profile of sorghum bran may promote gastrointestinal health by modulating the microbiota. This study evaluated gut microbiota and modulation of short-chain fatty acids (SCFA) by sorghum bran polyphenols in in vitro batch fermentation derived from normal weight (NW, n = 11) and overweight/obese (OO, n = 11) subjects’ fecal samples. Six separate treatments were applied on each batch fermentation: negative control (NC), fructooligosaccharides (FOS), black sorghum bran extract (BSE), sumac sorghum bran extract (SSE), FOS + BSE, or FOS + SSE; and samples were collected before and after 24 h. No significant differences in total and individual SCFA production were observed between NW and OO subjects. Differential responses to treatment according to weight class were observed in both phyla and genera. Sorghum bran polyphenols worked with FOS to enhance Bifidobacterium and Lactobacillus, and independently stimulated Roseburia and Prevotella (p < 0.05). Our results indicate that sorghum bran polyphenols have differential effects on gut health and may positively impact gut ecology, with responses varying depending on weight class.

Relationship of Src activity and prior oxaliplatin on outcomes after hepatectomy for metastatic colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3561-3561
Author(s):  
Van Karlyle Morris ◽  
Nila Parikh ◽  
Michael J. Overman ◽  
Zhi-Qin Jiang ◽  
Dipen M Maru ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Automated Image Analysis ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Nonreceptor Tyrosine Kinase ◽  
Mesenchymal Transition ◽  
Before And After

3561 Background: The nonreceptor tyrosine kinase Src regulates pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. In vitro, Src is activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance, but not after 5-FU alone. Activation of Src and its substrate FAK in metastatic colorectal cancer treated with oxaliplatin has not been studied in human specimens. Methods: Samples from 170 hepatic resections from two cohorts of patients with metastatic colorectal cancer were examined by IHC for expression of activated Src (pSrc) and FAK (total and pFAK). In the first cohort (n=50), tissue was collected at consecutive hepatic resections before and after oxaliplatin. Patients in the second cohort (n=120) were compared based on whether or not oxaliplatin was administered after resection. IHC was graded semi-quantitatively, 0 to 4 based on intensity (first cohort), and by automated image analysis (second cohort). Results: In the first cohort, pFAK expression increased after oxaliplatin exposure (mean IHC score 2.04 vs. 1.18, p<0.01). In the second cohort, Src activation was correlated with pFAK expression (p<0.01). Patients pretreated with oxaliplatin demonstrated increased expression of activated FAK (p=0.02) compared to 5-FU alone or irinotecan regimens. There was a weak association between total Src expression and the number of oxaliplatin cycles (p=0.06). Among patients in the second cohort, five-year relapse-free survival was inversely related to levels of pFAK (21.1%, 16.5%, and 7.4% for low, medium, and high levels of pFAK, respectively; p=0.02) and of pSrc (19.6%, 13.6%, and 8.2% for low, medium, and high levels of pSrc, respectively; p= 0.01). Conclusions: Patients treated with neoadjuvant oxaliplatin demonstrated increased Src signaling in liver metastases, a finding associated with worse relapse-free survival. These results are consistent with prior in vitro studies correlating oxaliplatin exposure with Src pathway activation and support the idea that inhibition of Src, when used in combination with platinum chemotherapy, warrants further investigation in patients with metastatic colorectal cancer.

scholarly journals Gut microbiota modulate T cell trafficking into human colorectal cancer

Gut ◽  
2018 ◽  
Vol 67 (11) ◽  
pp. 1984-1994 ◽  
Author(s):  
Eleonora Cremonesi ◽  
Valeria Governa ◽  
Jesus Francisco Glaus Garzon ◽  
Valentina Mele ◽  
Francesca Amicarella ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Gut Microbiota ◽  
Cell Trafficking ◽  
Human Colorectal Cancer ◽  
Chemokine Production ◽  
T Cell Trafficking

ObjectiveTumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers.DesignExpression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing.ResultsCRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival.ConclusionsGut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.

MiR-202 inhibits the proliferation and invasion of colorectal cancer by targeting UHRF1

2019 ◽  
Vol 51 (6) ◽  
pp. 598-606 ◽  
Author(s):  
Yilin Lin ◽  
Zhihua Chen ◽  
Suyong Lin ◽  
Yan Zheng ◽  
Yisu Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Gene Prediction ◽  
Ring Finger ◽  
Tumor Formation ◽  
Luciferase Assay ◽  
Control Group ◽  
Proliferation And Invasion

Abstract The purpose of this study was to investigate the expression of microRNA-202 (miR-202) and its role in colorectal cancer (CRC) in vivo and in vitro. We examined the expression of miR-202 in CRC tissues by quantitative real-time PCR (qRT-PCR) assay. Lentiviral vectors were constructed to overexpress or inhibit the expression of miR-202 in the CRC cell lines HCT116 and SW480 to determine its effects on cell invasion and proliferation. We found that overexpression of miR-202 significantly inhibited the proliferation and invasion of HCT116 cells. MiRNA target gene prediction, dual luciferase assay, and western blot analysis demonstrated that miR-202 regulated ubiquitin-like with PHD and RING finger domain 1 (UHRF1) expression in both cell lines. The effect of miR-202 on cell proliferation and invasion was partially reversed by activating the expression of UHRF1. Furthermore, miR-202 induced tumor formation in HCT116 xenograft BALB/c nude mice. Mice vaccinated with miR-202-overexpressing cells had smaller tumors and lower UHRF1 expression than the control group. These results indicate the possibility that miR-202 is under-expressed in CRC tissues, and that miR-202 inhibits the proliferation and invasion of CRC via targeting UHRF1. MiR-202 is a potential therapeutic target for CRC.

scholarly journals Anticancer Effects of Lingonberry and Bilberry on Digestive Tract Cancers

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 850
Author(s):  
Tuulia Onali ◽  
Anne Kivimäki ◽  
Matti Mauramo ◽  
Tuula Salo ◽  
Riitta Korpela
Keyword(s):  
Colorectal Cancer ◽  
Cell Growth ◽  
Digestive Tract ◽  
Cancer Cell ◽  
Tumor Formation ◽  
Cancer Cell Growth ◽  
Antitumor Effects ◽  
Anticancer Effects ◽  
Wild Berries

Wild berries are part of traditional Nordic diets and are a rich source of phytochemicals, such as polyphenols. Various berry treatments have shown to interfere with cancer progression in vitro and in vivo. Here, we systematically reviewed the anticancer effects of two Nordic wild berries of the Vaccinium genus, lingonberry (Vaccinium vitis-idaea) and bilberry (Vaccinium myrtillus), on digestive tract cancers. The review was conducted according to the PRISMA 2020 guidelines. Searches included four databases: PubMed, Scopus, Web of Science, and CAB abstracts. Publications not written in English, case-reports, reviews, and conference abstracts were excluded. Moreover, studies with only indirect markers of cancer risk or studies with single compounds not derived from lingonberry or bilberry were not included. Meta-analysis was not performed. The majority (21/26) of studies investigated bilberry and colorectal cancer. Experimental studies on colorectal cancer indicated that bilberry inhibited intestinal tumor formation and cancer cell growth. One uncontrolled pilot human study supported the inhibitory potential of bilberry on colorectal cancer cell proliferation. Data from all 10 lingonberry studies suggests potent inhibition of cancer cell growth and tumor formation. In conclusion, in vitro and animal models support the antiproliferative and antitumor effects of various bilberry and lingonberry preparations on digestive tract cancers.

scholarly journals Bioconversion Variation of Ginsenoside CK Mediated by Human Gut Microbiota From Healthy Volunteers and Colorectal Cancer Patients

2021 ◽  
Author(s):  
Yin-Ping Guo ◽  
Li Shao ◽  
Li Wang ◽  
Man-Yun Chen ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
16S Rrna ◽  
Gut Microbiota ◽  
Healthy Volunteers ◽  
Healthy Subjects ◽  
Positive Association ◽  
16S Rrna Gene Sequencing ◽  
Rrna Gene ◽  
Significant Difference

Abstract Background: Ginsenoside CK (GCK) serves as the potential anti-colorectal cancer (CRC) protopanaxadiol (PPD)-type saponin, which could be mainly bio-converted to yield PPD by gut microbiota. Meanwhile, the anti-CRC effects of GCK could be altered by gut microbiota due to its different diversity in CRC patients. We aimed to investigate the bioconversion variation of GCK mediated by gut microbiota from CRC patients by comparing with healthy subjects.Methods: Gut microbiota profiled by 16S rRNA gene sequencing was collected from healthy volunteers and CRC patients. GCK was incubated with gut microbiota in vitro. A LC-MS/MS method was validated to quantify GCK and PPD after incubation at different time points.Results: The bioconversion of GCK in healthy subjects group was much faster than CRC group, as well as the yield of PPD. Moreover, significant difference of PPD concentration between healthy subjects group and CRC group could be observed at 12 h, 48 h and 72 h check points. According to 16S rRNA sequencing, the profiles of gut microbiota derived from healthy volunteers and CRC patients significantly varied, in which 12 differentially abundant taxon were found, such as Bifidobacterium, Roseburia, Bacteroides and Collinsella. Spearman’s correlation analysis showed bacteria enriched in healthy subjects group were positively associated with biotransformation of GCK, while bacteria enriched in CRC group displayed non correlation characters. Among them, Roseburia which could secrete β-glycosidase showed the strongest positive association with the bioconversion of GCK.Conclusion: The bioconversion of GCK in healthy subjects was much faster than CRC patients mediated by gut microbiota, which might alter the anti-CRC effects of GCK.

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