Background: Tumor environment has been recognized to affect cancer cell progression, such as tumor-associated macrophages. However, increasing evidences suggest that tumor cells are capable of regulating polarization of tumor-associated macrophages. In this study, we investigate the mechanism of how colon cancer cell impacts tumor-associated macrophages polarization. Methods: We employed flow cytometry to detect marker molecules on macrophage membrane, such as CD68, CD16, and CD204. In addition, we used enzyme-linked immunosorbent assay to examine the level of these cytokines (interleukin-6, interleukin-1β, interleukin-10, and Arginase-1) secreted by colon cancer cells into the culture medium. Western blot was utilized to probe downstream proteins of epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Results: We cocultured colon cancer cell lines (HCT8 or HCT116) with human myeloid leukemia mononuclear cells (THP-1) and found that interleukin-6 and interleukin-1β levels were reduced, and instead, interleukin-10 and Arginase-1 levels were elevated, suggesting that colon cancer cells contributed to M2 polarization of THP-1. Meanwhile, high level of various growth factors (transforming growth factor-β [TGF-β], epidermal growth factor [EGF], and hepatocyte growth factor [HGF]) was observed in the medium of THP-1 cocultured with colon cancer cells. Furthermore, the protein level of phosphorylated PI3K, AKT, and mTOR significantly increased in THP-1 cell cocultured with colon cancer cells compared to THP-1 group. Besides, we established that colon cancer cells exerted their stimulatory effect on M2 polarization of macrophage from monocyte THP-1 using EGFR antibody mAb225 and PI3K inhibitor LY294002. Conclusion: We provide evidence that EGF which are secreted by colon cancer cells play contributory role in M2 polarization of macrophages, which support the notion that tumor environment, including tumor-associated macrophages, can be targeted to develop effective strategies for treating cancer.
Colorectal carcinoma (CRC) is one of the most common cancers in the world, and identification of new CRC biomarkers will be helpful for the diagnosis and treatment of CRC. For isobaric tags for relative and absolute quantitation (iTRAQ) analysis, fresh CRC and adjacent, colonic adenoma, ulcerative colitis, Crohn's disease, and noncancerous colonic epithelial tissue were obtained from patients at the 2nd Xiangya Hospital of Central South University, China. The function of heterogeneous nuclear ribonucleoprotein M (HnRNP M) during the proliferation, invasion, and metastasis of CRC cells in vitro was evaluated. One hundred and twenty-six differentially expressed proteins were identified by iTRAQ analysis. The expression of HnRNP M exhibited progressive changes during the carcinogenic process and was validated by Western blot. The upregulation of HnRNP M correlated with cancer recurrence and regional lymph node metastasis. Furthermore, biological role exploration suggests that HnRNP M positively regulates cell cycle progression, promotes cell growth and invasion in vitro, and increases the colony-forming ability of LS174T cells. The present data demonstrate that the upregulation of HnRNP M is involved in human colorectal epithelial carcinogenesis and may serve as a carcinoma biomarker for CRC.
Background and Aim: Westernized high-fat diet increases the risk for inflammatory bowel diseases (IBDs), yet with insufficient understanding of the role of high-protein diet. We aimed to identify the effect of high-protein diets from different dietary proteins (casein, whey protein, soy protein) on experimental colitis and its impact on microbiota, structure and function of colonic mucus layer. Methods: Female BALB/c mice were fed by standard diet, high-casein diet (HCD), high whey protein diet or high soy protein diet for 4 weeks. The susceptibility of dextran sulfate sodium (DSS)-induced colitis in mice and thickness of colonic mucus layer were compared after different dietary interventions, associated with the identification of the reversal effect of broad-spectrum antibiotic intervention (0.5 g/L of vancomycin and 1 g/L of neomycin sulfate, metronidazole and ampicillin in drinking water). Further analysis was performed on the synthesis of mucin, microbiota and sialidase involved in degradation of mucus layer. Results: High-protein diets aggravated acute DSS-induced colitis independent of protein composition, while broad-spectrum antibiotics reversed this effect. HCD significantly altered the composition of bacteria in the colonic mucus layer, especially Bacteroides thetaiotaomicron and total mucin-degrading bacteria; besides, it increased sialidase concentration and reduced the thickness of mucus layer. However, it exhibited no significant effect on the synthesis of Muc2. Broad-spectrum antibiotics decreased the abundance of mucin-degrading bacteria and sialidase concentration while increased the thickness of mucus layer. Conclusion:High-protein diet shifts microbial composition and thickness of colonic mucus layer, leading to the aggravation of acute DSS-induced colitis.High protein diet and mucin degrading bacteria L Chen et al.
Rationale:Chronic diarrhea in adult patients due to various causes is very common in clinic, but patient suffering with mal-absorption due to immunoproliferative small intestinal disease was rarely reported in China.Patient concerns and Diagnoses:A 35-year-old female presented with more than three years history of chronic diarrhea, rickets, high serum value of immunoglobulin A protein, and anemia. Bone marrow aspiration suggested that the patient was in a sideropenic and megalobastic anemia stage. Duodenal and ileac biopsies revealed atrophy and blunting villi. The bowel lamina propria was infiltrated with slightly increased intraepithelial lymphocytes and mainly with diffuse plasma cells. The following enzyme labeling immunohistochemistry results were strongly positive to alpha-heavy-chain. Computed tomography manifested she had diffuse thickening of small intestine wall. At last a diagnosis of immunoproliferative small intestinal disease was made.Interventions and Outcomes:On the first month, the patient was treated with vitamin D supplements, calcium, magnesium, potassium, iron, folic acid, mecobalamin replacements and microflora probiotics. The patient frequency of water diarrhea alleviated slightly, but her weight loss, anxiety neurosis and other disorders were still severe. After taking with prednisone (40 mg per day, and gradually reduced to the lowest dose) for another month, the symptoms was gradually subsided.Lessons:The study shows that immunohistochemical staining for alpha-heavy chain proteins should be completed on small intestine biopsy specimens if the patient is suspected a diagnosis of immunoproliferative small intestinal disease.
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