流行病学研究揭示红肉摄入过多增加结直肠癌的发生风险,但机制未明。血红素铁是一种广泛存在于动物红肉、肝脏、血液中的有机铁,为探究红肉摄入对结直肠癌肿瘤发生及增殖的影响,并进一步解析作用机制。该文建立原发结直肠癌肿瘤小鼠模型,发现在血红素铁的干预下,能够显著增加氧化应激及结直肠癌肿瘤的发生发展程度;通过蛋白质印迹法分析,在动物模型的结肠组织中,血红素铁刺激结直肠癌肿瘤小鼠,黄嘌呤氧化酶(xanthine oxidase,XOD)、p-H2AX及p-STAT3表达量均会上调,同时肿瘤组织较瘤旁组织表达更为明显,通过细胞实验发现,在一定剂量的蔗糖铁和脂多糖的共同作用下可以上调经佛波酯诱导THP-1细胞分化成的巨噬细胞XOD的表达量;通过免疫组化实验发现,在小鼠结肠部位中XOD的表达位置和巨噬细胞表达位置相重合。结论显示,血红素铁会增加结直肠癌肿瘤小鼠的肿瘤发生及发展程度,且此现象与XOD表达上调有关。
Epidemiological study has revealed that excessive intake of red meat could increase the risk of colorectal cancer, but the mechanism is unclear. The aim of this study was to explore the effect of red meat on the occurrence and proliferation of colorectal cancer, and to further analyze the mechanism of action using a mouse model with primary colorectal cancer tumors. The results showed that the intervention of heme iron can significantly increase the occurrence and development of colorectal cancer tumors. Western blot analysis further revealed that in the colon tissue of the animal model, heme iron stimulating colorectal cancer tumor mice, xanthine oxidase(XOD), p-H2AX, and p-STAT3 expression levels were up-regulated, and the tumor tissue expression was more obvious than the adjacent tissues. Moreover, a certain dose of iron sucrose and LPS can up-regulate the expression of xanthine oxidase in macrophages differentiated into THP-1 induced by PMA. Through immunohistochemical experiments, the expression position of xanthine oxidase and the expression position of macrophages were overlapped in the mouse colon. The conclusion shows that heme iron can increase the tumorigenesis and development of colorectal tumor mice, and this phenomenon is related to the up-regulation of XOD expression.
[1] BONOVOLIAS I D,TSIFTSOGLOU A S.Hemin counteracts the repression of Bcl-2 and NrF2 genes and the cell killing induced by imatinib in human Bcr-Abl(+) CML cells[J].Oncology Research,2009,17(11-12):535-547.
[2] KANG Y P,WARD N P,DENICOLA G M.Recent advances in cancer metabolism:A technological perspective[J].Experimental & Molecular Medicine,2018,50(4):1-16.
[3] LARSSON S C,WOLK A.Meat consumption and risk of colorectal cancer:A meta-analysis of prospective studies[J].International Journal of Cancer,2006,119(11):2 657-2 664.
[4] LIPPI G,MATTIUZZI C,CERVELLIN G.Meat consumption and cancer risk:A critical review of published meta-analyses[J].Critical Reviews in Oncology/Hematology,2016,97:1-14.
[5] WILLETT W C,STAMPFER M J,COLDITZ G A,et al.Relation of meat,fat,and fiber intake to the risk of colon cancer in a prospective study among women[J].The New England Journal of Medicine,1990,323(24):1 664-1 672.
[6] GIOVANNUCCI E,RIMM E B,STAMPFER M J,et al.Intake of fat,meat,and fiber in relation to risk of colon cancer in men[J].Cancer Research,1994,54(9):2 390-2 397.
[7] WEST A R,OATES P S.Mechanisms of heme iron absorption:Current questions and controversies[J].World Journal of Gastroenterology,2008,14(26):4 101-4 110.
[8] KAGAN V E,KOZLOV A V,TYURINA Y Y,et al.Antioxidant mechanisms of nitric oxide against iron-catalyzed oxidative stress in cells[J].Antioxidants & Redox Signaling,2001,3(2):189-202.
[9] ITOH T,YAMADA T,KODERA Y,et al.Hemin(Fe3+)-and heme(Fe2+)-Smectite conjugates as a model of hemoprotein based on spectrophotometry[J].Bioconjugate Chemistry,2001,12(1):3-6.
[10] NAGABABU E,RIFKIND J M.Heme degradation by reactive oxygen species[J].Antioxidants & Redox Signaling,2004,6(6):967-978.
[11] NAGABABU E,RIFKIND J M.Heme degradation by reactive oxygen species[J].Antioxidants & Redox Signaling,2004,6(6):967-978.
[12] SHIMIZU T.Binding of cysteine thiolate to the Fe(III) heme complex is critical for the function of heme sensor proteins[J].Journal of Inorganic Biochemistry,2012,108:171-177.
[13] GEMELLI C,DONGMO B M,FERRARINI F,et al.Cytotoxic effect of hemin in colonic epithelial cell line:Involvement of 18kDa translocator protein(TSPO)[J].Life Sciences,2014,107(1-2):14-20.
[14] XUE X,RAMAKRISHNAN S K,WEISZ K,et al.Iron uptake via DMT1 integrates cell cycle with JAK-STAT3 signaling to promote colorectal tumorigenesis[J].Cell Metabolism,2016,24(3):447-461.
[15] BASTIDE N M,PIERRE F H F,CORPET D E.Heme iron from meat and risk of colorectal cancer:A meta-analysis and a review of the mechanisms involved[J].Cancer Prevention Research(Philadelphia,Pa.),2011,4(2):177-184.
[16] BINGHAM S A,HUGHES R,CROSS A J.Effect of white versus red meat on endogenous N-nitrosation in the human colon and further evidence of a dose response[J].The Journal of Nutrition,2002,132(11):3 522S-3 525S.
[17] SINHA R,KNIZE M G,SALMON C P,et al.Heterocyclic amine content of pork products cooked by different methods and to varying degrees of doneness[J].Food and Chemical Toxicology,1998,36(4):289-297.
[18] SESINK A L,TERMONT D S,KLEIBEUKER J H,et al.Red meat and colon cancer:The cytotoxic and hyperproliferative effects of dietary heme[J].Cancer Research,1999,59(22):5 704-5 709.
[19] WINTERBOURN C C.Toxicity of iron and hydrogen peroxide:The Fenton reaction[J].Toxicology Letters,1995,82-83:969-974.
[20] WISEMAN M,CANNON G,MARTIN G,et al.Food,nutrition,physical activity,and the prevention of cancer:A global perspective[M].Washington DC:World Cancer Research Fund/American Institute for Cancer Research,2007.
[21] FRANCESCANGELI F,DE ANGELIS M L,ZEUNER A.Dietary factors in the control of gut homeostasis,intestinal stem cells,and colorectal cancer[J].Nutrients,2019,11(12):E2936.
[22] CONSTANTE M,FRAGOSO G,CALVÉ A,et al.Dietaryheme induces gut dysbiosis,aggravates colitis,and potentiates the development of adenomas in mice[J].Frontiers in Microbiology,2017,8:1 809.
[23] ELINAV E,NOWARSKI R,THAISS C A,et al.Inflammation-induced cancer:Crosstalk betweentumours,immune cells and microorganisms[J].Nature Reviews Cancer,2013,13(11):759-771.
[24] DE OLIVEIRA OTTO M C C,ALONSO A,LEE D H,et al.Dietary micronutrient intakes are associated with markers of inflammation but not with markers of subclinical atherosclerosis[J].The Journal of Nutrition,2011,141(8):1 508-1 515.
[25] HEBELS D G A J,SVEJE K M,DE KOK M C,et al.Red meat intake-induced increases in fecal water genotoxicity correlate with pro-carcinogenic gene expression changes in the human colon[J].Food and Chemical Toxicology,2012,50(2):95-103.
[26] ASLAN M,RYAN T M,ADLER B,et al.Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease[J].PNAS,2001,98(26):15 215-15 220.
[27] SCHWARTZ S,ELLEFSON M.Quantitative fecal recovery of ingested hemoglobin-heme in blood:Comparisons by HemoQuant assay with ingested meat and fish[J].Gastroenterology,1985,89(1):19-26.
