大麦若叶(barley leaf,BL)对肠道健康具有潜在益处,但对结直肠癌的预防作用及机制尚未明确。为探究BL对结直肠癌的影响并阐述作用机制,研究分别建立了氧化偶氮甲烷/葡聚糖硫酸钠(azoxymethane/dextran sodium sulfate,AOM/DSS)诱导的结直肠癌小鼠模型和CT26移植瘤小鼠模型,研究发现BL明显减少了AOM/DSS诱导模型小鼠肿瘤结节数量但并不影响移植瘤小鼠肿瘤的生长。同时,通过蛋白印迹法,发现BL降低了结肠组织中重要结直肠癌致癌基因环氧合酶-2与表皮生长因子受体的蛋白表达水平;通过16S测序分析以及GC-MS分析,发现5%(质量分数)BL干预能够改善肠道菌群失调,使乙酸含量提升了2.53倍、丙酸3.63倍、丁酸3.81倍;通过细胞实验,发现乙酸钠、丙酸钠及丁酸钠可以抑制由表皮生长因子介导细胞恶性转化过程相关信号通路中p-AKT和p-ERK蛋白表达水平,从而明显抑制小鼠表皮细胞JB 6P+的恶性转化。综上所述,大麦若叶通过改善小鼠肠道菌群失调,提高部分短链脂肪酸的含量,下调肿瘤相关信号通路中关键蛋白的表达,抑制肿瘤细胞的增殖,进而缓解结直肠癌的发生和发展。
Barley leaf (BL) is potentially beneficial to intestinal health.But the impact on colorectal cancer (CRC) is unclear.To investigate the impact and mechanism, this study established two mouse models of CRC induced by azoxymethane (AOM) /dextran sodium sulfate (DSS) and CT26 subcutaneous injection.Results showed that BL could significantly reduce the AOM/DSS-induced tumorigenesis and had no impacts on transplanted tumor growth.Meanwhile, by means of western blot, 16S analysis, and gas chromatography-mass spectrometer (GC-MS) analysis, this study found that 5% BL significantly decreased the expression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) in the colon, improved dysbacteriosis, and increased the concentration of short-chain fatty acid (SCFA).Cell experiments showed that the sodium salt of SCFA could restrain the malignant transformation of epithelial cells by reducing the expression of p-AKT and p-ERK.In summary, barely leaf could attenuate the AOM/DSS-induced tumorigenesis via dysbacteriosis amelioration, increasing the concentration of part SCFA and down-regulating the expression of key proteins in tumor-related signaling pathways.
[1] SIEGEL R L, MILLER K D, FUCHS H E, et al.Cancer statistics, 2022[J].CA:A Cancer Journal for Clinicians, 2022, 72(1):7-33.
[2] MILLER K D, NOGUEIRA L, DEVASIA T, et al.Cancer treatment and survivorship statistics, 2022[J].CA:a Cancer Journal for Clinicians, 2022, 72(5):409-436.
[3] XIA C F, DONG X S, LI H, et al.Cancer statistics in China and United States, 2022:Profiles, trends, and determinants[J].Chinese Medical Journal, 2022, 135(5):584-590.
[4] FARVID M S, SIDAHMED E, SPENCE N D, et al.Consumption of red meat and processed meat and cancer incidence:A systematic review and meta-analysis of prospective studies[J].European Journal of Epidemiology, 2021, 36(9):937-951.
[5] ABU-GHAZALEH N, CHUA W J, GOPALAN V.Intestinal microbiota and its association with colon cancer and red/processed meat consumption[J].Journal of Gastroenterology and Hepatology, 2021, 36(1):75-88.
[6] WU C.Systemic therapy for colon cancer[J].Surgical Oncology Clinics of North America, 2018, 27(2):235-242.
[7] MACDONALD J S.Adjuvant therapy for colon cancer[J].CA:a Cancer Journal for Clinicians, 1997, 47(4):243-256.
[8] GARRETT W S.The gut microbiota and colon cancer[J].Science, 2019, 364(6446):1133-1135.
[9] VERNIA F, LONGO S, STEFANELLI G, et al.Dietary factors modulating colorectal carcinogenesis[J].Nutrients, 2021, 13(1):143.
[10] DENG J Q, ZHAO L L, YUAN X Y, et al.Pre-administration of berberine exerts chemopreventive effects in AOM/DSS-induced colitis-associated carcinogenesis mice via modulating inflammation and intestinal microbiota[J].Nutrients, 2022, 14(4):726.
[11] MALLA R R.Microbiome conundrum in colon cancer:Development, progression, and therapeutics[J].Critical Reviews in Oncogenesis, 2020, 25(2):129-139.
[12] KAMIYAMA M, SHIBAMOTO T.Flavonoids with potent antioxidant activity found in young green barley leaves[J].Journal of Agricultural and Food Chemistry, 2012, 60(25):6260-6267.
[13] LI D T, FENG Y, TIAN M L, et al.Gut microbiota-derived inosine from dietary barley leaf supplementation attenuates colitis through PPARγ signaling activation[J].Microbiome, 2021, 9(1):83.
[14] SIVAPRAKASAM S, BHUTIA Y D, YANG S P, et al.Short-chain fatty acid transporters:Role in colonic homeostasis[J].Comprehensive Physiology, 2017, 8(1):299-314.
[15] SUNG H, FERLAY J, SIEGEL R L, et al.Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA:a Cancer Journal for Clinicians, 2021, 71(3):209-249.
[16] THANIKACHALAM K, KHAN G.Colorectal cancer and nutrition[J].Nutrients, 2019, 11(1):164.
[17] YANG Y F, YANG L, ZHOU L P, et al.A critical review of the effect of dietary fiber intake on the prevention of colorectal cancer in Eastern Asian countries[J].Journal of Healthcare Engineering, 2021: 6680698.
[18] TIAN M L, LI D T, MA C, et al.Barley leaf insoluble dietary fiber alleviated dextran sulfate sodium-induced mice colitis by modulating gut microbiota[J].Nutrients, 2021, 13(3):846.
[19] WANG C H, YANG S X, GAO L, et al.Carboxymethyl pachyman (CMP) reduces intestinal mucositis and regulates the intestinal microflora in 5-fluorouracil-treated CT26 tumour-bearing mice[J].Food & Function, 2018, 9(5):2695-2704.
[20] SNIDER A J, BIALKOWSKA A B, GHALEB A M, et al.Murine model for colitis-associated cancer of the colon[J].Methods in Molecular Biology, 2016, 1438:245-254.
[21] TAKETO M M.COX-2 and colon cancer[J].Inflammation Research, 1998, 47(2):112-116.
[22] HARDBOWER D M, COBURN L A, ASIM M, et al.EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis[J].Oncogene, 2017, 36(27):3807-3819.
[23] MONIRI N H, FARAH Q.Short-chain free-fatty acid G protein-coupled receptors in colon cancer[J].Biochemical Pharmacology, 2021, 186:114483.
[24] GOMES S D, OLIVEIRA C S, AZEVEDO-SILVA J, et al.The role of diet related short-chain fatty acids in colorectal cancer metabolism and survival:Prevention and therapeutic implications[J].Current Medicinal Chemistry, 2020, 27(24):4087-4108.
[25] REVATHIDEVI S, MUNIRAJAN A K.Akt in cancer:Mediator and more[J].Seminars in Cancer Biology, 2019, 59:80-91.
[26] GUO Y J, PAN W W, LIU S B, et al.ERK/MAPK signalling pathway and tumorigenesis[J].Experimental and Therapeutic Medicine, 2020, 19(3):1997-2007.
