| 邵乐宁,朱宝松,杨晓东,等.雷帕霉素激活M2巨噬细胞自噬影响大肠癌放射敏感性的研究[J].中华放射医学与防护杂志,2022,42(9):657-663.Shao Lening,Zhu Baosong,Yang Xiaodong,et al.Rapamycin affects radiosensitivity of colorectal cancer by activating the autophagy of M2 macrophage[J].Chin J Radiol Med Prot,2022,42(9):657-663 |
| 雷帕霉素激活M2巨噬细胞自噬影响大肠癌放射敏感性的研究 |
| Rapamycin affects radiosensitivity of colorectal cancer by activating the autophagy of M2 macrophage |
| 投稿时间：2022-06-06 |
| DOI：10.3760/cma.j.cn112271-20220606-00240 |
| 中文关键词: 雷帕霉素 M2巨噬细胞 自噬 大肠癌 放射敏感性 |
| 英文关键词:Rapamycin M2 macrophages Autophagy Colorectal cancer Radiation sensitivity |
| 基金项目:省部共建放射医学与辐射防护国家重点实验室开放课题(GZK1202010,GZK1202021) |
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| 中文摘要: |
| 目的 探讨雷帕霉素(RAP)激活M2巨噬细胞(type-Ⅱ macrophage)自噬对大肠癌移植瘤放射敏感性的影响。方法 经佛波酯(PMA)单独及联合人重组白介素4(IL-4)诱导人单核白血病细胞THP-1分化为M0和M2型巨噬细胞。使用RAP激活M2自噬,设置巴弗洛霉素(bafilomycin A1)下调M2已被激活的自噬作为对照。将大肠癌LoVo细胞接种于BALB/c-nu/nu裸鼠,待形成直径10 mm瘤体后,利用随机数表法,将18只裸鼠分为M2自噬未激活组、激活组和激活后下调组,LoVo细胞单独成瘤为阴性对照组,每组6只。对荷瘤鼠行2次8 Gy X射线局部照射,分析各组间移植瘤放射敏感性的变化。结果 M2巨噬细胞标志物Arg-1、CCL-22的相对表达量显著高于M0巨噬细胞(t=78.77、60.02,P＜0.05)。M2自噬未激活组瘤体质量、体积和微血管密度(MVD)[(1.93±0.05)g、(2.14±0.06) cm3、36.37±1.04]较阴性对照组[(1.35±0.05) g、(1.77±0.02) cm3、25.69±1.34]显著提高(t=20.07、14.56、10.92,P＜0.05);激活M2自噬后,瘤体重量、体积和微血管密度均显著下降[(0.89±0.03) g、(1.24±0.01) cm3、13.60±1.52](t=44.37、40.32、21.43,P＜0.05)。利用巴弗洛霉素下调M2自噬后,瘤体质量、体积和微血管密度有所回升[(1.02±0.07) g、(1.37±0.02) cm3、21.06±1.41](t=4.67、13.79、6.23,P＜0.05)。与阴性对照组相比,自噬未激活的M2能够抑制Livin和Survivin在瘤体组织中的表达(t=2.64、7.90,P＜0.05);RAP激活M2自噬后,可进一步下调上述蛋白的表达(t=5.43、9.39,P＜0.05)。利用巴弗洛霉素下调M2自噬后,Livin、Survivin表达量均有所回升(t=2.80、3.17,P＜0.05)。结论 利用RAP激活M2自噬,可抑制M2促进肿瘤微血管形成的能力,从而抑制移植瘤生长;同时,通过下调大肠癌移植瘤中抗凋亡基因Livin与Survivin的表达,诱导大肠癌移植瘤放疗后凋亡的发生,提高大肠癌的放射敏感性。 |
| 英文摘要: |
| Objective To investigate the effects of rapamycin on the autophagy activation of M2 macrophages and the radiosensitivity in colorectal cancer xenograft.Methods THP-1 cells were induced into Type-Ⅱ macrophages with PMA and/or IL-4.Rapamycin and Bafilomycin A1 were uesd to activate and suppress autophagy of M2 macrophage,respectively.Colorectal cancer LoVo cells were inoculated on BALB/c-nu/nu nude mice.After the xenograft tumor size approached to 10 mm in diameter,the nude mice were divided into the following groups randomly:M2 macrophage autophagy inactive group and active group,autophagy downregulation of the activated group,and nontreatment control group.The tumors in mice were irradiated with 8 Gy X-rays in two fractions,and the radiosensitivity of colorectal cancer xenograft in each group was analyzed.Results The expression levels of M2 macrophage markers Arg-1 and CCL-22 were significantly higher than those in M0 macrophage.The tumor weight,volume[(1.93±0.05) g,(2.14±0.06) cm3]and micro-vessel density (36.37±1.04) in M2 autophagy inactive group were higher than those in control group[(1.35±0.05) g,(1.77±0.02) cm3,25.69±1.34](t=20.07,14.56,10.92,P < 0.05).After activation of M2 autophagy,the tumor weight,volume and micro-vessel density were significantly decreased to (0.89±0.03) g,(1.24±0.01) cm3,and 13.60±1.52(t=44.37,40.32,21.43,P< 0.05).After down-regulation of M2 autophagy with bafilomycin A1,the tumor weight,volume and micro-vessel density were increased to (1.02±0.07) g,(1.37±0.02) cm3,and 21.06±1.41(t=4.67,13.79,6.23,P < 0.05).Autophagy inaction suppressed the expression of Livin and Survivin in tumor (t=2.64,7.90,P < 0.05),and the activation of M2 autophagy further down-regulated the expression of Livin,Survivin (t=5.43,9.39,P < 0.05).The expression levels of Livin and Survivin were increased after the treatment with bafilomycin A1(t=2.80,3.17,P<0.05).Conclusions M2 macrophagy promoted the growth of colorectal cancer xenograft by inducing the formation of micro-vessels in the tumor,which is one of the mechanisms of tumor-associated macrophages participating in the radiotherapy resistance of colorectal cancer.Activation of M2 autophagy by rapamycin inhibited the ability of M2 macrophagy in promoting tumor growth,and induced apoptosis of colorectal cancer cells after radiotherapy by down-regulating the expression of anti-apoptotic genes Livin and Survivin,thus increased the radiosensitivity of colorectal cancer. |
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