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应激对小鼠乳腺癌生长转移的作用及机制
作者:芦婷婷 胡颖芸 张提 秦君芳 
单位:300071 天津 南开大学医学院免疫学教研室(芦婷婷、胡颖芸、张提、秦君芳) 
关键词:应激 乳腺癌 自噬 去甲肾上腺素 
分类号:R737.9
出版年,卷(期):页码:2019,44(6):459-465
摘要:

 [摘要]  目的  探讨应激对小鼠乳腺癌生长转移的作用及机制。方法  6~8周龄BALB/c小鼠接种4T1细胞制备乳腺癌移植瘤模型,分为对照组、慢性应激组、Iso[异丙肾上腺素,10 mg/(kg.d)]组、慢性应激+DMSO(二甲基亚砜)组和慢性应激+Rapa[雷帕霉素,15 mg/(kg.d)]组。记录癌组织体积变化,并于造模第21天处死小鼠,检测瘤内Beclin 1、微管相关蛋白1轻链3-(LC3-)p62表达变化;同时进行肺墨汁染色,计数小鼠肺内转移结节。采用去甲肾上腺素(NE)处理4T1细胞,观察自噬相关分子Beclin 1LC3-Ⅱ、p62 mRNA和蛋白表达的变化。结果  与对照组[(1359.7±173.9) mm3]相比,应激刺激[(2119.7±130.0) mm3]Iso注射[(1947.0±102.8) mm3]可促进乳腺瘤体的生长(P<0.05),同时,肺内转移结节数也呈现同样的变化趋势[慢性应激组(10.3±1.1)个,Iso(8.8±0.5)vs. 对照组(4.3±0.3)个,P<0.05];慢性应激组瘤内Beclin 1LC3-Ⅱ表达减少,而自噬的抑制性分子标志物p62表达增加(P<0.05);自噬诱导剂Rapa可逆转应激的促瘤效果[(2275.477±187.397) mm3 vs. (1360.097±213.938) mm3P<0.05]。与生理盐水组相比,NE处理后4T1细胞内Beclin 1表达减少约60%(100% vs. 39.8%±2.0%P<0.05),绿色荧光蛋白(GFP)- LC3的点状聚集也明显减少(P<0.05)。生物信息学分析显示高表达Beclin 1的乳腺癌患者生存预后更好,高表达p62者则正相反(P<0.001)结论  应激通过抑制细胞自噬促进乳腺癌的生长和转移。

[Abstract]  Objective  To investigate the potential mechanisms of chronic stress-induced breast cancer progression. Methods  Mouse breast cancer xenograft model was established by injecting 4T1 cells into 6-week-old BALB/c mice, followed by randomized into the control group (no induced stress or drug treatment), chronic stress group, Iso injection group [10 mg/(kg.d), served as positive control], chronic stress + DMSO group (served as control for drug treatment), and chronic stress +Rapa group [15 mg/(kg.d)]. The tumor size was monitored up to 21 days. The intratumor expression levels of Beclin1, LC3-, and p62 were detected. The pulmonary metastatic nodules were visualized and counted using lung ink staining. The expression of autophagy-related molecules in 4T1 cells after NE treatment was also examined in vitro. Results  Compared with the control group [(1359.7±173.9) mm3], chronic stress [(2119.7±130.0) mm3], and Iso [(1947.0±102.8) mm3] promoted the growth of breast cancer cells (P<0.05). Consistently, the lung nodules numbers were significantly increased in the chronic stress group (10.3±1.1) and the Iso group (8.8±0.5), compared to control group (4.3±0.3, P<0.05). In addition, compared to the control group, Beclin1 expression from samples of the stress group were decreased while p62 expression increased (P<0.05). Interestingly, the autophagy inducer Rapa reversed the pro-tumorigenic effect of chronic stress [(2275.477±187.397) mm3 vs. (1360.097±213.938) mm3, P<0.05]. We further confirmed that 4T1 cells treated with NE resulted in 60% decreased of Beclin1 expression in 4T1 (100% vs. 39.8%±2.0%, P<0.05) the fluorescence intensity of LC3 decreased as well (P<0.05). Bioinformatics analysis showed that breast cancer patients with high expression of Beclin1 had better survival prognosis, while those with high expression of p62 showed worse outcome (P<0.001). Conclusion  Stress promotes the growth and metastasis of breast cancer through suppressing cell autophagy.

基金项目:
国家自然科学基金(31800661);天津市自然科学基金(16JCQNJC11700);天津市大学生创新训练计划百项工程(201710055336)
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