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陈雪珍,朱蓉,杨满英,谢婷,杨争,袁博,胡金辉.基于PI3K/Akt信号轴探究补肾活血汤治疗乳腺癌骨转移的机制研究[J].湖南中医药大学学报英文版,2023,43(2):232-239.[Click to copy
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| 基于PI3K/Akt信号轴探究补肾活血汤治疗乳腺癌骨转移的机制研究 |
| 陈雪珍,朱蓉,杨满英,谢婷,杨争,袁博,胡金辉 |
| (张家界市中医医院, 湖南 张家界 427000;湖南中医药大学, 湖南 长沙 410208;湖南中医药大学第一附属医院, 湖南 长沙 410007) |
| 摘要: |
| 目的 通过体内实验观察补肾活血汤对乳腺癌骨转移裸鼠组织破骨细胞活性及肿瘤侵袭性的影响，探究补肾活血汤治疗乳腺癌骨转移的作用机制。方法 按照完全随机法选取6只裸鼠作为空白组（蒸馏水灌胃20 mL·kg-1，每天1次）；取对数生长期4T1乳腺癌细胞接种于其余BALB/c裸鼠右侧胫骨，接种后标记，成模后进行完全随机分组并干预：模型组（蒸馏水灌胃20 mL·kg-1，每天1次）、补肾活血汤组（中药液灌胃36.67 g·kg-1，每天1次)、LY294002组（LY294002腹腔注射，50 mg·kg-1，每周2次）、补肾活血汤联合LY294002组（中药液灌胃，36.67 g·kg-1，每天1次；LY294002腹腔注射，50 mg·kg-1，每周2次）；每组6只；记录生长状况及右下肢直径。给药结束后脱颈处死，剖取瘤组织，称重，X线检测骨质破坏情况，采用HE染色法观察瘤组织病理情况，抗酒石酸酸性磷酸酶（tartrate-resistant acid phosphase, TRAP）染色评估破骨细胞活性，采用Western blot检测瘤组织中磷酸化磷酸肌醇3-激酶（phosphorylated phosphatidylinositol-3-ki-ases, p-PI3K）、磷酸化蛋白质激酶B（phosphorylated protein kinase B, p-Akt）、基质金属蛋白酶2（matrix metalloproteinase 2, MMP-2）、活化T细胞胞质核因子1（nuclear factor of activated T cells c1, NFATc1）蛋白的表达水平。结果 与空白组相比，模型组、补肾活血汤组、LY294002组及补肾活血汤联合LY294002组裸鼠右下肢可见局部肿胀，瘤体增长，以模型组增长速度最为迅速（P<0.01）。除空白组外，余各组HE染色均可见肿瘤细胞浸润，核大深染，明确发生骨转移；X线检测可见裸鼠右侧胫骨均呈现溶骨性改变，严重者骨干消失；TRAP染色可见骨转移发生后，组织破骨细胞数量增多，补肾活血汤组、LY294002组、补肾活血汤联合LY294002组破骨细胞数量均较模型组有不同程度减少。与空白组比较，模型组补肾活血汤组裸鼠瘤组织中p-PI3K、p-Akt、MMP-2和NFATc1蛋白的表达均升高（P<0.01或P<0.05）；与模型组比较，补肾活血汤组、LY294002组及补肾活血汤联合LY294002组肿瘤增长受到抑制，其中以补肾活血汤联合LY294002组抑制肿瘤生长作用最为明显（P<0.05），瘤组织中p-PI3K、p-Akt、MMP-2和NFATc1的表达均降低（P<0.01或P<0.05）；与补肾活血汤组比较，LY294002组MMP-2表达水平下降，补肾活血汤联合LY294002组裸鼠瘤组织中p-PI3K、p-Akt、MMP-2的表达均降低（P<0.01或P<0.05）。结论 补肾活血汤可通过抑制PI3K/Akt信号通路下调MMP-2及NFATc1的表达，削弱破骨细胞的活性和肿瘤细胞发生转移的能力来治疗乳腺癌骨转移。 |
| 关键词: 乳腺癌 骨转移 补肾活血汤 磷酸化肌醇3-激酶 磷酸化蛋白质激酶B 基质金属蛋白酶2 活化T细胞胞质核因子1 |
| DOI：10.3969/j.issn.1674-070X.2023.02.009 |
| Received:August 20, 2022 |
| 基金项目:湖南省教育厅基金项目（20A373）；湖南省中医药管理局重点基金项目（C2022020）；湖南省卫生健康委员会科研计划项目一般指导课题（D202304139639）；湖南中医药大学校级基金项目（2019XJJJ039）。 |
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| The mechanism of Bushen Huoxue Decoction for treating breast cancer bone metastasis based on PI3K/Akt signaling axis |
| CHEN Xuezhen,ZHU Rong,YANG Manying,XIE Ting,YANG Zheng,YUAN Bo,HU Jinhui |
| (Zhangjiajie Hospital of Chinese Medicine, Zhangjiajie, Hunan 427000, China;Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China) |
| Abstract: |
| Objective To observe the effects of Bushen Huoxue Decoction on osteoclast activity and tumor invasiveness in nude mice with breast cancer bone metastasis in vivo experiments and explore the mechanism of Bushen Huoxue Decoction for treating breast cancer bone metastasis. Methods Six nude mice were randomly selected as blank group (distilled water 20 mL/kg by gavage, once a day). The 4T1 breast cancer cells at logarithmic growth stage were inoculated into the right tibia of other BALB/c nude mice, marked and then grouped by complete randomized design and intervened after modeling. They were divided in to model group (distilled water 20 mL/kg by gavage, once a day), Bushen Huoxue Decoction group (Chinese medicine liquid 36.67 g/kg by gavage, once a day), LY294002 group (LY294002 50 mg/kg by intraperitoneal injection, twice a week), Bushen Huoxue Decoction combined with LY294002 group (Chinese medicine liquid 36.67 g/kg by gavage, once a day LY294002 50 mg/kg by intraperitoneal injection, twice a week), with 6 in each group. Growth status and diameters of right lower limb were recorded. The mice were sacrificed by cervical dislocation, the tumor tissues were dissected, weighed, and the bone destruction was detected by X-ray afterwards. The histopathologic condition of the tumor was observed by HE staining, and the activity of osteoclasts was evaluated by tartrate-resistant acid phosphatase staining (TRAP). The proteins expression levels of phosphorylated phosphoinositol-3-ki-ases (p-PI3K), phosphorylated protein kinase B (p-Akt), matrix metalloproteinase-2 (MMP-2), and nuclear factor of activated T cells c1 (NFATc1) were detected by Western blot. Results Compared with blank group, the model group, Bushen Huoxuetang group, LY294002 group and Bushen Huoxuetang combined with LY294002 group showed local swelling and tumor growth in the right lower limb of nude mice, with the fastest growth rate in the model group (P<0.01). Except the blank group, HE staining showed tumor cell infiltration, large and deep staining of nuclei, and bone metastasis. X-ray examination showed that the right tibia of nude mice showed osteolytic changes, and the diaphysis disappeared in severe cases. TRAP staining showed that the number of tissue osteoclasts increased after the occurrence of bone metastasis, and the number of osteoclasts in the Bushen Huoxuetang group, LY294002 group, Bushen Huoxuetang combined with LY294002 group were reduced to varying degrees compared with the model group. Compared with the blank group, the expressions of p-PI3K, p-Akt, MMP-2 and NFATc1 protein in the model group increased (P<0.01 or P<0.05). Compared with the model group, the tumor growth of Bushen Huoxuetang group, LY294002 group and Bushen Huoxuetang combined LY294002 group was inhibited, among which Bushen Huoxuetang combined LY294002 group had the most obvious inhibitory effect on tumor growth (P<0.05), and the expressions of p-PI3K, p-Akt, MMP-2 and NFATc1 in tumor tissues were all decreased (P<0.01 or P<0.05). Compared with Bushen Huoxuettang group, the expression level of MMP-2 in LY294002 group decreased, and the expressions of p-PI3K, p-Akt and MMP-2 in nude mice tumor tissues of Bushen Huoxuetang combined with LY294002 group decreased (P<0.01 or P<0.05). Conclusion Bushen Huoxue Decoction can inhibit the PI3K/Akt pathway to downregulate the expression of MMP-2 and NFATc1, and weaken the activity of osteoclasts and the ability of tumor cells to metastasize, so as to treat breast cancer bone metastasis. |
| Key words: breast cancer bone metastasis Bushen Huoxue Decoction phosphatidylinositol-3-ki-ases protein kinase B matrix metalloproteinase 2 nuclear factor of activated T cells c1 |
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