| 孙闻悦,宗 丹,葛宜枝,等.γ-干扰素联合顺铂通过调控xCT抑制三阴性乳腺癌转移的实验研究[J].肿瘤学杂志,2023,29(9):759-766. |
| γ-干扰素联合顺铂通过调控xCT抑制三阴性乳腺癌转移的实验研究 |
| Experimental Study on IFN-γ Combined with Cisplatin Inhibiting Triple-Negative Breast Cancer Metastasis by Regulating xCT |
| 投稿时间：2023-03-26 |
| DOI：10.11735/j.issn.1671-170X.2023.09.B007 |
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| 中文关键词: γ-干扰素 顺铂 xCT 谷胱甘肽 三阴性乳腺癌 转移 |
| 英文关键词:interferon-gamma cisplatin xCT glutathione triple-negative breast cancer metastasis |
| 基金项目:国家自然科学基金面上项目（81872192）；江苏省科技厅重点研发计划（BE2019756）；江苏省卫生健康委员会科研项目（K2019028） |
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| 中文摘要: |
| 摘 要：［目的］ 探讨γ-干扰素（interferon-gamma，IFN-γ）联合顺铂（cisplatin，DDP）抑制三阴性乳腺癌转移的机制。［方法］ 采用BALB/c小鼠构建三阴性乳腺癌模型，观察IFN-γ联合DDP的治疗效果。用流式细胞术检测细胞凋亡水平；CCK-8实验检测细胞增殖；实时荧光定量逆转录PCR（qRT-PCR）检测相关基因的表达；UALCAN 和 Kaplan-Meier Plotter 数据平台分析目的基因表达与乳腺癌预后的相关性；免疫组化检测肿瘤组织中目的蛋白的表达。［结果］ 各治疗组小鼠原位肿瘤体积均显著性缩小（P<0.05），而IFN-γ与DDP联合治疗组小鼠肺转移灶数目显著减少（P<0.01）。 IFN-γ联合DDP促进小鼠三阴性乳腺癌细胞4T1凋亡（P<0.001），并显著性抑制肿瘤细胞增殖（P<0.001）。成纤维细胞L929上清能促进4T1细胞增殖（P<0.01），且该作用被IFN-γ抑制（P<0.01）。谷胱甘肽促进4T1细胞增殖（P<0.001），并且消除了IFN-γ对L929上清促肿瘤增殖的抑制作用（P<0.01）。qRT-PCR结果显示，L929中胱氨酸/谷氨酸反转运体x（xCT） mRNA表达水平显著性下调（P<0.05）。数据库分析结果显示，乳腺癌患者的xCT 表达水平明显高于正常乳腺组织（P<0.001），xCT高表达与较差的无远处转移生存期存在显著性相关（P<0.01）。免疫组化结果表明，发生肺转移的乳腺癌患者肿瘤组织中xCT表达水平显著性高于未发生肺转移者（P<0.001）。 ［结论］ IFN-γ联合DDP可能通过抑制L929 xCT的表达减少谷胱甘肽分泌，从而抑制三阴性乳腺癌转移。研究有望为三阴性乳腺癌转移的临床治疗提供新思路。 |
| 英文摘要: |
| Abstract：［Objective］ To explore the mechanism of interferon-gamma(IFN-γ) and cisplatin(DDP) on inhibiting triple-negative breast cancer metastasis. ［Methods］ BALB/c mouse was used to construct triple-negative breast cancer model to evaluate the combined effect of IFN-γ and DDP. Cell apoptosis level was measured by flow cytometry and proliferation ability was measured by CCK-8 assay. Reverse transcriptial quantitative real-time PCR(qRT-PCR) was used to detect expression levels of relative genes. UALCAN and Kaplan-Meier plotter data platforms were used to analyze the correlation between prognosis and expression level of target gene. Immunohistochemistry staining was performed to detect protein expression level in clinical tumor samples. ［Results］ Tumor volume in situ greatly decreased in all groups(P<0.05). Combined therapy of IFN-γ and DDP significantly inhibited lung metastasis(P<0.01). IFN-γ combined with DDP promoted apoptosis of triple-negative breast cancer cell 4T1(P<0.001)， and greatly restrained cell proliferation(P<0.001). Fibroblast L929 supernatant actived 4T1 cell proliferation(P<0.01)， which was obviously suppressed by IFN-γ(P<0.01). Glutathione notably increased 4T1 proliferation ability(P<0.001) and relieved the inhibition of IFN-γ on L929 supernatant’s promoting 4T1 proliferation(P<0.01). qRT-PCR results revealed that mRNA expression level of cystine-glutamate trunsporter（xCT） in L929 incredibly declined(P<0.05). Database analysis results showed that xCT expression in cancer tissue was apparently higher than that in normal breast tissue(P<0.001). High level of xCT expression had incredible relevance with poor distant metastasis-free survival in patients(P<0.01). Results from immunohistochemistry demonstrated that xCT expression level in breast cancer tissues was greatly higher in patients with lung metastasis than that without lung metastasis(P<0.001). ［Conclusion］ Combined therapy of IFN-γ and DDP decreases glutathione secretion by inhibiting xCT expression in L929， thereby suppressing triple-negative breast cancer metastasis. Our study is supposed to provide a new perspective for clinical treatment of triple-negative breast cancer metastasis. |
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