DTNBP1基因在三阴性乳腺癌中的作用及其预后价值

doi:10.3877/cma.j.issn.1674-0807.2024.03.005

目的

探讨DTNBP1基因在三阴性乳腺癌(TNBC)中的作用及预后价值。

方法

收集TCGA数据库建库至今TNBC患者的RNA测序表达结果，共获得621个TNBC患者样本和32个正常样本。选取了与正常样本差异表达较大的前497个TNBC患者样本进行分析；通过生物信息学方法筛选差异表达基因；Kaplan-Meier生存分析探讨DTNBP1基因表达对497例TNBC患者预后的影响；采用主成分分析、GO及KEGG富集分析，探索DTNBP1基因的功能；用Cox单因素及多因素回归分析，寻找TNBC的预后因素，构建预后模型；采用实时定量PCR(qRT-PCR)检测DTNBP1在人正常乳腺上皮细胞(MCF-10A)，激素受体阳性乳腺癌细胞(MCF-7)及TNBC(HCC1937、MDA-MB-231、MDA-MB-361、MDA-MB-468)细胞系中的表达情况；选取MDA-MB-231和MDA-MB-468细胞系进行转染实验，构建DTNBP1低表达TNBC细胞；克隆形成实验和流式细胞术分别检测DTNBP1低表达细胞和对照组细胞的增殖能力和细胞周期。

结果

与正常乳腺组织相比，TNBC有3 196个差异表达基因，其中2 056个基因上调，1140个基因下调。以TNBC患者DTNBP1基因mRNA的中位表达量8.12为临界值，将497例TNBC患者分为DTNBP1高表达组(248例)和低表达组(249例)，生存分析结果提示2组患者的中位DFS分别为9.8年和18.2年，组间比较差异有统计学意义( t＝3.824，P<0.001)；主成分分析结果显示，DTNBP1高、低表达2组患者共发现1 138个差异表达基因，其中表达上调的基因有647个，表达下调的基因有491个。GO功能富集分析发现DTNBP1基因可能参与的生物过程有白细胞迁移、细胞外基质形成和细胞外骨架形成等；可能参与的细胞组分有含胶原的细胞外基质、细胞-基质结和焦点粘连等；可能参与的分子功能有细胞外基质结构组成、抗原结合和细胞黏附分子结合等。KEGG通路富集分析显示，DTNBP1可能参与的细胞通路有细胞周期、PI3K-Akt、MAPK、Hippo和TNF信号通路。Cox单因素分析发现年龄(HR＝1.099，95%CI：1.080～1.135，P＝0.004)，临床分期(HR＝2.885，95%CI：1.743～4.284，P<0.001)，T分期(HR＝12.576，95%CI：6.514～26.583，P<0.001)，远处转移(HR＝1.676，95%CI：1.477～2.201，P＝0.034)，N分期(HR＝1.922，95%CI：1.567～2.756，P＝0.006)及DTNBP1基因表达(HR＝2.934，95%CI：1.904～4.513，P<0.001)与TNBC患者的预后相关。Cox多因素分析结果显示年龄(HR＝1.168，95%CI：1.126～1.214，P<0.001)，T分期(HR＝3.771，95%CI：2.731～6.682，P＝0.002)及DTNBP1基因表达(HR＝1.563，95%CI：1.315～1.961，P<0.001)是TNBC患者的独立预后因素。采用年龄、T分期DTNBP1基因表达构建TNBC患者的临床预后模型，其校准曲线较接近于理想曲线。MCF-10A、MCF-7、HCC1937、MDA-MB-231、MDA-MB-361、MDA-MB-468中DTNBP1基因的mRNA表达量分别为1.00±0.28、1.71±0.41、3.25±0.42、6.81±0.55、2.43±0.21、5.57±0.26，组间比较差异有统计学意义(F＝7.250，P＝0.032)。与MCF-10A细胞相比，DTNBP1在MDA-MB-231(t＝－0.947，P<0.001)和MDA-MB-468细胞中表达增加(t＝－0.978，P＝0.021)；MDA-MB-231细胞分别转染sh-NC和sh-DTNBP1质粒后DTNBP1基因的mRNA表达量分别为1.00±0.05和0.33±0.04，组间比较差异有统计学意义( t＝0.078，P＝0.031)；MDA-MB-468细胞分别转染sh-NC和sh-DTNBP1质粒后DTNBP1基因的mRNA表达量分别为1.00±0.10和0.18±0.07，组间比较差异有统计学意义( t＝0.080，P<0.001)；MDA-MB-231细胞转染sh-NC和sh-DTNBP1质粒后的细胞克隆数分别为100.00±10.00和24.00±7.00，组间比较差异有统计学意义( t＝158.771，P<0.001)；MDA-MB-468细胞转染sh-NC和sh-DTNBP1质粒后的细胞克隆数分别为100.00±7.00和17.00±4.00，组间比较差异有统计学意义( t＝169.778，P<0.001)；流式细胞周期实验结果显示，转染sh-NC质粒的MDA-MB-231细胞在G₀/G₁期、S期及G₂/M期的细胞数分别为31.94±4.50、25.23±1.20和42.83±1.80，转染sh-DTNBP1质粒的MDA-MB-231细胞在G₀/G₁期、S期及G₂/M期细胞数分别为52.39±3.10、20.11±1.90和27.25±2.40，2组细胞周期分布比较差异有统计学意义( t＝－74.063，P＝0.026)；转染sh-NC质粒的MDA-MB-468细胞在G₀/G₁期、S期及G₂/M期的细胞数分别为43.15±2.50、31.26±2.90和25.59±3.60，转染sh-DTNBP1质粒的MDA-MB-468细胞在G₀/G₁期、S期及G₂/M期的细胞数分别为64.70±3.00、23.24±3.10和12.06±2.30，2组细胞周期分布比较差异有统计学意义( t＝－64.992，P＝0.037)。

结论

DTNBP1可能作为TNBC的潜在治疗靶点，其表达水平与TNBC患者的预后密切相关。

关键词: 乳腺肿瘤, 生物信息学, 预后, DTNBP1

Objective

To investigate the role and prognostic value of the DTNBP1 gene in triple negative breast cancer (TNBC).

Methods

RNA sequencing expression profiles of TNBC patients were collected in the TCGA database from the establishment, yielding 621 TNBC patient samples and 32 normal samples. For accuracy, the top 497 TNBC patient samples with the most significant differential expression compared with normal samples were selected for analysis. Differentially expressed genes were screened using bioinformatics methods. The impact of DTNBP1 gene expression on the prognosis of 497 TNBC patients was assessed through Kaplan-Meier survival analysis. Principal component analysis (PCA), GO, and KEGG enrichment analyses were employed to explore the function of the DTNBP1 gene. Cox univariate and multivariate regression analyses were conducted to identify prognostic factors for TNBC and construct a prognostic model. Real-time quantitative PCR (qRT-PCR) was used to detect DTNBP1 expression in normal human mammary epithelial cells (MCF-10A), hormone receptor-positive breast cancer cells (MCF-7), and TNBC cells (HCC1937, MDA-MB-231, MDA-MB-361, MDA-MB-468). Transfection experiments were performed on MDA-MB-231 and MDA-MB-468 cells to construct DTNBP1 low-expression TNBC cells. Clonogenic assays and flow cytometry were used to assess the proliferation and cell cycle of DTNBP1 low-expression cells and control cells.

Results

Compared with normal breast tissue, TNBC tissue sample exhibited 3 196 differentially expressed genes, with 2 056 upregulated and 1 140 downregulated. Using a median DTNBP1 mRNA expression level of 8.12 as a threshold, 497 TNBC patients were divided into high expression (248 cases) and low expression (249 cases) groups. Survival analysis indicated median DFS of 9.8 years for the high expression group and 18.2 years for the low expression group, with a statistically significant difference (t=3.824, P<0.001). PCA identified 1 138 differentially expressed genes between high and low DTNBP1 expression groups, with 647 upregulated and 491 downregulated. GO enrichment analysis suggested that DTNBP1 may be involved in different biological processes (such as leukocyte migration, extracellular matrix formation, and extracellular matrix organization), cellular components (including collagen-containing extracellular matrix, cell-matrix junctions, and focal adhesions), and molecular functions (such as extracellular matrix structural constituent, antigen binding, and cell adhesion molecule binding). KEGG pathway enrichment analysis indicated potential involvement of DTNBP1 in cell cycle, PI3K-Akt signaling pathway, MAPK signaling pathway, Hippo signaling pathway and TNF signaling pathway. Cox univariate analysis identified age (HR=1.099, 95%CI: 1.080-1.135, P=0.004), clinical stage (HR=2.885, 95%CI: 1.743-4.284, P<0.001), tumor stage (HR=12.576, 95%CI: 6.514-26.583, P<0.001), distant metastasis (HR=1.676, 95%CI: 1.477-2.201, P=0.034), node stage (HR=1.922, 95%CI: 1.567-2.756, P=0.006), and DTNBP1 gene expression (HR=2.934, 95%CI: 1.904-4.513, P<0.001) as factors related to TNBC prognosis. Multivariate analysis indicated that age (HR=1.168, 95%CI: 1.126-1.214, P<0.001), tumor stage (HR=3.771, 95%CI: 2.731-6.682, P=0.002), and DTNBP1 gene expression (HR=1.563, 95%CI: 1.315-1.961, P<0.001) were independent prognostic factors for TNBC. A clinical prognostic model for TNBC patients was constructed using age, tumor stage, and DTNBP1 gene expression, with its calibration curve closely matching the ideal curve. The mRNA expression levels of the DTNBP1 gene in normal human mammary epithelial cells (MCF-10A), hormone receptor-positive breast cancer cell lines (MCF-7), and TNBC cell lines (HCC1937, MDA-MB-231, MDA-MB-361, MDA-MB-468) were 1.00±0.28, 1.71±0.41, 3.25±0.42, 6.81±0.55, 2.43±0.21 and 5.57±0.26, respectively, with significant differences between groups (F=7.250, P=0.032). Compared with MCF-10A cells, DTNBP1 expression increased in MDA-MB-231 (t=-0.947, P<0.001) and MDA-MB-468 cells (t=-0.978, P=0.021). After transfection with sh-NC and sh-DTNBP1 plasmids, the mRNA expression levels of DTNBP1 in MDA-MB-231 cells were 1.00±0.05 and 0.33±0.04, respectively, with significant differences between groups (t=0.078, P=0.031). For MDA-MB-468 cells, the mRNA expression levels were 1.00±0.10 and 0.18±0.07, respectively, with significant differences between groups (t=0.080, P<0.001). The number of cell colonies in MDA-MB-231 cells transfected with sh-NC and sh-DTNBP1 plasmids were 100.00±10.00 and 24.00±7.00, respectively, with significant differences between groups (t=158.771, P<0.001). For MDA-MB-468 cells, the number of colonies were 100.00±7.00 and 17.00±4.00, respectively, with significant differences between groups (t=169.778, P<0.001). Flow cytometry cell cycle analysis showed that the numbers of MDA-MB-231 cells in G₀/G₁, S, and G₂/M phases transfected with sh-NC plasmid were 31.94±4.50, 25.23±1.20, and 42.83±1.80, respectively. For cells transfected with sh-DTNBP1 plasmid, the numbers of MDA-MB-231 cells were 52.39±3.10, 20.11±1.90, and 27.25±2.40, respectively, with significant differences between groups (t=-74.063, P=0.026). For MDA-MB-468 cells transfected with sh-NC plasmid, the numbers of cells in G₀/G₁, S, and G₂/M phases were 43.15±2.50, 31.26±2.90, 25.59±3.60, respectively. For cells transfected with sh-DTNBP1 plasmid, the numbers of cells were 64.70±3.00, 23.24±3.10, and 12.06±2.30, respectively, with significant differences between groups (t=-64.992, P=0.037).

Conclusion

DTNBP1 may serve as a potential therapeutic target for TNBC, with its expression level closely related to the prognosis of TNBC patients.

Key words: Breast neoplasms, Bioinformatics, Prognosis, DTNBP1

表1 多因素Cox比例风险模型变量赋值表

变量	变量类型	赋值
年龄	X₁	年龄<65岁＝1；年龄≥65岁＝2
肿瘤分期	X₂	I期＝1；II期＝2；III期＝3；IV期＝4
T分期	X₃	T₁＝1；T₂＝2；T₃＝3；T₄＝4
N分期	X₄	N₀＝1；N₁＝2；N₂＝3；N₃＝4
是否远处转移	X₅	否＝1；是＝2
DTNBP1表达水平	X₆	低表达＝1；高表达＝2
生存结局	Y	生存＝0；死亡＝1

表1 多因素Cox比例风险模型变量赋值表

变量	变量类型	赋值
年龄	X₁	年龄<65岁＝1；年龄≥65岁＝2
肿瘤分期	X₂	I期＝1；II期＝2；III期＝3；IV期＝4
T分期	X₃	T₁＝1；T₂＝2；T₃＝3；T₄＝4
N分期	X₄	N₀＝1；N₁＝2；N₂＝3；N₃＝4
是否远处转移	X₅	否＝1；是＝2
DTNBP1表达水平	X₆	低表达＝1；高表达＝2
生存结局	Y	生存＝0；死亡＝1

图1 癌症基因组图谱数据库中三阴性乳腺癌与正常对照组之间差异表达的基因筛选　a、b图分别为三阴性乳腺癌与正常乳腺之间差异表达基因的热图和火山图注：a图中的每一行代表一个基因，每一列代表一个样本。颜色表示基因表达的相对水平，红色表示上调基因，蓝色表示下调基因，右上角的数值表示基因表达量，数值越高代表表达量越高；b图中每个点代表一个基因，红色点表示显著上调的基因，蓝色点表示显著下调的基因，黑色点表示无显著差异的基因，logFC为基因表达的对数倍数变化，表示某个基因在三阴性乳腺癌组和正常对照组之间表达水平的变化倍数。正值表示该基因在三阴性乳腺癌中上调，负值表示下调；-log10(fdr)为假发现率的负对数10变换值，其值越大，表示差异表达基因的显著性越高

图2 DTNBP1高、低表达三阴性乳腺癌患者的无瘤生存曲线比较注：2组比较：t＝3.824，P<0.001；DTNBP1为肌营养不良蛋白结合蛋白-1

图3 DTNBP1基因功能分析　a图为主成分分析图，DTNBP1高、低表达组之间重复性低；b图为DTNBP1高、低表达组患者差异表达基因的热图；c图为DTNBP1高、低表达组患者差异表达基因的KEGG通路富集分析；d图为DTNBP1高、低表达组患者差异表达基因之间的相关性分析注：a图中PC1为主成分1，PC2为主成分2，PC3为主成分3；b图中横坐标为样本编号，纵坐标为各个差异基因，图中红色代表基因上调表达，且红色程度越深代表基因表达越高，蓝色代表基因表达下调，蓝色程度越深代表基因表达越低，右上角的数值表示基因表达量，数值越高代表表达量越高；c图中红色代表基因表达上调，蓝色代表下调；d图中红色代表正相关，绿色代表负相关，数值代表相关程度；DTNBP1为肌营养不良蛋白结合蛋白-1

图4 三阴性乳腺癌预后预测模型的列线图注：DTNBP1为肌营养不良蛋白结合蛋白－1

图5 三阴性乳腺癌患者预后预测模型的校准曲线a、b、c图分别为1年、3年、5年的肿瘤特异性生存校准曲线

图6 DTNBP1基因敲低后MDA-MB-231和MDA-MB-468细胞克隆形成实验结果注：a、b图分别为MDA-MB-231细胞转染sh-NC(空白质粒)和sh-DTNBP1质粒后的细胞克隆；c、d图分别为MDA-MB-468细胞转染sh-NC(空白质粒)和sh-DTNBP1质粒后的细胞克隆；DTNBP1为肌营养不良蛋白结合蛋白-1

图7 DTNBP1基因敲低后MDA-MB-231和MDA-MB-468细胞流式细胞周期检测结果注：a、b图分别为MDA-MB-231细胞转染sh-NC(空白质粒)和sh-DTNBP1质粒后的细胞周期检测结果；c、d图分别为MDA-MB-468细胞转染sh-NC(空白质粒)和sh-DTNBP1质粒后的细胞周期检测结果；DTNBP1为肌营养不良蛋白结合蛋白-1

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Role of DTNBP1 in triple negative breast cancer and its prognostic value

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Role of DTNBP1 in triple negative breast cancer and its prognostic value