目的:探究乳腺癌组织中14-3-3β蛋白的表达水平及其与临床病理特征的关系。方法:14-3-3β蛋白是YWHAB基因编码的产物,使用TCGA数据库分析YWHAB在乳腺癌及其邻近组织的表达情况。运用WGCNA算法和DAVID Bioinformatics Resources数据库进行GO生物功能及KEGG通路富集分析。通过TIMER 2.0数据库和CIBERSORT算法研究YWHAB与免疫细胞浸润之间的相关性。利用 Kaplan-Meier分析YWHAB在乳腺癌患者中的预后价值。通过免疫组织化学技术检测103例乳腺癌组织、53例乳腺纤维腺瘤组织及49例乳腺良性增生组织中14-3-3β蛋白的表达情况,结合患者的临床资料,分析14-3-3β蛋白的表达与乳腺癌临床病理特征的关系。结果:TCGA数据库分析表明YWHAB在乳腺癌组织中的表达高于其在癌旁组织中的表达(P＜0.05),YWHAB高表达的乳腺癌患者总生存期更短(P=0.026)。GO生物功能及KEGG通路富集分析显著富集于PI3K_Akt信号通路、Hepatitis C等通路,提示YWHAB可能与细胞增殖、细胞黏附及细胞迁移等功能相关。免疫相关性分析提示YWHAB的表达与肿瘤相关中性粒细胞、髓系树突状细胞以及肿瘤相关成纤维细胞存在显著相关性(P＜0.001)。相较于乳腺纤维腺瘤组织和乳腺良性增生组织,14-3-3β蛋白在乳腺癌组织中的阳性率更高(P＜0.05)。14-3-3β蛋白的表达与乳腺癌患者淋巴结转移情况及Ki67状态具有相关性(P＜0.05),而与患者的年龄、肿瘤大小、分子分型和临床分期无明显关联(P＞0.05)。结论:YWHAB表达与乳腺癌患者预后及免疫浸润具有相关性,14-3-3β蛋白在乳腺癌组织中的表达高于乳腺纤维腺瘤组织和乳腺良性增生组织,14-3-3β蛋白可能是乳腺癌的早期诊断及靶向治疗的重要生物学标志物。
Objective: To investigate the expression level of 14-3-3β protein in breast cancer tissues and its relationship with clinicopathological features. Methods: The 14-3-3β protein is a product encoded by the YWHAB gene,TCGA database was used to analyze the expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta (YWHAB) in breast cancer and its adjacent tissues. GO biological function and KEGG pathway enrichment analysis were performed using WGCNA algorithm and DAVID Bioinformatics Resources database. The correlation between YWHAB and immune cell infiltration was studied by TIMER 2.0 database and CIBERSORT algorithm. Kaplan-Meier was used to analyze the prognostic value of YWHAB in breast cancer patients. The expression of 14-3-3β protein in 103 cases of breast cancer tissues, 53 cases of breast fibroadenoma tissues and 49 cases of benign breast hyperplasia tissues was detected by immunohistochemistry. Combined with the clinical data of patients, the relationship between the expression of 14-3-3β and the clinicopathological features of breast cancer was analyzed. Results: TCGA database analysis showed that the expression of YWHAB in breast cancer tissues was higher than that in adjacent tissues (P＜0.05), and the overall survival of breast cancer patients with high expression of YWHAB was shorter (P=0.026). GO functional analysis and KEGG pathway enrichment analysis revealed significant enrichment in pathways such as PI3K-Akt signaling and Hepatitis C, suggesting that YWHAB may be associated with cellular proliferation, adhesion, and migration.Immune correlation analysis suggested that there was a significant correlation between the expression of YWHAB and immune cells such as tumor-associated neutrophils, myeloid dendritic cells, and tumor-associated fibroblasts (P＜0.001). Compared with breast fibroadenoma tissues and benign breast hyperplasia tissues, the positive expression rate of 14-3-3β in breast cancer tissues was higher (P＜0.05). The expression of 14-3-3β was correlated with lymph node metastasis and Ki67 status in breast cancer patients (P＜0.05), but not with age, tumor size, molecular typing and clinical stage (P＞0.05). Conclusion: The expression of YWHAB is correlated with the prognosis and immune infiltration of breast cancer patients. The expression of 14-3-3β protein in breast cancer tissues is higher than that in breast fibroadenoma tissues and benign breast hyperplasia tissues. 14-3-3β protein may be an important biomarker for early diagnosis and targeted therapy of breast cancer.
[1] Sibylle Loibl, Philip Poortmans, Monica Morrow, et al. Breast cancer[J]. Lancet, 2021, 397 (10286): 1750-1769.
[2] 丛佳, 石杨, 刘远远. 环状RNA同源域相互作用蛋白激酶3促进三阴乳腺癌细胞增殖和迁移的作用机制研究[J]. 实用临床医药杂志, 2022, 26(13): 93-99.
[3] Chang WH, Su KY, Yu SL. YYEI motif and oncogenicity of 14-3-3 proteins[J]. J Clin Oncol, 2015, 33(15_suppl) :e22232.
[4] Guo LL. The role of the 14-3-3 protein family in disease[J]. Theor Nat Sci, 2023, 21(1): 40-43.
[5] Seo SB, Lee JJ, Yun HH, et al. 14-3-3β depletion drives a senescence program in glioblastoma cells through the ERK/SKP2/p27 pathway[J]. Mol Neurobiol, 2018, 55(2): 1259-1270.
[6] Wu QM, Zhu J, Li F, et al. Downregulation of 14-3-3βinhibits proliferation an migration in osteosarcoma cells[J]. Mol Med Rep, 2018, 17(2): 2493-2500.
[7] 邬昊, 吕青. 全球及中国乳腺癌的流行病学趋势及防控启示:2018–2022年《全球癌症统计报告》解读[J]. 中国普外基础与临床杂志, 2024, 31(7): 796 -802.
[8] Ma DX, Yang Q, Yin K, et al. Analysis of the clinicopathological characteristics and prognosis of triple-positive breast cancer and HER2-positive breast cancer-a retrospective study[J]. Front Oncol, 2023, 12: 999894.
[9] Xia CF, Dong XS, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants[J]. Chin Med J (Engl), 2022, 135(5):584-590.
[10] Frontini-López YR, Gojanovich AD, Del Veliz S, et al. 14-3-3β isoform is specifically acetylated at Lys51 during differentiation to the osteogenic lineage[J]. J Cell Biochem, 2021, 122(12): 1767-1780.
[11] Zhao QW, Wang QZ, Li B, et al. The deubiquitinase OTUB1 inhibits gluconeogenesis by stabilizing YWHAB[J]. Cell Signal, 2024, 124: 111408.
[12] Liu L, Liu Z, Wang H, et al. 14-3-3β exerts glioma-promoting effects and is associated with malignant progression and poor prognosis in patients with glioma[J]. Exp Ther Med, 2018, 15(3): 2381-2387.
[13] Ben Djoudi Ouadda A, He Y, Calabrese V, et al. CdGAP/ARHGAP31 is regulated by RSK phosphorylation and binding to 14-3-3β adaptor protein[J]. Oncotarget, 2018, 9(14): 11646-11664.
[14] Kim Y, Kim H, Jang SW, et al. The role of 14-3-3β in transcriptional activation of estrogen receptor α and its involvement in proliferation of breast cancer cells[J]. Biochem Biophys Res Commun, 2011, 414(1): 199-204.
[15] Cao W, Zhou Q, Wang H, et al. Hypoxia promotes glioma stem cell proliferation by enhancing the 14-3-3β expression via the PI3K pathway[J]. J Immunol Res, 2022, 2022: 5799776.
[16] Ning Z F, Deng X, Li L, et al. miR-128-3p regulates chicken granulosa cell function via 14-3-3β/FoxO and PPAR-γ/LPL signaling pathways[J]. Int J Biol Macromol, 2023, 241: 124654.
[17] Frontini-López YR, Gojanovich AD, Del Veliz S, et al. 14-3-3β isoform is specifically acetylated at Lys51 during differentiation to the osteogenic lineage[J]. J Cell Biochem, 2021, 122(12): 1767-1780.
[18] Wu B, Shi X, Jiang MX, et al. Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment[J]. Mol Cancer, 2023, 22(1): 38.
[19] Sitkovskaya AO, Zlatnik EY, Kit OI, et al. Circulation of tumor cells to destroy correlations in immune system of colorectal cancer patients[J]. J Clin Oncol, 2021, 39(15_suppl): e15508.
[20] DiGiulio, Sarah. Engineering immune cells themselves to fight cancer[J]. Oncology Times, 2021, 43(12):17, 19.
[21] Liu N, Zhou HJ, Zhang XP, et al. FAM163A, a positive regulator of ERK signaling pathway, interacts with 14-3-3β and promotes cell proliferation in squamous cell lung carcinoma[J]. Onco Targets Ther, 2019, 12: 6393-6406.
[22] Boieri M, Malishkevich A, Guennoun R, et al. CD4+ T helper 2 cells suppress breast cancer by inducing terminal differentiation[J]. J Exp Med, 2022, 219(7): e20201963.
