结直肠癌中含溴结构域蛋白9的亚细胞定位模式及其临床意义

doi:10.6040/j.issn.1671-7554.0.2024.0184

摘要/Abstract

摘要： 目的探讨结直肠癌(colorectal cancer, CRC)中含溴结构域蛋白9(bromodomain containing 9, BRD9)的蛋白表达水平、亚细胞定位模式及其临床意义。方法收集CRC手术切除标本,采用免疫组织化学技术EnVision法检测BRD9的蛋白表达水平及其亚细胞定位,并分析其与患者临床病理特征及预后的关系。结果在508例CRC组织标本中,BRD9高表达患者为71.46%(363/508),BRD9细胞核阳性患者为80.31%(408/508);BRD9的表达与患者肿瘤大小(P=0.025)、淋巴结转移(P=0.004)、神经侵犯(P=0.043)、分化程度(P=0.017)及TNM分期(P=0.002)相关,BRD9的亚细胞定位与患者淋巴结转移(P=0.040)及TNM分期(P=0.026)相关,差异有统计学意义;BRD9高表达可作为患者的独立不良预后因素(HR=1.994,P=0.002),同时,在BRD9低表达患者中,BRD9细胞浆阳性可作为患者的独立不良预后因素(HR=8.056,P=0.001)。结论在CRC患者中BRD9的亚细胞定位模式具有异质性,其高表达及细胞浆定位与CRC的发生发展密切相关,并能够作为独立预测因子预测患者的生存预后。

关键词: 结直肠癌, 免疫组织化学, 含溴结构域蛋白9, 亚细胞定位, 预后

Abstract: Objective To investigate the protein expression level, subcellular localization pattern and clinical significance of bromodomain containing 9(BRD9)in colorectal cancer(CRC). Methods Surgical resection specimens of CRC were collected, and immunohistochemistry(EnVision method)was used to detect BRD9 protein expression and subcellular localization. The relationship between BRD9 expression and clinicopathological features and prognosis of CRC patients was analyzed. Results Among 508 CRC tissue specimens, BRD9 was overexpressed in 71.46%(363/508)of patients, and 80.31%(408/508)of patients showed nuclear positive staining in immunohistochemistry for BRD9. The expression of BRD9 was correlated with tumor size(P=0.025), lymph node metastasis(P=0.004), nerve invasion(P=0.043), differentiation grade(P=0.017)and TNM stage(P=0.002). The subcellular localization of BRD9 was correlated with lymph node metastasis(P=0.040)and TNM stage(P=0.026). The difference was statistically significant. Meanwhile, BRD9 high expression served as an independent poor prognostic factor(HR=1.994, P=0.002). More important, in patients with BRD9 low expression, cytoplasmic BRD9 expression was an independent poor prognostic factor of patients(HR=8.056, P=0.001). Conclusion The subcellular localization of BRD9 is heterogeneous in CRC patients. The high expression and cytoplasmic localization of BRD9 are related to the occurrence and development of CRC, and could be used as an independent predictor for the prognosis of CRC patients.

Key words: Colorectal cancer, Immunohistochemistry, Bromodomain containing 9, Subcellular localization, Prognosis

中图分类号:

R735.3

刘春铖,刘晓晗,魏闫若雪,李梓绮,刘玉昆,赵然. 结直肠癌中含溴结构域蛋白9的亚细胞定位模式及其临床意义[J]. 山东大学学报 (医学版), 2024, 62(4): 24-30.

LIU Chuncheng, LIU Xiaohan, WEI Yanruoxue, LI Ziqi, LIU Yukun, ZHAO Ran. Subcellular localization pattern of bromodomain containing 9 in colorectal cancer and its clinical significance[J]. Journal of Shandong University (Health Sciences), 2024, 62(4): 24-30.

参考文献

[1] Morgan E, Arnold M, Gini A,et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN [J]. Gut, 2023, 72(2):338-344.
[2] Li N, Lu B, Luo C, et al. Incidence, mortality, survival, risk factor and screening of colorectal cancer: a comparison among China, Europe, and northern America [J].Cancer Lett,2021, 522: 255-268.doi: 10.1016/j.canlet.2021.09.034.
[3] Mauri G, Sartore-Bianchi A, Russo AG, et al. Early-onset colorectal cancer in young individuals [J]. Mol Oncol, 2019, 13(2): 109-131.
[4] Ali MM, Naz S, Ashraf S, et al. Epigenetic modulation by targeting bromodomain containing protein 9(BRD9): Its therapeutic potential and selective inhibition [J]. Int J Biol Macromol, 2023, 230: 123428. doi: 10.1016/j.ijbiomac.2023.123428.
[5] Chen P, Du R, Chang Z, et al. Bromodomain-containing protein 9 activates proliferation and epithelial-mesenchymal transition of colorectal cancer via the estrogen pathway in vivo and in vitro [J]. J Gastrointest Oncol,2023, 14(2): 980-996.
[6] Zhao R, Liu Y, Wu C, et al. BRD7 promotes cell proliferation and tumor growth through stabilization of c-Myc in colorectal cancer [J]. Front Cell Dev Biol, 2021, 9: 659392. doi: 10.3389/fcell.2021.659392.
[7] Liu Y, Zhao R, Wei Y, et al. BRD7 expression and c-Myc activation forms a double-negative feedback loop that controls the cell proliferation and tumor growth of nasopharyngeal carcinoma by targeting oncogenic miR-141 [J]. J Exp Clin Cancer Res, 2018, 37(1): 64. doi: 10.1186/s13046-018-0734-2.
[8] Chen Y, Gao Z, Mohd-Ibrahim I, et al. Pan-cancer analyses of bromodomain containing 9 as a novel therapeutic target reveals its diagnostic, prognostic potential and biological mechanism in human tumours [J]. Clin Transl Med, 2024, 14(2): e1543. doi: 10.1002/ctm2.1543.
[9] Ahmed NS, Gatchalian J, Ho J, et al. BRD9 regulates interferon-stimulated genes during macrophage activation via cooperation with BET protein BRD4 [J]. Proc Natl Acad Sci U S A, 2022, 119(1): e2110812119. doi: 10.1073/pnas.2110812119.
[10] Kurata K, Samur MK, Liow P, et al. BRD9 degradation disrupts ribosome biogenesis in multiple myeloma [J]. Clin Cancer Res, 2023, 29(9): 1807-1821.
[11] Alpsoy A, Utturkar SM, Carter BC, et al. BRD9 is a critical regulator of androgen receptor signaling and prostate cancer progression [J]. Cancer Res, 2021, 81(4): 820-833.
[12] Liu T, Li Q, Jin Q, et al. Targeting HMGB1: A potential therapeutic strategy for chronic kidney disease [J]. Int J Biol Sci, 2023, 19(15): 5020-5035.
[13] Hao SH, Ma XD, Xu L, et al. Dual specific phosphatase 4 suppresses ferroptotosis and enhances sorafenib resistance in hepatocellular carcinoma [J]. Drug Resist Updat, 2024, 73: 101052. doi: 10.1016/j.drup.2024.101052.
[14] Crodian JS, Weldon BM, Tseng YC, et al. Nuclear trafficking dynamics of Bromodomain-containing protein 7(BRD7), a switch/sucrose non-fermentable(SWI/SNF)chromatin remodelling complex subunit, in porcine oocytes and cleavage-stage embryos [J]. Reprod Fertil Dev, 2019, 31(9): 1497-1506.
[15] Vivenza D, Garrone O, Brizio R, et al. Expression and subcellular localization of the bromodomain-containing protein 7 is a prognostic biomarker in breast cancer [J]. Anticancer Drugs, 2020, 31(4): 423-430.
[16] Dariya B, Aliya S, Merchant N, et al. Colorectal cancer biology, diagnosis, and therapeutic approaches [J]. Crit Rev Oncog, 2020, 25(2): 71-94.
[17] Zygulska AL, Pierzchalski P. Novel diagnostic biomarkers in colorectal cancer [J]. Int J Mol Sci, 2022, 23(2): 852. doi: 10.3390/ijms23020852.
[18] Chen H, Zhai C, Xu X, et al. Multilevel heterogeneity of colorectal cancer liver metastasis [J]. Cancers(Basel), 2023, 16(1): 59. doi: 10.3390/cancers16010059.
[19] Punt CJ, Koopman M, Vermeulen L. From tumour heterogeneity to advances in precision treatment of colorectal cancer [J]. Nat Rev Clin Oncol, 2017, 14(4): 235-246.
[20] Saoudi González N, Salvà F, Ros J, et al. Unravelling the complexity of colorectal cancer: heterogeneity, clonal evolution, and clinical implications [J]. Cancers(Basel),2023,15(16): 4020. doi: 10.3390/cancers15164020.
[21] Nguyen LH, Goel A, Chung DC. Pathways of colorectal carcinogenesis [J]. Gastroenterology, 2020, 158(2): 291-302.
[22] Hong SN. Genetic and epigenetic alterations of colorectal cancer [J]. Intest Res, 2018, 16(3): 327-337.
[23] Singh MP, Rai S, Suyal S, et al. Genetic and epigenetic markers in colorectal cancer screening: recent advances [J]. Expert Rev Mol Diagn, 2017, 17(7): 665-685.
[24] Pan Z, Zhao Y, Wang X, et al. Targeting bromodomain-containing proteins: research advances of drug discovery [J]. Mol Biomed, 2023, 4(1): 13. doi: 10.1186/s43556-023-00127-1.
[25] Marmorstein R, Zhou MM. Writers and readers of histone acetylation: structure, mechanism, and inhibition [J]. Cold Spring Harb Perspect Biol, 2014, 6(7): a018762. doi: 10.1101/cshperspect.a018762.
[26] Fujisawa T, Filippakopoulos P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer [J]. Nat Rev Mol Cell Biol, 2017, 18(4): 246-262.

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