中心体蛋白2通过调控DNA损伤修复促进上皮性卵巢癌铂类耐药的研究进展与展望

doi:10.12280/gjfckx.20251119

摘要/Abstract

摘要：

上皮性卵巢癌（epithelial ovarian cancer，EOC）是致命的恶性肿瘤，其治疗失败和复发主要归因于铂类化疗耐药。中心体蛋白2（centrin 2，CETN2）是一种高度保守的中心体相关蛋白和DNA修复蛋白，与EOC铂类耐药相关。系统性梳理CETN2的结构与功能特征，重点聚焦于其在核苷酸切除修复（nucleotide excision repair，NER）通路中的核心作用，该通路是清除铂类药物导致的DNA交联损伤的关键机制。CETN2可能通过多重机制驱动铂类耐药，包括稳定NER损伤识别复合物（XPC复合物）增强DNA损伤修复效率、破坏中心体稳态影响基因组稳定性、调控细胞周期检查点，从而赋予EOC细胞在基因毒性压力下优势生存。此外，CETN2与XPC蛋白的关键相互作用为开发小分子抑制剂提供靶点成为可能，不仅有望直接逆转铂类耐药，还可能与多腺苷二磷酸核糖聚合酶[poly (ADP-ribose) polymerase，PARP]抑制剂产生协同效应，为同源重组修复功能正常的EOC患者提供新的联合治疗思路。但现有证据多基于生物信息学分析和临床相关性研究，缺乏功能实验验证。未来需通过分子机制深度解析和靶向干预策略开发，明确CETN2作为EOC铂类耐药逆转靶点的临床转化潜力。

关键词: 卵巢上皮癌, 铂化合物, 抗药性，肿瘤, DNA修复, 中心体蛋白2

Abstract:

Epithelial ovarian cancer (EOC) is a lethal malignancy whose treatment failure and recurrence are mainly attributed to platinum-based chemotherapy resistance. Centrin 2 (CETN2), a highly conserved centrosome-associated protein and DNA repair protein, has been implicated in platinum resistance in EOC. This review systematically outlines the structural and functional features of CETN2, focusing on its pivotal role in the nucleotide excision repair (NER) pathway, which serves as the key mechanism for removing platinum-induced DNA crosslink damage. CETN2 may drive platinum resistance through multiple mechanisms, including stabilizing the NER damage recognition complex (XPC complex) to enhance DNA damage repair efficiency, disrupting centrosome homeostasis to affect genomic stability, and regulating cell-cycle checkpoints, thereby conferring a survival advantage to EOC cells under genotoxic stress. Furthermore, the critical interaction between CETN2 and XPC protein provides a potential target for developing small-molecule inhibitors, which may not only directly reverse platinum resistance but also synergize with poly (ADP-ribose) polymerase (PARP) inhibitors, offering new combinatorial therapeutic strategies for EOC patients with intact homologous recombination repair function. However, current evidence relies heavily on bioinformatic analyses and clinical correlation studies, with a lack of functional experimental validation. Future research should focus on in-depth molecular mechanism elucidation and targeted intervention strategies to clarify the clinical translational potential of CETN2 as a reversal target for platinum resistance in EOC.

Key words: Carcinoma, ovarian epithelial, Platinum compounds, Drug resistance, neoplasm, DNA Repair, Centrin 2

韦林媛, 潘忠勉, 李力. 中心体蛋白2通过调控DNA损伤修复促进上皮性卵巢癌铂类耐药的研究进展与展望[J]. 国际妇产科学杂志, 2026, 53(2): 194-199.

WEI Lin-yuan, PAN Zhong-mian, LI Li. Research Progress and Perspectives of Centrin 2 in Promoting Platinum Resistance in Epithelial Ovarian Cancer through Regulation of DNA Damage Repair[J]. Journal of International Obstetrics and Gynecology, 2026, 53(2): 194-199.

参考文献 33

[1]	Matei E, Miron S, Blouquit Y, et al. C-terminal half of human centrin 2 behaves like a regulatory EF-hand domain[J]. Biochemistry, 2003, 42(6):1439-1450. doi: 10.1021/bi0269714. pmid: 12578356
[2]	Gatin A, Duchambon P, Rest GV, et al. Protein Dimerization via Tyr Residues: Highlight of a Slow Process with Co-Existence of Numerous Intermediates and Final Products[J]. Int J Mol Sci, 2022, 23(3):1174. doi: 10.3390/ijms23031174.
[3]	Yang J, Zhao Y, Yang B. Phosphorylation promotes the endonuclease-like activity of human centrin 2[J]. RSC Adv, 2022, 12(34):21892-21903. doi: 10.1039/d2ra03402f. pmid: 36043059
[4]	Craig TA, Benson LM, Bergen HR 3rd, et al. Metal-binding properties of human centrin-2 determined by micro-electrospray ionization mass spectrometry and UV spectroscopy[J]. J Am Soc Mass Spectrom, 2006, 17(8):1158-1171. doi: 10.1016/j.jasms.2006.04.029.
[5]	Feltes BC. Every protagonist has a sidekick: Structural aspects of human xeroderma pigmentosum-binding proteins in nucleotide excision repair[J]. Protein Sci, 2021, 30(11):2187-2205. doi: 10.1002/pro.4173. pmid: 34420242
[6]	van Eeuwen T, Shim Y, Kim HJ, et al. Cryo-EM structure of TFIIH/Rad4-Rad23-Rad33 in damaged DNA opening in nucleotide excision repair[J]. Nat Commun, 2021, 12(1):3338. doi: 10.1038/s41467-021-23684-x. pmid: 34099686
[7]	Zhao Y, Yang J, Chao J, et al. Calcium and phosphorylation double-regulating caltractin initiating target protein XPC function[J]. Int J Biol Macromol, 2019, 136:503-511. doi: 10.1016/j.ijbiomac.2019.06.095. pmid: 31202846
[8]	Khouj EM, Prosser SL, Tada H, et al. Differential requirements for the EF-hand domains of human centrin 2 in primary ciliogenesis and nucleotide excision repair[J]. J Cell Sci, 2019, 132(19):jcs228486. doi: 10.1242/jcs.228486.
[9]	Semer M, Bidon B, Larnicol A, et al. DNA repair complex licenses acetylation of H2A.Z.1 by KAT2A during transcription[J]. Nat Chem Biol, 2019, 15(10):992-1000. doi: 10.1038/s41589-019-0354-y. pmid: 31527837
[10]	Hamdi Y, Jerbi M, Romdhane L, et al. Genetic diversity and functional effect of common polymorphisms in genes involved in the first heterodimeric complex of the Nucleotide Excision Repair pathway[J]. DNA Repair(Amst), 2020, 86:102770. doi: 10.1016/j.dnarep.2019.102770.
[11]	Ronquillo CC, Hanke-Gogokhia C, Revelo MP, et al. Ciliopathy-associated IQCB1/NPHP5 protein is required for mouse photoreceptor outer segment formation[J]. FASEB J, 2016, 30(10):3400-3412. doi: 10.1096/fj.201600511R. pmid: 27328943
[12]	Ying G, Frederick JM, Baehr W. Deletion of both centrin 2 (CETN2) and CETN3 destabilizes the distal connecting cilium of mouse photoreceptors[J]. J Biol Chem, 2019, 294(11):3957-3973. doi: 10.1074/jbc.RA118.006371. pmid: 30647131
[13]	Ibrahim MM, Cai L. Top2b-Regulated Genes and Pathways Linked to Retinal Homeostasis and Degeneration[J]. Cells, 2025, 14(12):887. doi: 10.3390/cells14120887.
[14]	Bose A, Dalal SN. 14-3-3 proteins mediate the localization of Centrin2 to centrosome[J]. J Biosci, 2019, 44(2):42. doi: 10.1007/s12038-019-9867-5.
[15]	Sawant DB, Majumder S, Perkins JL, et al. Centrin 3 is an inhibitor of centrosomal Mps1 and antagonizes centrin 2 function[J]. Mol Biol Cell, 2015, 26(21):3741-3753. doi: 10.1091/mbc.E14-07-1248. pmid: 26354417
[16]	Steiert B, Icardi CM, Faris R, et al. The Chlamydia trachomatis type Ⅲ-secreted effector protein CteG induces centrosome amplification through interactions with centrin-2[J]. Proc Natl Acad Sci U S A, 2023, 120(20):e2303487120. doi: 10.1073/pnas.2303487120.
[17]	Tang H, Zi H, Zhou D, et al. Role of the nucleotide excision repair function of CETN2 in the inhibition of the sensitivity of hepatocellular carcinoma cells to oxaliplatin[J]. Carcinogenesis, 2025, 46(2):bgaf003. doi: 10.1093/carcin/bgaf003.
[18]	Qiu PY, Deng XH, Li L. High expression of CETN2 is associated with platinum resistance and poor prognosis in epithelial ovarian cancer[J]. Clin Transl Oncol, 2023, 25(5):1340-1352. doi: 10.1007/s12094-022-03031-2.
[19]	Chen Z, Xing J, Zheng C, et al. Identification of novel serum autoantibody biomarkers for early esophageal squamous cell carcinoma and high-grade intraepithelial neoplasia detection[J]. Front Oncol, 2023, 13:1161489. doi: 10.3389/fonc.2023.1161489.
[20]	Wang X, Xu C, Sun H. DNA Damage Repair-Related Genes Signature for Immune Infiltration and Outcome in Cervical Cancer[J]. Front Genet, 2022, 13:733164. doi: 10.3389/fgene.2022.733164.
[21]	Lu WC, Xie H, Yuan C, et al. Identification of potential biomarkers and candidate small molecule drugs in glioblastoma[J]. Cancer Cell Int, 2020, 20:419. doi: 10.1186/s12935-020-01515-1.
[22]	Wang T, Liu D, Wang L, et al. DNA Repair Genes Are Associated with Subtype Classification, Prognosis, and Immune Infiltration in Uveal Melanoma[J]. J Oncol, 2022, 2022:1965451. doi: 10.1155/2022/1965451.
[23]	Son JA, Ahn HR, You D, et al. Novel Gene Signatures as Prognostic Biomarkers for Predicting the Recurrence of Hepatocellular Carcinoma[J]. Cancers(Basel), 2022, 14(4):865. doi: 10.3390/cancers14040865.
[24]	Degl'Innocenti E, Poloni TE, Medici V, et al. Centrin 2: A Novel Marker of Mature and Neoplastic Human Astrocytes[J]. Front Cell Neurosci, 2022, 16:858347. doi: 10.3389/fncel.2022.858347.
[25]	Anurag M, Punturi N, Hoog J, et al. Comprehensive Profiling of DNA Repair Defects in Breast Cancer Identifies a Novel Class of Endocrine Therapy Resistance Drivers[J]. Clin Cancer Res, 2018, 24(19):4887-4899. doi: 10.1158/1078-0432.CCR-17-3702. pmid: 29793947
[26]	Kim J, Li CL, Chen X, et al. Lesion recognition by XPC, TFIIH and XPA in DNA excision repair[J]. Nature, 2023, 617(7959):170-175. doi: 10.1038/s41586-023-05959-z.
[27]	Dai D, Li Q, Zhou P, et al. Analysis of Omics Data Reveals Nucleotide Excision Repair-Related Genes Signature in Highly-Grade Serous Ovarian Cancer to Predict Prognosis[J]. Front Cell Dev Biol, 2022, 10:874588. doi: 10.3389/fcell.2022.874588.
[28]	Liu C, Zhao J, Lu W, et al. Individualized genetic network analysis reveals new therapeutic vulnerabilities in 6,700 cancer genomes[J]. PLoS Comput Biol, 2020, 16(2):e1007701. doi: 10.1371/journal.pcbi.1007701.
[29]	Damia G, Broggini M. Platinum Resistance in Ovarian Cancer: Role of DNA Repair[J]. Cancers(Basel), 2019, 11(1):119. doi: 10.3390/cancers11010119.
[30]	da Costa A, Baiocchi G. Genomic profiling of platinum-resistant ovarian cancer: The road into druggable targets[J]. Semin Cancer Biol, 2021, 77:29-41. doi: 10.1016/j.semcancer.2020.10.016. pmid: 33161141
[31]	Lheureux S, Mirza M, Coleman R. The DNA Repair Pathway as a Target for Novel Drugs in Gynecologic Cancers[J]. J Clin Oncol, 2019, 37(27):2449-2459. doi: 10.1200/JCO.19.00347. pmid: 31403862
[32]	Guffanti F, Alvisi MF, Caiola E, et al. Impact of ERCC1, XPF and DNA Polymerase β Expression on Platinum Response in Patient-Derived Ovarian Cancer Xenografts[J]. Cancers(Basel), 2020, 12(9):2398. doi: 10.3390/cancers12092398.
[33]	Degl'Innocenti E, Poloni TE, Medici V, et al. Astrocytic centrin-2 expression in entorhinal cortex correlates with Alzheimer's disease severity[J]. Glia, 2024, 72(12):2158-2177. doi: 10.1002/glia.24603. pmid: 39145525