三阴性乳腺癌顺铂化疗耐药新靶点

　　三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和HER2靶向治疗通常无效，全身治疗主要依靠化疗。顺铂是目前最有效的化疗药物之一，但是相当一部分患者或早或晚出现顺铂耐药，最终导致化疗失败。因此，迫切需要确定针对三阴性乳腺癌进展和顺铂耐药的新靶点。

　　2024年4月3日，美国科学促进会《科学》旗下《科学进展》在线发表复旦大学附属肿瘤医院邓玲①、廖莉①、张银玲①、杨绍英、胡书源、李美株、凌云霄、马晓燕、张方淋✉、邵志敏✉、李大强✉等学者的研究报告，首次发现剪接因子3a亚基2（SF3A2）通过马科林环指蛋白1（MKRN1）选择性剪接可促进三阴性乳腺癌进展和顺铂耐药。

　　该研究首先通过细胞增殖、集落形成、可穿透性细胞培养小室迁移和侵袭测定证实：SF3A2在三阴性乳腺癌组织中显著升高，并促进三阴性乳腺癌进展。

　　随后机制分析表明，泛素蛋白连接酶UBR5可促进SF3A2泛素化降解，而SF3A2反过来又调节UBR5，从而形成反馈环对这两种癌蛋白进行平衡。

　　此外，SF3A2至少部分通过特异性调节MKRN1选择性剪接并促进其主要致癌亚型MKRN1-T1表达，从而加速三阴性乳腺癌进展。

　　而且，SF3A2还可参与外源性和内源性调节细胞凋亡，导致三阴性乳腺癌细胞产生顺铂耐药。

　　因此，该研究结果表明，SF3A2可促进三阴性乳腺癌进展和顺铂耐药，有望成为三阴性乳腺癌治疗的新靶点。

Sci Adv. 2024 Apr 3;10(14):eadj4009. IF: 13.6

SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1.

Deng L, Liao L, Zhang YL, Yang SY, Hu SY, Andriani L, Ling YX, Ma XY, Zhang FL, Shao ZM, Li DQ.

Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, China.

Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins. Moreover, SF3A2 accelerated TNBC progression by, at least in part, specifically regulating the alternative splicing of makorin ring finger protein 1 (MKRN1) and promoting the expression of the dominant and oncogenic isoform, MKRN1-T1. Furthermore, SF3A2 participated in the regulation of both extrinsic and intrinsic apoptosis, leading to cisplatin resistance in TNBC cells. Collectively, these findings reveal a previously unknown role of SF3A2 in TNBC progression and cisplatin resistance, highlighting SF3A2 as a potential therapeutic target for patients with TNBC.

PMID: 38569025

DOI: 10.1126/sciadv.adj4009

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