RNA 结合蛋白 ZCCHC24 促进了三阴性乳腺癌的致瘤性。

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2024-10-17 DOI:10.1038/s44319-024-00282-8

Yutaro Uchida, Ryota Kurimoto, Tomoki Chiba, Takahide Matsushima, Goshi Oda, Iichiroh Onishi, Yasuto Takeuchi, Noriko Gotoh, Hiroshi Asahara

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引用次数: 0

摘要

三阴性乳腺癌（TNBC）缺乏激素和 HER2 受体的表达，恶性程度高，但没有有效的治疗靶点。在 TNBC 中，癌症干样细胞（CSC）群被认为是导致耐药性的主要原因。因此，针对这一群体的治疗可以大大提高患者的生存率。在这里，我们发现RNA结合蛋白ZCCHC24在间质样TNBC群体中富集。ZCCHC24通过直接与mRNA中的顺式元件 "UGUWHWWA "结合，促进了一组与肿瘤致病性和耐药性相关的基因的表达，从而稳定了这些基因。ZCCHC24 的靶标之一 ZEB1 是一种转录因子，它能促进癌症干性基因的表达，并相互诱导 ZCCHC24 的表达。通过 siRNA 敲除 ZCCHC24 有治疗效果，并能减少 TNBC 患者异种移植中的间质样细胞数量。在抑制 TNBC 患者异种移植的肿瘤生长方面，ZCCHC24 基因敲除与 BET 抑制剂 JQ1 还具有叠加效应。

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RNA binding protein ZCCHC24 promotes tumorigenicity in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) lacks the expression of hormone and HER2 receptors and is highly malignant with no effective therapeutic targets. In TNBC, the cancer stem-like cell (CSC) population is considered to be the main cause of resistance to treatment. Thus, the therapeutic targeting of this population could substantially improve patient survival. Here, we identify the RNA-binding protein ZCCHC24 as enriched in the mesenchymal-like TNBC population. ZCCHC24 promotes the expression of a set of genes related to tumorigenicity and treatment resistance by directly binding to the cis-element "UGUWHWWA" in their mRNAs, thereby stabilizing them. One of the ZCCHC24 targets, ZEB1, is a transcription factor that promotes the expression of cancer stemness genes and reciprocally induces ZCCHC24 expression. ZCCHC24 knockdown by siRNAs shows a therapeutic effect and reduces the mesenchymal-like cell population in TNBC patient-derived xenografts. ZCCHC24 knockdown also has additive effects with the BET inhibitor JQ1 in suppressing tumor growth in TNBC patient-derived xenografts.

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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