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RNA结合蛋白ZCCHC24促进三阴性乳腺癌的致瘤性。

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

作者信息

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

机构信息

Department of Systems Biomedicine, Institute of Science Tokyo, Tokyo, 113-8510, Japan.

Department of Surgery, Breast Surgery, Institute of Science Tokyo, Tokyo, 113-8510, Japan.

出版信息

EMBO Rep. 2024 Dec;25(12):5352-5382. doi: 10.1038/s44319-024-00282-8. Epub 2024 Oct 17.

DOI:10.1038/s44319-024-00282-8
PMID:39420119
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11624195/
Abstract

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.

摘要

三阴性乳腺癌（TNBC）缺乏激素和HER2受体的表达，恶性程度高且没有有效的治疗靶点。在TNBC中，癌症干细胞样细胞（CSC）群体被认为是治疗耐药的主要原因。因此，针对这一群体的治疗可能会显著提高患者的生存率。在此，我们发现RNA结合蛋白ZCCHC24在间充质样TNBC群体中富集。ZCCHC24通过直接结合一组与肿瘤发生和治疗耐药相关基因mRNA中的顺式元件“UGUWHWWA”来促进这些基因的表达，从而使其稳定。ZCCHC24的一个靶点ZEB1是一种转录因子，可促进癌症干性基因的表达并反过来诱导ZCCHC24的表达。通过小干扰RNA（siRNA）敲低ZCCHC24显示出治疗效果，并减少了TNBC患者来源异种移植瘤中间充质样细胞群体。敲低ZCCHC24在抑制TNBC患者来源异种移植瘤的肿瘤生长方面与BET抑制剂JQ1也具有相加作用。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db05/11624195/f6f7cedfdd4b/44319_2024_282_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db05/11624195/c4030115dbff/44319_2024_282_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db05/11624195/e28ce0a460bd/44319_2024_282_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db05/11624195/5a57f1d71bf3/44319_2024_282_Fig9_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db05/11624195/5a121e03feb6/44319_2024_282_Fig11_ESM.jpg

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