FOXM1 调控的驱动蛋白家族成员 23 通过激活 Wnt/β-连环蛋白通路促进三阴性乳腺癌进展。

Kinesin family member 23, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway.

机构信息

Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, PR China.

Department of Breast and Thyroid Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.

出版信息

J Exp Clin Cancer Res. 2022 May 7;41(1):168. doi: 10.1186/s13046-022-02373-7.

BACKGROUND

Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. KIF23 plays a crucial role in the tumorigenesis and cancer progression. However, the role of KIF23 in development of TNBC and the underlying mechanism remain unknown. The study aimed to elucidate the biological function and regulatory mechanism of KIF23 in TNBC.

METHODS

Quantitative real-time PCR and Western blot were used to determine the KIF23 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of KIF23 on tumor growth and metastasis in TNBC. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of KIF23 in TNBC.

RESULTS

We found that KIF23 was significantly up-regulated and associated with poor prognosis in TNBC. KIF23 could promote TNBC proliferation, migration and invasion in vitro and in vivo. KIF23 could activate Wnt/β-catenin pathway and promote EMT progression in TNBC. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of KIF23 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression.

CONCLUSIONS

Our findings elucidate WDR5/FOXM1/KIF23/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment.

背景

三阴性乳腺癌（TNBC）由于缺乏治疗靶点，与其他乳腺癌亚型相比，其恶性程度更高，预后更差。KIF23 在肿瘤发生和癌症进展中起着至关重要的作用。然而，KIF23 在 TNBC 发展中的作用及其潜在机制尚不清楚。本研究旨在阐明 KIF23 在 TNBC 中的生物学功能和调控机制。

方法

采用定量实时 PCR 和 Western blot 检测乳腺癌组织和细胞系中 KIF23 的表达。然后，进行体外和体内功能实验，研究 KIF23 对 TNBC 肿瘤生长和转移的影响。进行染色质免疫沉淀实验以阐明 KIF23 在 TNBC 中的潜在调控机制。

结果

我们发现 KIF23 在 TNBC 中显著上调，并与不良预后相关。KIF23 可以促进 TNBC 在体外和体内的增殖、迁移和侵袭。KIF23 可以激活 Wnt/β-catenin 通路并促进 EMT 进展在 TNBC 中。此外，FOXM1 通过 H3K4me3 修饰被 WDR5 上调，直接结合 KIF23 基因的启动子，促进其转录，并通过 Wnt/β-catenin 通路加速 TNBC 的进展。FOXM1 和 WDR5 的小分子抑制剂均可抑制 TNBC 的进展。