靶向 TUBB2B 可抑制三阴性乳腺癌的生长和脑转移定植。

IF 11.4 1区 医学 Q1 ONCOLOGY
Qingling He, Jianyang Hu, Fung-Yin Ngo, Huiqi Zhang, Lin He, Hao Huang, Tan Wu, Yilin Pan, Zihan Yang, Yuanyuan Jiang, William C Cho, Wah Cheuk, Gary M Tse, Julia Y Tsang, Mengsu Yang, Liang Zhang, Xin Wang, Pui-Chi Lo, C Geoffrey Lau, Y Rebecca Chin
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引用次数: 0

摘要

本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting TUBB2B inhibits triple-negative breast cancer growth and brain-metastatic colonization.

Background: The triple-negative subtype of breast cancer is particularly challenging to treat due to its aggressiveness with a high risk of brain metastasis, and the lack of effective targeted therapies. Tubulin beta 2B class IIb (TUBB2B), a β-tubulin isoform regulating axon guidance during embryonic development, was found to be overexpressed in various types of cancers including triple-negative breast cancer (TNBC). However, its functional roles in breast cancer or metastasis remain unclear.

Methods: To identify TUBB2B as a novel molecular target in TNBC, we performed bioinformatics analysis to assess the association of TUBB2B expression and survival of patients. RNAscope in situ hybridization was used to examine TUBB2B expression in clinical breast tumor samples. The effect of TUBB2B knockdown on TNBC growth and brain metastasis colonization was evaluated by in vitro and in vivo assays. Mass spectrometry (MS) and biochemical experiments were performed to explore the underlying mechanisms. Preclinical efficacy of targeting TUBB2B was determined in xenograft studies using the siRNA-gold nanoparticle (siRNA-AuNP) approach.

Results: TUBB2B, but not other β-tubulin isoforms, is frequently overexpressed in TNBC primary tumors as well as brain metastases. We also find that upregulation of TUBB2B is associated with poor prognosis in breast cancer patients. Silencing TUBB2B induces tumor cell death and inhibits the outgrowth of brain metastasis. Mechanistically, we identify eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) as a novel interacting partner of TUBB2B, revealing a previously unexplored role of TUBB2B in translational regulation. In line with its neural-related functions, TUBB2B overexpression in TNBC cells activates astrocytes, which in turn upregulate TUBB2B in tumor cells. These findings suggest a feed-forward interaction between TUBB2B in TNBC cells and astrocytes that promotes brain metastatic colonization. Furthermore, we demonstrate the potent inhibition of TNBC xenograft growth as well as brain metastatic colonization using TUBB2B siRNA-AuNP treatment, indicating potential clinical applications of targeting TUBB2B for TNBC.

Conclusions: TUBB2B is a novel TNBC gene that plays a key role in promoting tumor cell survival and brain metastatic colonization, and can be targeted by siRNA-AuNPs as a treatment strategy.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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