tRF-27 与 G3BPs 竞争性结合并激活 MTORC1,从而增强 HER2 阳性乳腺癌对曲妥珠单抗的耐受性。

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY International Journal of Biological Sciences Pub Date : 2024-07-15 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.87415
Yaozhou He, Yincheng Liu, Jue Gong, Fan Yang, Chunxiao Sun, Xueqi Yan, Ningjun Duan, Yijia Hua, Tianyu Zeng, Ziyi Fu, Yan Liang, Wei Li, Xiang Huang, Jinhai Tang, Yongmei Yin
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引用次数: 0

摘要

大约 20% 的乳腺癌患者 HER2 呈阳性。tRNA衍生片段(tRFs)在多种癌症中显示出重要的调控作用。本研究旨在评估tRF-27在调节HER2阳性乳腺癌对曲妥珠单抗耐药性中的作用。tRF-27的高表达促进了曲妥珠单抗暴露细胞的生长和增殖。通过RNA-pulldown检测和质谱分析鉴定了Ras GTPase激活蛋白结合蛋白1和2(G3BPs)(tRF-27靶向的两种蛋白);通过RNA-免疫沉淀(RIP)确认了它们的结合;通过共免疫沉淀(co-IP)和RNA-pulldown检测确定了G3BPs和tRF-27之间的结合域。tRF-27与溶酶体相关膜蛋白1(LAMP1)竞争NTF2结构域,从而抑制了G3BPs和结节性硬化症复合体(TSC)的溶酶体定位。tRF-27的过表达抑制了TSCs的磷酸化,并促进了雷帕霉素机制靶点复合物1(MTORC1)的活化,从而增强了细胞增殖,诱使HER2阳性乳腺癌对曲妥珠单抗产生耐药性。
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tRF-27 competitively Binds to G3BPs and Activates MTORC1 to Enhance HER2 Positive Breast Cancer Trastuzumab Tolerance.

About 20% of breast cancer patients are positive for HER2. The efficacy of current treatments is limited by primary and secondary resistance to trastuzumab. tRNA-derived fragments (tRFs) have shown crucial regulatory roles in various cancers. This study aimed to evaluate the role of tRF-27 in regulating the resistance of HER2-positive breast cancer against trastuzumab. tRF-27 was highly expressed in trastuzumab-resistant cells, and its expression level could predict the resistance to trastuzumab. High expression of tRF-27 promoted the growth and proliferation of trastuzumab-exposed cells. RNA-pulldown assay and mass spectrometry were performed to identify Ras GTPase-activating protein-binding proteins 1 and 2 (G3BPs) (two proteins targeted by tRF-27); RNA-immunoprecipitation (RIP) to confirm their bindings; co-immunoprecipitation (co-IP) and RNA-pulldown assay to determine the binding domains between G3BPs and tRF-27.tRF-27 bound to the nuclear transport factor 2 like domain(NTF2 domain) of G3BPs through a specific sequence. tRF-27 relied on G3BPs and NTF2 domain to increase trastuzumab tolerance. tRF-27 competed with lysosomal associated membrane protein 1(LAMP1) for NTF2 domain, thereby inhibiting lysosomal localization of G3BPs and tuberous sclerosis complex (TSC). Overexpression of tRF-27 inhibited phosphorylation of TSCs and promoted the activation of mechanistic target of rapamycin complex 1(MTORC1) to enhance cell proliferation and entice the resistance of HER2-positive breast cancer against trastuzumab.

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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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