{"title":"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。","authors":"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","doi":"10.7150/ijbs.87415","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>tRF-27</i> in regulating the resistance of HER2-positive breast cancer against trastuzumab. <i>tRF-27</i> was highly expressed in trastuzumab-resistant cells, and its expression level could predict the resistance to trastuzumab. High expression of <i>tRF-27</i> 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 <i>tRF-27</i>); RNA-immunoprecipitation (RIP) to confirm their bindings; co-immunoprecipitation (co-IP) and RNA-pulldown assay to determine the binding domains between G3BPs and <i>tRF-27</i>.<i>tRF-27</i> bound to the nuclear transport factor 2 like domain(NTF2 domain) of G3BPs through a specific sequence. <i>tRF-27</i> relied on G3BPs and NTF2 domain to increase trastuzumab tolerance. <i>tRF-27</i> competed with lysosomal associated membrane protein 1(LAMP1) for NTF2 domain, thereby inhibiting lysosomal localization of G3BPs and tuberous sclerosis complex (TSC). Overexpression of <i>tRF-27</i> 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.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 10","pages":"3923-3941"},"PeriodicalIF":8.2000,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302882/pdf/","citationCount":"0","resultStr":"{\"title\":\"<i>tRF-27</i> competitively Binds to G3BPs and Activates MTORC1 to Enhance HER2 Positive Breast Cancer Trastuzumab Tolerance.\",\"authors\":\"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\",\"doi\":\"10.7150/ijbs.87415\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <i>tRF-27</i> in regulating the resistance of HER2-positive breast cancer against trastuzumab. <i>tRF-27</i> was highly expressed in trastuzumab-resistant cells, and its expression level could predict the resistance to trastuzumab. High expression of <i>tRF-27</i> 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 <i>tRF-27</i>); RNA-immunoprecipitation (RIP) to confirm their bindings; co-immunoprecipitation (co-IP) and RNA-pulldown assay to determine the binding domains between G3BPs and <i>tRF-27</i>.<i>tRF-27</i> bound to the nuclear transport factor 2 like domain(NTF2 domain) of G3BPs through a specific sequence. <i>tRF-27</i> relied on G3BPs and NTF2 domain to increase trastuzumab tolerance. <i>tRF-27</i> competed with lysosomal associated membrane protein 1(LAMP1) for NTF2 domain, thereby inhibiting lysosomal localization of G3BPs and tuberous sclerosis complex (TSC). Overexpression of <i>tRF-27</i> 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.</p>\",\"PeriodicalId\":13762,\"journal\":{\"name\":\"International Journal of Biological Sciences\",\"volume\":\"20 10\",\"pages\":\"3923-3941\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2024-07-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302882/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Biological Sciences\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.7150/ijbs.87415\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Biological Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.7150/ijbs.87415","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
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.