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Vascular mimicry induced by m(6)A mediated IGFL2-AS1/AR axis contributes to pazopanib resistance in clear cell renal cell carcinoma

Metastatic clear cell renal cell carcinoma (ccRCC) is a lethal sub-type of kidney cancer. Vascular mimicry (VM) has been postulated as an alternative route to supply tumors with nutrients, playing key role in tumor development. Whether VM development is linked to pazopanib efficacy, however, remains...

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Autores principales: Cheng, Bo, Xie, Mingyue, Zhou, Yong, Li, Tian, Liu, Wanting, Yu, Wenjing, Jia, Man, Yu, Shuang, Chen, Lixuan, Dai, Rongyang, Wang, Ronghao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086028/
https://www.ncbi.nlm.nih.gov/pubmed/37037853
http://dx.doi.org/10.1038/s41420-023-01423-z
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author Cheng, Bo
Xie, Mingyue
Zhou, Yong
Li, Tian
Liu, Wanting
Yu, Wenjing
Jia, Man
Yu, Shuang
Chen, Lixuan
Dai, Rongyang
Wang, Ronghao
author_facet Cheng, Bo
Xie, Mingyue
Zhou, Yong
Li, Tian
Liu, Wanting
Yu, Wenjing
Jia, Man
Yu, Shuang
Chen, Lixuan
Dai, Rongyang
Wang, Ronghao
author_sort Cheng, Bo
collection PubMed
description Metastatic clear cell renal cell carcinoma (ccRCC) is a lethal sub-type of kidney cancer. Vascular mimicry (VM) has been postulated as an alternative route to supply tumors with nutrients, playing key role in tumor development. Whether VM development is linked to pazopanib efficacy, however, remains unclear. Here, our in vitro and in vivo models identified that VM development was profoundly increased in pazopanib resistant ccRCC as compared to the sensitive controls, which was due to the activation of IGFL2-AS1/AR/TWIST1 signaling. IGFL2-AS1, a m(6)A modified long coding RNA, was demethylated by METTL3/METTL14 complex and stabilized owing to its failing recognition by YTHDF2 upon chronic pazopanib treatment. Further mechanistic dissection illustrated that IGFL2-AS1 physically interacted with the 5’-UTR AR mRNA and neutralized the negative regulation of 5’-uORF (upstream open reading frame) on AR translation. Indeed, IGFL2-AS1 short of AR binding region failed to promote AR expression, VM formation and pazopanib resistance. In vivo xenografted mouse model also elucidated that inhibition of AR activity with enzalutamide or silence of IGFL2-AS1 with siRNAs all led to retarded growth of pazopanib resistant ccRCC tumors. Together, these results suggest that IGFL2-AS1 may represent a key player to mediate pazopanib-induced VM formation of ccRCC cells via regulating AR expression and targeting this newly identified IGFL2-AS1/AR signaling may help us to better suppress ccRCC VM formation and to increase the therapeutic efficacy of pazopanib.
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spelling pubmed-100860282023-04-12 Vascular mimicry induced by m(6)A mediated IGFL2-AS1/AR axis contributes to pazopanib resistance in clear cell renal cell carcinoma Cheng, Bo Xie, Mingyue Zhou, Yong Li, Tian Liu, Wanting Yu, Wenjing Jia, Man Yu, Shuang Chen, Lixuan Dai, Rongyang Wang, Ronghao Cell Death Discov Article Metastatic clear cell renal cell carcinoma (ccRCC) is a lethal sub-type of kidney cancer. Vascular mimicry (VM) has been postulated as an alternative route to supply tumors with nutrients, playing key role in tumor development. Whether VM development is linked to pazopanib efficacy, however, remains unclear. Here, our in vitro and in vivo models identified that VM development was profoundly increased in pazopanib resistant ccRCC as compared to the sensitive controls, which was due to the activation of IGFL2-AS1/AR/TWIST1 signaling. IGFL2-AS1, a m(6)A modified long coding RNA, was demethylated by METTL3/METTL14 complex and stabilized owing to its failing recognition by YTHDF2 upon chronic pazopanib treatment. Further mechanistic dissection illustrated that IGFL2-AS1 physically interacted with the 5’-UTR AR mRNA and neutralized the negative regulation of 5’-uORF (upstream open reading frame) on AR translation. Indeed, IGFL2-AS1 short of AR binding region failed to promote AR expression, VM formation and pazopanib resistance. In vivo xenografted mouse model also elucidated that inhibition of AR activity with enzalutamide or silence of IGFL2-AS1 with siRNAs all led to retarded growth of pazopanib resistant ccRCC tumors. Together, these results suggest that IGFL2-AS1 may represent a key player to mediate pazopanib-induced VM formation of ccRCC cells via regulating AR expression and targeting this newly identified IGFL2-AS1/AR signaling may help us to better suppress ccRCC VM formation and to increase the therapeutic efficacy of pazopanib. Nature Publishing Group UK 2023-04-11 /pmc/articles/PMC10086028/ /pubmed/37037853 http://dx.doi.org/10.1038/s41420-023-01423-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Cheng, Bo
Xie, Mingyue
Zhou, Yong
Li, Tian
Liu, Wanting
Yu, Wenjing
Jia, Man
Yu, Shuang
Chen, Lixuan
Dai, Rongyang
Wang, Ronghao
Vascular mimicry induced by m(6)A mediated IGFL2-AS1/AR axis contributes to pazopanib resistance in clear cell renal cell carcinoma
title Vascular mimicry induced by m(6)A mediated IGFL2-AS1/AR axis contributes to pazopanib resistance in clear cell renal cell carcinoma
title_full Vascular mimicry induced by m(6)A mediated IGFL2-AS1/AR axis contributes to pazopanib resistance in clear cell renal cell carcinoma
title_fullStr Vascular mimicry induced by m(6)A mediated IGFL2-AS1/AR axis contributes to pazopanib resistance in clear cell renal cell carcinoma
title_full_unstemmed Vascular mimicry induced by m(6)A mediated IGFL2-AS1/AR axis contributes to pazopanib resistance in clear cell renal cell carcinoma
title_short Vascular mimicry induced by m(6)A mediated IGFL2-AS1/AR axis contributes to pazopanib resistance in clear cell renal cell carcinoma
title_sort vascular mimicry induced by m(6)a mediated igfl2-as1/ar axis contributes to pazopanib resistance in clear cell renal cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086028/
https://www.ncbi.nlm.nih.gov/pubmed/37037853
http://dx.doi.org/10.1038/s41420-023-01423-z
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