Lnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids

Abstract Background Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Met...

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Autores principales:	Qingguo Li, Huizhen Sun, Dakui Luo, Lu Gan, Shaobo Mo, Weixing Dai, Lei Liang, Yufei Yang, Midie Xu, Jing Li, Peiyong Zheng, Xinxiang Li, Yan Li, Ziliang Wang
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Lnc-RP11-536 K7.3 Organoid Oxaliplatin Colon cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/8081b82ccf514fbfbfb89fb2a0cf39cc
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spelling	oai:doaj.org-article:8081b82ccf514fbfbfb89fb2a0cf39cc2021-11-08T10:44:43ZLnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids10.1186/s13046-021-02143-x1756-9966https://doaj.org/article/8081b82ccf514fbfbfb89fb2a0cf39cc2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02143-xhttps://doaj.org/toc/1756-9966Abstract Background Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.Qingguo LiHuizhen SunDakui LuoLu GanShaobo MoWeixing DaiLei LiangYufei YangMidie XuJing LiPeiyong ZhengXinxiang LiYan LiZiliang WangBMCarticleLnc-RP11-536 K7.3OrganoidOxaliplatinColon cancerNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Lnc-RP11-536 K7.3 Organoid Oxaliplatin Colon cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Lnc-RP11-536 K7.3 Organoid Oxaliplatin Colon cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Qingguo Li Huizhen Sun Dakui Luo Lu Gan Shaobo Mo Weixing Dai Lei Liang Yufei Yang Midie Xu Jing Li Peiyong Zheng Xinxiang Li Yan Li Ziliang Wang Lnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids
description	Abstract Background Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.
format	article
author	Qingguo Li Huizhen Sun Dakui Luo Lu Gan Shaobo Mo Weixing Dai Lei Liang Yufei Yang Midie Xu Jing Li Peiyong Zheng Xinxiang Li Yan Li Ziliang Wang
author_facet	Qingguo Li Huizhen Sun Dakui Luo Lu Gan Shaobo Mo Weixing Dai Lei Liang Yufei Yang Midie Xu Jing Li Peiyong Zheng Xinxiang Li Yan Li Ziliang Wang
author_sort	Qingguo Li
title	Lnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids
title_short	Lnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids
title_full	Lnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids
title_fullStr	Lnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids
title_full_unstemmed	Lnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids
title_sort	lnc-rp11-536 k7.3/sox2/hif-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids
publisher	BMC
publishDate	2021
url	https://doaj.org/article/8081b82ccf514fbfbfb89fb2a0cf39cc
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Lnc-RP11-536 K7.3/SOX2/HIF-1α signaling axis regulates oxaliplatin resistance in patient-derived colorectal cancer organoids

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