Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis

ObjectivePancreatic cancer is associated with poor prognosis and dismal survival rates. This study aims to investigate roles of lncRNA UCA1-loaded exosomes secreted by pancreatic stellate cells (PSCs) in Gemcitabine (Gem) resistance of pancreatic cancer under hypoxia, which involves the methylation...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Yuan Chi, He Xin, Zhaoyu Liu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	pancreatic cancer hypoxia pancreatic stellate cells exosomes lncRNA UCA1 gemcitabine resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/3c8b393a922741f4b1d7d38f4ad2871c
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3c8b393a922741f4b1d7d38f4ad2871c
record_format	dspace
spelling	oai:doaj.org-article:3c8b393a922741f4b1d7d38f4ad2871c2021-11-19T06:20:38ZExosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis2234-943X10.3389/fonc.2021.671082https://doaj.org/article/3c8b393a922741f4b1d7d38f4ad2871c2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.671082/fullhttps://doaj.org/toc/2234-943XObjectivePancreatic cancer is associated with poor prognosis and dismal survival rates. This study aims to investigate roles of lncRNA UCA1-loaded exosomes secreted by pancreatic stellate cells (PSCs) in Gemcitabine (Gem) resistance of pancreatic cancer under hypoxia, which involves the methylation of SOCS3 and EZH2 recruitment.MethodsThe exosomes were isolated from PSCs and hypoxic PSCs (HPSCs), and co-cultured with pancreatic cancer cells transduced with manipulated lncRNA UCA1, EZH2, and SOCS3. The interaction among lncRNA UCA1, EZH2, and SOCS3 was characterized by RIP and ChIP assays. Next, MTT assay, flow cytometry and TUNEL staining and Transwell assay were used to detect cell viability, apoptosis, invasion, and migration. Gem-resistant pancreatic cancer cell line (GemMIA-R3) was established, which was applied in a mouse xenograft model of pancreatic cancer, with MTT assay to determine Gem sensitivity.ResultsLncRNA UCA1 was highly expressed, while SOCS3 was poorly expressed in pancreatic cancer tissues. Hypoxia induced activation of PSCs and promoted release of exosomes. LncRNA UCA1 delivered by hypoxic PSC-derived exosomes (HPSC-EXO) regulated histone methylation level in SOCS3 gene region through recruitment of EZH2. In vitro and in vivo experimental results confirmed that lncRNA UCA1-loaded HPSC-EXO promoted malignant phenotypes, inhibited apoptosis, and promoted Gem resistance of pancreatic cancer cells as well as tumorigenesis in mice.ConclusionUnder hypoxic conditions, exosomes secreted by hypoxia-induced PSCs deliver lncRNA UCA1 into pancreatic cancer cells, where lncRNA UCA1 recruits EZH2 and regulates histone methylation level in SOCS3 gene region, thereby augmenting pancreatic cancer resistance to Gem.Yuan ChiHe XinZhaoyu LiuFrontiers Media S.A.articlepancreatic cancerhypoxiapancreatic stellate cellsexosomeslncRNA UCA1gemcitabine resistanceNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pancreatic cancer hypoxia pancreatic stellate cells exosomes lncRNA UCA1 gemcitabine resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	pancreatic cancer hypoxia pancreatic stellate cells exosomes lncRNA UCA1 gemcitabine resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yuan Chi He Xin Zhaoyu Liu Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis
description	ObjectivePancreatic cancer is associated with poor prognosis and dismal survival rates. This study aims to investigate roles of lncRNA UCA1-loaded exosomes secreted by pancreatic stellate cells (PSCs) in Gemcitabine (Gem) resistance of pancreatic cancer under hypoxia, which involves the methylation of SOCS3 and EZH2 recruitment.MethodsThe exosomes were isolated from PSCs and hypoxic PSCs (HPSCs), and co-cultured with pancreatic cancer cells transduced with manipulated lncRNA UCA1, EZH2, and SOCS3. The interaction among lncRNA UCA1, EZH2, and SOCS3 was characterized by RIP and ChIP assays. Next, MTT assay, flow cytometry and TUNEL staining and Transwell assay were used to detect cell viability, apoptosis, invasion, and migration. Gem-resistant pancreatic cancer cell line (GemMIA-R3) was established, which was applied in a mouse xenograft model of pancreatic cancer, with MTT assay to determine Gem sensitivity.ResultsLncRNA UCA1 was highly expressed, while SOCS3 was poorly expressed in pancreatic cancer tissues. Hypoxia induced activation of PSCs and promoted release of exosomes. LncRNA UCA1 delivered by hypoxic PSC-derived exosomes (HPSC-EXO) regulated histone methylation level in SOCS3 gene region through recruitment of EZH2. In vitro and in vivo experimental results confirmed that lncRNA UCA1-loaded HPSC-EXO promoted malignant phenotypes, inhibited apoptosis, and promoted Gem resistance of pancreatic cancer cells as well as tumorigenesis in mice.ConclusionUnder hypoxic conditions, exosomes secreted by hypoxia-induced PSCs deliver lncRNA UCA1 into pancreatic cancer cells, where lncRNA UCA1 recruits EZH2 and regulates histone methylation level in SOCS3 gene region, thereby augmenting pancreatic cancer resistance to Gem.
format	article
author	Yuan Chi He Xin Zhaoyu Liu
author_facet	Yuan Chi He Xin Zhaoyu Liu
author_sort	Yuan Chi
title	Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis
title_short	Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis
title_full	Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis
title_fullStr	Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis
title_full_unstemmed	Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis
title_sort	exosomal lncrna uca1 derived from pancreatic stellate cells promotes gemcitabine resistance in pancreatic cancer via the socs3/ezh2 axis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/3c8b393a922741f4b1d7d38f4ad2871c
work_keys_str_mv	AT yuanchi exosomallncrnauca1derivedfrompancreaticstellatecellspromotesgemcitabineresistanceinpancreaticcancerviathesocs3ezh2axis AT hexin exosomallncrnauca1derivedfrompancreaticstellatecellspromotesgemcitabineresistanceinpancreaticcancerviathesocs3ezh2axis AT zhaoyuliu exosomallncrnauca1derivedfrompancreaticstellatecellspromotesgemcitabineresistanceinpancreaticcancerviathesocs3ezh2axis
_version_	1718420306614288384

Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis

Ejemplares similares