Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer

BackgroundMany studies have reported the roles of the extracellular hypoxia microenvironment in the tumorigenesis and metastasis of multiple cancers. However, long noncoding RNAs (lncRNAs) that induce cancer oncogenicity and metastasis of pancreatic cancer (PC) under hypoxia conditions remain unclea...

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Autores principales:	Yan Jin, Zhengming Zhang, Qiao Yu, Zhu Zeng, Hong Song, Xiaoxu Huang, Qi Kong, Hao Hu, Yabin Xia
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	pancreatic cancer lncRNA-ZEB1-AS1 Zeb1 HIF-1α metastasis hypoxia Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/adcb2240084b46029af20c9afd82eda5
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spelling	oai:doaj.org-article:adcb2240084b46029af20c9afd82eda52021-11-22T06:27:04ZPositive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer2234-943X10.3389/fonc.2021.761979https://doaj.org/article/adcb2240084b46029af20c9afd82eda52021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.761979/fullhttps://doaj.org/toc/2234-943XBackgroundMany studies have reported the roles of the extracellular hypoxia microenvironment in the tumorigenesis and metastasis of multiple cancers. However, long noncoding RNAs (lncRNAs) that induce cancer oncogenicity and metastasis of pancreatic cancer (PC) under hypoxia conditions remain unclear.MethodsIn PC cells, the expression levels of lncRNAs in different conditions (normoxia or hypoxia) were compared through RNA sequencing (RNA-seq). The effects of the zinc finger E-box-binding homeobox 1 (ZEB1-AS1) antisense lncRNA on PC cells cultured in normoxia/hypoxia medium were measured through gain and loss-of-function experiments. Fluorescence in situ hybridization and luciferase reporter assays in addition to in vivo studies were utilized to explore the adaptive mechanisms of ZEB1-AS1 in the hypoxia-promoted proliferation, migration, and invasion ability of PC cells. Moreover, the level of ZEB1-AS1 and its associated targets or pathways were investigated in both PC and pancreatic normal tissues.ResultsRNA-seq revealed that ZEB1-AS1 was significantly upregulated in PC cells under hypoxia conditions. The ZEB1-AS1 expression level was closely associated with poor prognosis of PC patients. Knockdown of ZEB1-AS1 suppressed the proliferation, migration, and invasion of PC cells in vitro as well as PC xenograft tumor growth in vivo. In PC cells, RNAi-mediated reduction of ZEB1-AS1 inhibited zinc finger E-box-binding homeobox 1 (ZEB1), while ZEB1-AS1 overexpression rescued ZEB1 expression, indicating that ZEB1-AS1 promotes ZEB1 expression. Moreover, hypoxia-inducible factor-1α (HIF-1α)induced the expression of ZEB1-AS1 by binding to the ZEB1-AS1 promoter, which contains a putative hypoxia response element (HRE). Mechanistically, ZEB1-AS1 scaffolded the interaction among HIF-1α, ZEB1, and histone deacetylase 1 (HDAC1), leading to deacetylation-mediated stabilization of HIF-1α. We further revealed that ZEB1 induced the deacetylase capacity of HDAC1 to suppress the acetylation or degradation of HIF-1α, improving HIF-1α assembly. Thus, hypoxia-induced ZEB1-AS1 facilitated ZEB1 transcription and the stability of HIF-1α, which promoted the metastasis of PC cells. Clinically, dysregulated ZEB1 and HIF-1α expression was significantly correlated with histological grade, lymphatic metastasis, and distant metastasis in PC patients.ConclusionsOur results emphasized that the positive reciprocal loop of HIF-1α/ZEB1-AS1/ZEB1/HDAC1 contributes to hypoxia-promoted oncogenicity and PC metastasis, indicating that it might be a novel therapeutic target for PC.Yan JinZhengming ZhangQiao YuZhu ZengHong SongXiaoxu HuangQi KongHao HuYabin XiaFrontiers Media S.A.articlepancreatic cancerlncRNA-ZEB1-AS1Zeb1HIF-1αmetastasishypoxiaNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pancreatic cancer lncRNA-ZEB1-AS1 Zeb1 HIF-1α metastasis hypoxia Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	pancreatic cancer lncRNA-ZEB1-AS1 Zeb1 HIF-1α metastasis hypoxia Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yan Jin Zhengming Zhang Qiao Yu Zhu Zeng Hong Song Xiaoxu Huang Qi Kong Hao Hu Yabin Xia Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer
description	BackgroundMany studies have reported the roles of the extracellular hypoxia microenvironment in the tumorigenesis and metastasis of multiple cancers. However, long noncoding RNAs (lncRNAs) that induce cancer oncogenicity and metastasis of pancreatic cancer (PC) under hypoxia conditions remain unclear.MethodsIn PC cells, the expression levels of lncRNAs in different conditions (normoxia or hypoxia) were compared through RNA sequencing (RNA-seq). The effects of the zinc finger E-box-binding homeobox 1 (ZEB1-AS1) antisense lncRNA on PC cells cultured in normoxia/hypoxia medium were measured through gain and loss-of-function experiments. Fluorescence in situ hybridization and luciferase reporter assays in addition to in vivo studies were utilized to explore the adaptive mechanisms of ZEB1-AS1 in the hypoxia-promoted proliferation, migration, and invasion ability of PC cells. Moreover, the level of ZEB1-AS1 and its associated targets or pathways were investigated in both PC and pancreatic normal tissues.ResultsRNA-seq revealed that ZEB1-AS1 was significantly upregulated in PC cells under hypoxia conditions. The ZEB1-AS1 expression level was closely associated with poor prognosis of PC patients. Knockdown of ZEB1-AS1 suppressed the proliferation, migration, and invasion of PC cells in vitro as well as PC xenograft tumor growth in vivo. In PC cells, RNAi-mediated reduction of ZEB1-AS1 inhibited zinc finger E-box-binding homeobox 1 (ZEB1), while ZEB1-AS1 overexpression rescued ZEB1 expression, indicating that ZEB1-AS1 promotes ZEB1 expression. Moreover, hypoxia-inducible factor-1α (HIF-1α)induced the expression of ZEB1-AS1 by binding to the ZEB1-AS1 promoter, which contains a putative hypoxia response element (HRE). Mechanistically, ZEB1-AS1 scaffolded the interaction among HIF-1α, ZEB1, and histone deacetylase 1 (HDAC1), leading to deacetylation-mediated stabilization of HIF-1α. We further revealed that ZEB1 induced the deacetylase capacity of HDAC1 to suppress the acetylation or degradation of HIF-1α, improving HIF-1α assembly. Thus, hypoxia-induced ZEB1-AS1 facilitated ZEB1 transcription and the stability of HIF-1α, which promoted the metastasis of PC cells. Clinically, dysregulated ZEB1 and HIF-1α expression was significantly correlated with histological grade, lymphatic metastasis, and distant metastasis in PC patients.ConclusionsOur results emphasized that the positive reciprocal loop of HIF-1α/ZEB1-AS1/ZEB1/HDAC1 contributes to hypoxia-promoted oncogenicity and PC metastasis, indicating that it might be a novel therapeutic target for PC.
format	article
author	Yan Jin Zhengming Zhang Qiao Yu Zhu Zeng Hong Song Xiaoxu Huang Qi Kong Hao Hu Yabin Xia
author_facet	Yan Jin Zhengming Zhang Qiao Yu Zhu Zeng Hong Song Xiaoxu Huang Qi Kong Hao Hu Yabin Xia
author_sort	Yan Jin
title	Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer
title_short	Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer
title_full	Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer
title_fullStr	Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer
title_full_unstemmed	Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer
title_sort	positive reciprocal feedback of lncrna zeb1-as1 and hif-1α contributes to hypoxia-promoted tumorigenesis and metastasis of pancreatic cancer
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/adcb2240084b46029af20c9afd82eda5
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Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer

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