Cargando…

Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis

For decades, lung cancer has been the leading cause of cancer-related death worldwide. Hypoxia-inducible factors (HIFs) play critical roles in mediating lung cancer development and metastasis. The present study aims to clarify how HIF’s over-activation affects lung cancer angiogenesis not only in a...

Descripción completa

Detalles Bibliográficos
Autores principales: Tsai, Ying-Ming, Wu, Kuan-Li, Chang, Yung-Yun, Chang, Wei-An, Huang, Yung-Chi, Jian, Shu-Fang, Tsai, Pei-Hsun, Lin, Yi-Shiuan, Chong, Inn-Wen, Hung, Jen-Yu, Hsu, Ya-Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404111/
https://www.ncbi.nlm.nih.gov/pubmed/32708433
http://dx.doi.org/10.3390/ijms21145081
_version_ 1783567080285536256
author Tsai, Ying-Ming
Wu, Kuan-Li
Chang, Yung-Yun
Chang, Wei-An
Huang, Yung-Chi
Jian, Shu-Fang
Tsai, Pei-Hsun
Lin, Yi-Shiuan
Chong, Inn-Wen
Hung, Jen-Yu
Hsu, Ya-Ling
author_facet Tsai, Ying-Ming
Wu, Kuan-Li
Chang, Yung-Yun
Chang, Wei-An
Huang, Yung-Chi
Jian, Shu-Fang
Tsai, Pei-Hsun
Lin, Yi-Shiuan
Chong, Inn-Wen
Hung, Jen-Yu
Hsu, Ya-Ling
author_sort Tsai, Ying-Ming
collection PubMed
description For decades, lung cancer has been the leading cause of cancer-related death worldwide. Hypoxia-inducible factors (HIFs) play critical roles in mediating lung cancer development and metastasis. The present study aims to clarify how HIF’s over-activation affects lung cancer angiogenesis not only in a normoxic condition, but also a hypoxic niche. Our study shows that human lung cancer exhibits elevated levels of ceruloplasmin (CP), which has a negative impact on the prognosis of patients. CP affects the cellular Fe(2+) level, which inactivates prolyl hydroxylase (PHD) 1 and 2, resulting in HIF-2α enhancement. Increased HIF-2α leads to vascular endothelial growth factor-A (VEGF-A) secretion and angiogenesis. The expression of CP is under the epigenetic control of miR-145-5p. Restoration of miR-145-5p by miRNA mimics transfection decreases CP expression, increases Fe(2+) and PHD1/2 levels and HIF hydroxylation while reduced HIF-2α levels resulting in the inhibition of tumor angiogenesis. In contrast, inhibition of miR-145-5p by miRNA inhibitors increases the expression of CP and VEGF-A in lung cancer cells. Significantly, miR-145-5p expression is lost in the tumor samples of lung cancer patients, and low miR-145-5p expression is strongly correlated with a shorter overall survival time. In conclusion, the current study reveals the clinical importance and prognostic value of miR-145-5p and CP. It identifies a unique mechanism of HIF-2α over-activation, which is mediated by iron imbalance of the iron-PHD coupling that modulates tumor angiogenesis.
format Online
Article
Text
id pubmed-7404111
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-74041112020-08-11 Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis Tsai, Ying-Ming Wu, Kuan-Li Chang, Yung-Yun Chang, Wei-An Huang, Yung-Chi Jian, Shu-Fang Tsai, Pei-Hsun Lin, Yi-Shiuan Chong, Inn-Wen Hung, Jen-Yu Hsu, Ya-Ling Int J Mol Sci Article For decades, lung cancer has been the leading cause of cancer-related death worldwide. Hypoxia-inducible factors (HIFs) play critical roles in mediating lung cancer development and metastasis. The present study aims to clarify how HIF’s over-activation affects lung cancer angiogenesis not only in a normoxic condition, but also a hypoxic niche. Our study shows that human lung cancer exhibits elevated levels of ceruloplasmin (CP), which has a negative impact on the prognosis of patients. CP affects the cellular Fe(2+) level, which inactivates prolyl hydroxylase (PHD) 1 and 2, resulting in HIF-2α enhancement. Increased HIF-2α leads to vascular endothelial growth factor-A (VEGF-A) secretion and angiogenesis. The expression of CP is under the epigenetic control of miR-145-5p. Restoration of miR-145-5p by miRNA mimics transfection decreases CP expression, increases Fe(2+) and PHD1/2 levels and HIF hydroxylation while reduced HIF-2α levels resulting in the inhibition of tumor angiogenesis. In contrast, inhibition of miR-145-5p by miRNA inhibitors increases the expression of CP and VEGF-A in lung cancer cells. Significantly, miR-145-5p expression is lost in the tumor samples of lung cancer patients, and low miR-145-5p expression is strongly correlated with a shorter overall survival time. In conclusion, the current study reveals the clinical importance and prognostic value of miR-145-5p and CP. It identifies a unique mechanism of HIF-2α over-activation, which is mediated by iron imbalance of the iron-PHD coupling that modulates tumor angiogenesis. MDPI 2020-07-18 /pmc/articles/PMC7404111/ /pubmed/32708433 http://dx.doi.org/10.3390/ijms21145081 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tsai, Ying-Ming
Wu, Kuan-Li
Chang, Yung-Yun
Chang, Wei-An
Huang, Yung-Chi
Jian, Shu-Fang
Tsai, Pei-Hsun
Lin, Yi-Shiuan
Chong, Inn-Wen
Hung, Jen-Yu
Hsu, Ya-Ling
Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis
title Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis
title_full Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis
title_fullStr Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis
title_full_unstemmed Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis
title_short Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis
title_sort loss of mir-145-5p causes ceruloplasmin interference with phd-iron axis and hif-2α stabilization in lung adenocarcinoma-mediated angiogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404111/
https://www.ncbi.nlm.nih.gov/pubmed/32708433
http://dx.doi.org/10.3390/ijms21145081
work_keys_str_mv AT tsaiyingming lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT wukuanli lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT changyungyun lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT changweian lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT huangyungchi lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT jianshufang lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT tsaipeihsun lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT linyishiuan lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT chonginnwen lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT hungjenyu lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis
AT hsuyaling lossofmir1455pcausesceruloplasmininterferencewithphdironaxisandhif2astabilizationinlungadenocarcinomamediatedangiogenesis