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...
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MDPI AG
2020-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/14/5081 |
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| author | Ying-Ming Tsai Kuan-Li Wu Yung-Yun Chang Wei-An Chang Yung-Chi Huang Shu-Fang Jian Pei-Hsun Tsai Yi-Shiuan Lin Inn-Wen Chong Jen-Yu Hung Ya-Ling Hsu |
| author_facet | Ying-Ming Tsai Kuan-Li Wu Yung-Yun Chang Wei-An Chang Yung-Chi Huang Shu-Fang Jian Pei-Hsun Tsai Yi-Shiuan Lin Inn-Wen Chong Jen-Yu Hung Ya-Ling Hsu |
| author_sort | Ying-Ming Tsai |
| collection | DOAJ |
| 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<sup>2+ </sup>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<sup>2+ </sup>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. |
| first_indexed | 2024-03-10T18:23:49Z |
| format | Article |
| id | doaj.art-82e91803e35845b8be952ad55fd4a6d5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T18:23:49Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-82e91803e35845b8be952ad55fd4a6d52023-11-20T07:11:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-07-012114508110.3390/ijms21145081Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated AngiogenesisYing-Ming Tsai0Kuan-Li Wu1Yung-Yun Chang2Wei-An Chang3Yung-Chi Huang4Shu-Fang Jian5Pei-Hsun Tsai6Yi-Shiuan Lin7Inn-Wen Chong8Jen-Yu Hung9Ya-Ling Hsu10Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanFor 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<sup>2+ </sup>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<sup>2+ </sup>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.https://www.mdpi.com/1422-0067/21/14/5081angiogenesisceruloplasminHIF-2αlung cancermiR-145-5p |
| spellingShingle | Ying-Ming Tsai Kuan-Li Wu Yung-Yun Chang Wei-An Chang Yung-Chi Huang Shu-Fang Jian Pei-Hsun Tsai Yi-Shiuan Lin Inn-Wen Chong Jen-Yu Hung Ya-Ling Hsu Loss of miR-145-5p Causes Ceruloplasmin Interference with PHD-Iron Axis and HIF-2α Stabilization in Lung Adenocarcinoma-Mediated Angiogenesis International Journal of Molecular Sciences angiogenesis ceruloplasmin HIF-2α lung cancer miR-145-5p |
| 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 | angiogenesis ceruloplasmin HIF-2α lung cancer miR-145-5p |
| url | https://www.mdpi.com/1422-0067/21/14/5081 |
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