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

• Published in: International journal of molecular sciences Vol. 21; no. 14; p. 5081
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.07.2020; MDPI
• Subjects: Activation; Adenocarcinoma; Adenocarcinoma of Lung - enzymology; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - mortality; Angiogenesis; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Hypoxia - genetics; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation - genetics; Ceruloplasmin; Ceruloplasmin - genetics; Ceruloplasmin - metabolism; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Growth factors; HIF-2α; Humans; Hydroxylase; Hydroxylation; Hypoxia; Hypoxia-inducible factors; Iron; Iron - metabolism; Kinases; Lung cancer; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Metabolism; Metastases; MicroRNAs - genetics; MicroRNAs - metabolism; miR-145-5p; miRNA; Mutation; Neovascularization, Pathologic - enzymology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Prognosis; Prolyl hydroxylase; Prolyl Hydroxylases - metabolism; Proteins; Spheroids, Cellular - metabolism; Transfection; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; lung cancer; ceruloplasmin; HIF-2α; angiogenesis; miR-145-5p
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21145081

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 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 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.