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

Abstract

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 Fe2+ 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 Fe2+ 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.

LncRNA ST8SIA6-AS1 Promotes Cholangiocarcinoma Progression by Suppressing the miR-145-5p/MAL2 Axis

“…[35][36][37] Zhou et al revealed that miR-145-5p suppressed the proliferation, migration and invasion of gastric cancer epithelial cells via the ANGPT2/NOD_LIKE_RECEPTOR axis. 39 Additionally, the loss of miR-145-5p caused ceruloplasmin interference with the PHD-Iron axis and HIF-2α stabilization in lung adenocarcinoma-mediated angiogenesis. 40 In CHOL cells, Zeng et al clarified that lncRNA TUG1 sponged miR-145-5p to promote intrahepatic CAA progression and regulate glutamine metabolism via the sirt3/GDH axis.…”

Ceruloplasmin correlates with immune infiltration and serves as a prognostic biomarker in breast cancer

“…SARI knockout enhanced angiogenesis by regulating the expression of HIF-1α, VEGF and ceruloplasmin in mice [ 38 ]. In lung cancer cells, silencing ceruloplasmin enhanced the iron concentration and upregulated the activity of PHD1/2 to induce the hydroxylation of HIF-2 [ 39 ]. These results suggest that ceruloplasmin regulates HIF-2α activity through an iron/PHD cascade-dependent pathway.…”

“…These results suggest that ceruloplasmin regulates HIF-2α activity through an iron/PHD cascade-dependent pathway. Additionally, miR-145-5p directly targets ceruloplasmin expression, and increased ceruloplasmin contributes to activation of the PHD/HIF-2α/VEGF-A axis to facilitate cancer growth and metastasis in LUAD [ 39 ]. In addition to HIF-related pathways, other signaling pathways have been reported to mediate the dysregulation of ceruloplasmin.…”

Non-coding RNAs in lung cancer: emerging regulators of angiogenesis

“…MiR-145-5p can directly target ceruloplasmin (CP), and loss of miR-145-5p in LUAD induces overexpression of CP. Overexpression of CP decreases Fe 2+ and prolyl hydroxylase domain (PHD) 1/2 levels while inhibiting HIF-2α, leading to the activation of tumor angiogenesis [ 42 ]. The expression of miR-320b is down-regulated and related to improved overall survival in patients with lung cancer.…”