Suppression of endothelial miR-22 mediates non-small cell lung cancer cell-induced angiogenesis

Abstract

MicroRNAs (miRNAs) expressed in endothelial cells (ECs) are powerful regulators of angiogenesis, which is essential for tumor growth and metastasis. Here, we demonstrated that miR-22 is preferentially and highly expressed in ECs, while its endothelial level is significantly downregulated in human non-small cell lung cancer (NSCLC) tissues when compared to matched nontumor lung tissues. This reduction of endothelial miR-22 is possibly induced by NSCLC cell-secreted interleukin-1β and subsequently activated transcription factor nuclear factor-κB. Endothelial miR-22 functions as a potent angiogenesis inhibitor that inhibits all of the key angiogenic activities of ECs and consequently NSCLC growth through directly targeting sirtuin 1 and fibroblast growth factor receptor 1 in ECs, leading to inactivation of AKT/mammalian target of rapamycin signaling. These findings provide insight into the molecular mechanisms of NSCLC angiogenesis and indicate that endothelial miR-22 represents a potential target for the future antiangiogenic treatment of NSCLC.

FGFR families: biological functions and therapeutic interventions in tumors

“…160 In addition, miR-22 in vascular endothelial cells in NSCLC tissues directly targets sirtuin 1 and FGFR1, inactivating their common AKT/mTOR pathway to inhibit angiogenesis and tumor cell growth. 161 In small cell lung cancer, the promotion of tumor development by FGFR1 is mediated by the phospholipase C gamma 1 pathway, and retinoblastoma-like protein 2 is negatively correlated with the expression of FGFR1. 162 FGFR1 amplification also plays a role in ovarian cancer, 163 bladder cancer, 59 renal cell carcinoma, 164 prostate cancer, 165,166 esophageal carcinoma, 167 gastric cancer, 168 colorectal cancer, 169 pancreatic cancer, 63,170 head and neck squamous cell carcinoma, 62,171 and osteosarcoma.…”

Hypoxia-induced downregulation of microRNA-186-5p in endothelial cells promotes non-small cell lung cancer angiogenesis by upregulating protein kinase C alpha

“…To assess EC purity after isolation, as previously described, 52 the cells were stained with a mouse anti-human CD31 antibody conjugated to fluorescein isothiocyanate (1:100; BD Pharmingen; BD Biosciences, Heidelberg, Germany), followed by measurement with a FACScan flow cytometer (BD Biosciences). For each sample, more than 10,000 events were acquired and analyzed using the CellQuest Pro software (BD Biosciences).…”

“…The effects of endothelial miR-186 on NSCLC vascularization and growth were investigated in a mouse flank tumor model as previously described. 52 Briefly, 1.8 × 10 6 NCm- or miR-186m-transfected HDMECs together with 1.5 × 10 5 NCI-H460 cells were suspended in 75 μL of phosphate-buffered saline and then injected subcutaneously into the right flank of NOD-SCID mice (n = 9 per group; age, 8–12 weeks; weight, ∼25 g). The mice were anesthetized with isoflurane (5% induction and 1%–2% maintenance) during injection.…”

Replacement in angiogenesis research: Studying mechanisms of blood vessel development by animal-free in vitro, in vivo and in silico approaches

“…For this purpose, the cells are first grown to a confluent monolayer in a culture dish. Subsequently, a “wound” is manually scratched into the monolayer by means of a pipette tip or a cell scraper ( Gu et al, 2021 ). Because this may result in wounds of unequal size, it is also possible to put standardized silicon templates as placeholders in the culture dish prior to cell seeding, which are removed at the beginning of the experiment ( Cappiello et al, 2018 ).…”