Abstract
Lung cancer is the world's leading cause of cancer‐related morbidity and mortality despite advances in surgery, chemotherapy and immunotherapy; thus, there is an urgent need to find new molecules to develop novel treatment strategies. Although ncRNAs were found to account for 98% transcripts, the number of lncRNAs with distinct function in lung cancer is extremely limited. We previously demonstrated that Plasmodium infection inhibits tumour growth and metastasis, but the exact mechanisms involved have not been fully understood. In this study, we carried out RNA sequencing (RNA‐Seq) of tumour tissues isolated from LLC tumour‐bearing mice treated with either Plasmodium yoelli (Py)‐infected red blood cells or uninfected red blood cells. We found that F630028O10Rik (abbreviated as F63) is a novel lncRNA that was significantly up‐regulated in tumours isolated from mice treated with Py‐infected red blood cells compared to the control. By using gene silencing technique, F63 was found to inhibit both tumour Vascular Endothelial Growth Factor A (VEGFA) secretion and endothelial cells clone formation, migration, invasion and tube formation. Injection of cholesterol‐modified siRNA‐F63 into mice tumour tissues produced a significant increase in tumour volume, blood vessel formation and angiogenesis 17 days after injection. We further showed that inhibiting miR‐223‐3p results in the down‐regulation of VEGFA and VEGFR2 which are vital molecules for angiogenesis. These results reveal that F63 inhibit tumour growth and progression by modulating tumour angiogenesis suggesting F63 can be a novel lncRNA with great potential as a candidate molecule for gene therapy in lung cancer.
Highlights
Cancer is the major cause of death globally and is estimated to account for 9.6 million deaths in 2018, among which lung cancer is the most common,[1] and Non–small-cell lung cancer (NSCLC) accounted for about 85%
Over the past twenty years, long non-coding RNAs have been demonstrated to be involved in diverse cellular processes, including regulation of gene expression, nuclear organization and nuclear-cytoplasm trafficking through complex mechanisms.[7]
As many studies have shown, the specific function of long non-coding RNAs (lncRNAs) was closely related to the subcellular localization of lncRNA
Summary
Cancer is the major cause of death globally and is estimated to account for 9.6 million deaths in 2018, among which lung cancer is the most common,[1] and Non–small-cell lung cancer (NSCLC) accounted for about 85%. Discovering new tumour-suppressing lncRNAs and elucidating their functions is important for understanding the mechanism of tumorigenesis and is the premise to further research and development of new therapeutic targets. Meg[3] is the first lncRNA that was identified as having tumour suppressive function by inhibiting the proliferation of cancer cells and modulating the Rb pathway. Some anti-lung cancer medicines like Pabosini can activate the Rb pathway and increase the expression of Meg[3] in A549 and SK-MES-1 lung cancer cells, which provides a potential method for the treatment of lung cancer.[3] tumour-suppressing lncRNAs have potential clinical application in the treatment of NSCLC. A lncRNA named F630028O10Rik (abbreviated as F63) was found to be differentially expressed in our animal model of lung cancer. By using subcellular location and pull down assay, we found that F63 mainly locates in the nucleus and interacts with many proteins that are associated with angiogenesis and blood vessel development; we hypothesized that F63 could modulate angiogenesis during tumour development
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