Exosomal lncRNA FOXD3-AS1 upregulates ELAVL1 expression and activates PI3K/Akt pathway to enhance lung cancer cell proliferation, invasion, and 5-fluorouracil resistance.

Long non-coding RNA (lncRNA) FOXD3-AS1 expression is upregulated in lung cancer; however, its effect and mechanism on 5-fluorouracil (5-FU) resistance remain unclear. In this study, we determined the effects of FOXD3-AS1-enriched exosomes derived from lung cancer cells on the proliferation, invasion, and 5-FU resistance of lung cancer cells. Online bioinformatics database analysis showed that FOXD3-AS1 was upregulated in lung cancer progression. Real-time quantitative PCR results confirmed that FOXD3-AS1 expression was upregulated in lung cancer tissues and cell lines, and FOXD3-AS1 was greatly enriched in lung cancer cell-derived exosomes. ELAV-like RNA-binding protein 1 (ELAVL1) was identified as an RNA-binding protein of FOXD3-AS1. The lung cancer cell-derived exosomes promoted A549 cell proliferation and invasion and inhibited apoptosis caused by 5-FU, and transfection of si-FOXD3-AS1 or si-ELAVL1 in exosome-incubated A549 cells reversed these effects. Moreover, exosome-incubated A549 cells were co-transfected with si-FOXD3-AS1 and pcDNA-ELAVL1, showing the same cell proliferation, invasion, and 5-FU resistance as those of A549 cells treated with lung cancer cell-derived exosomes alone. Mechanistic studies identified that lung cancer cell-derived exosomes activated the PI3K/Akt pathway, and transfection of si-FOXD3-AS1 or treatment with the PI3K inhibitor LY294002 reversed the activation of the PI3K/Akt axis induced by exosomes. In conclusion, our study revealed that lung cancer cell-derived exosomal FOXD3-AS1 upregulated ELAVL1 expression and activated the PI3K/Akt pathway to promote lung cancer progression. Our findings provide a new strategy for lung cancer treatment.

Mao G ，Mu Z ，Wu DA 《-》

LncRNA TP73-AS1 promoted the progression of lung adenocarcinoma via PI3K/AKT pathway.

Lung adenocarcinoma (LAD) is one of the most common malignancies that threats human health worldwide. Long non-coding RNAs (lncRNAs) have been reported to play significant roles in tumorigenesis and might be novel biomarkers and targets for diagnosis and treatment of cancers. TP73-AS1 is a newly discovered lncRNA involved in the tumorigenesis and development of several cancers. However, its role in LAD has not been investigated yet. In the present study, we first found that TP73-AS1 expression was markedly increased in LAD tissues and cell lines and its overexpression was strongly associated with poor clinical outcomes. Then the loss/gain-of-function assays elucidated that TP73-AS1 contributed to cell proliferation, migration, and invasion in vitro, and the in vivo experiments illustrated that its knockdown inhibited tumor growth and metastasis. What was more, we discovered that phosphoinositide 3-kinase and AKT (PI3K/AKT) pathway was activated both in LAD tissues and cell lines but inactivated under TP73-AS1 silence. Moreover, the activation of this pathway could rescue the inhibitory effects of TP73-AS1 suppression on LAD cellular processes partially. These data suggested that TP73-AS1 served as an oncogene in LAD partially through activating PI3K/AKT pathway and it could be a potential target for diagnosis and treatment of LAD.

Liu C ，Ren L ，Deng J ，Wang S ... -  《-》

Research on the mechanism of exosomes from different sources influencing the progression of lung cancer.

As a key regulator of intercellular communication, exosomes are essential for tumor cells. In our study, we will explore the mechanisms of exosomes from different sources on lung cancer. We isolated CD8+T cells and cancer-associated fibroblasts (CAFs) from venous blood and tumor tissues of lung cancer patients, and isolated exosomes. MiR-2682 was high expression in CD8+T-derived exosomes, and lncRNA-FOXD3-AS1 was upregulated in CAF-derived exosomes. Online bioinformatics database analysis showed that RNA Binding Motif Protein 39 (RBM39) was identified as the target of miR-2682, and eukaryotic translation initiation factors 3B (EIF3B) was identified as the RNA binding protein of FOXD3-AS1. CD8+T-derived exosomes inhibited the growth of A549 cells and promoted apoptosis, while miR-2682 inhibits reversed these effects of CD8+T-derived exosomes. CAF-derived exosomes promoted the growth of A549 cells and inhibited apoptosis, while FOXD3-AS1 siRNA reversed the effect of CAF-derived exosomes. Mechanism studies have found that miR-2682 inhibits the growth of lung cancer cells by inhibiting the expression of RBM39. FOXD3-AS1 promoted the growth of lung cancer cells by binding to EIF3B. In vivo experiments showed that CD8+T cell-derived exosome miR-2682 inhibited lung cancer tumor formation, while CAF-derived exosome FOXD3-AS1 promoted lung cancer tumor formation. This study provides mechanistic insights into the role of miR-2682 and FOXD3-AS1 in lung cancer progression and provides new strategies for lung cancer treatment.

Mao G ，Liu J 《-》

Long non-coding RNA FOXD3 antisense RNA 1 augments anti-estrogen resistance in breast cancer cells through the microRNA-363/ trefoil factor 1/ phosphatidylinositol 3-kinase/protein kinase B axis.

Ren L ，Zhou H ，Lei L ，Zhang Y ，Cai H ，Wang X ... -  《-》

Long non-coding RNA TTN-AS1 promotes the progression of lung adenocarcinoma by regulating PTEN/PI3K/AKT signaling pathway.

Long non-coding RNA (lncRNAs), which are increasingly identified to be dysregulated in cancers, has been verified to participate in tumorigenesis and cancer development. LncRNA TTN-AS1 has been validated as an oncogene in several cancers, such as esophageal squamous cell carcinoma and cervical cancer. Here, we studied the role of TTN-AS1 in lung adenocarcinoma (LAD). The online website UCSC, NCBI and NONCODE displayed that TTN-AS1 is poorly expressed in normal lung tissue. Furtherly, we found a remarkable increase of TTN-AS1 expression in LAD cell lines in comparison with BEAS-2B cells. Functionally, silencing TTN-AS1 resulted in inhibited cell proliferation and migration in LAD cells. Mechanically, TTN-AS1 knockdown enhanced the level of PTEN protein while reduced p-AKT level. Meanwhile, PTEN inhibition observably recovered the repressive effect of TTN-AS1 silence on the biological behaviors of A549 cells. What's more, we demonstrated that TTN-AS1 modulated PTEN expression not at mRNA level but protein level. Intriguingly, TTN-AS1 was uncovered to reduce PTEN stability via inhibiting the interactivity of PTEN with MAGI2. Jointly, our findings unveiled that TTN-AS1 plays a carcinogenic part in LAD progression through destabilizing PTEN protein so as to activate PI3K/AKT pathway, therefore indicating TTN-AS1 as a promising target for LAD treatment.

Luo J ，Liu Z 《-》