LINC00461/miR-4478/E2F1 feedback loop promotes non-small cell lung cancer cell proliferation and migration

Abstract

Non-small cell lung cancer (NSCLC) is a prevalent subtype of lung cancer, whose mortality is high. Long non-coding RNAs (lncRNAs) have caught rising attentions because of their intricate roles in regulating cancerization and cancer progression. Long intergenic non-protein coding RNA 461 (LINC00461) has recently shown oncogenic potential in several cancers, but the function of LINC00461 in NSCLC remains to be investigated. Our study planned to unveil the regulatory role of LINC00461 in NSCLC. It was validated that LINC00461 was highly expressed in NSCLC tissues and cell lines and exhibited prognostic significance. Furthermore, LINC00461 expression in advanced stage was much higher than in early stage. Loss-of-function experiments suggested that LINC00461 knockdown impaired cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT). Subcellular fractionation revealed the predominant location of LINC00461 in cytoplasm. Mechanistically, LINC00461 up-regulated E2F transcription factor 1 (E2F1) expression through sponging miR-4478. Besides, E2F1 bound to the promoter of LINC00461 to induce its transcription. Finally, rescue experiments verified that LINC00461 aggravated proliferation, migration, and EMT through targeting miR-4478/E2F1 axis. In consequence, the present study illustrated that LINC00461/miR-4478/E2F1 feedback loop promoted NSCLC cell proliferation and migration, providing a new prognostic marker for NSCLC.

<p>TMPO-AS1, a Novel E2F1-Regulated lncRNA, Contributes to the Proliferation of Lung Adenocarcinoma Cells via Modulating miR-326/SOX12 Axis</p>

“…E2F1, a member of the E2F family of transcription factors known for regulating many pivotal cellular processes including cell proliferation and apoptosis, 32 , 33 has been disclosed to be a key modulator responsible for controlling cell proliferation and apoptosis in LUAD through targeting several tumor-associated genes including lncRNA, such as lncRNA-PLACT1, 34 LINC00461. 18 In the present study, we identified TMPO-AS1 as novel transcriptional target gene of E2F1 in LUAD.…”

“…Interestingly, E2F1 has been reported to be up-regulated in LUAD and promote LUAD cell proliferation as a critical regulator. 18,19 Here, we found that the expression level of E2F1 was significantly up-regulated in LUAD tissues ( Figure 5A), and positively correlated with TMPO-AS1 expression level ( Figure 5B). Next, we evaluated the regulatory effect of E2F1 on the expression of TMPO-AS1 in LUAD cells through overexpressing or silencing E2F1, and qRT-PCR results indicated that overexpression of E2F1 could upregulate the TMPO-AS1 expression level in both H838 and SK-LU-1 cells ( Figure 5C), whereas E2F1 knockdown decreased TMPO-AS1 expression ( Figure 5D).…”

Therapeutic Effects of (5R)-5-Hydroxytriptolide on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via lncRNA WAKMAR2/miR-4478/E2F1/p53 Axis

“…The results showed that the overexpression of miR-4478 significantly inhibited the luciferase activity of WT-WAKMAR2 rather than Mut-WAKMAR2 ( Figure 6E ). It has been reported that miR-4478 could target E2F1 ( 42 ). The E2F1 activates p53 transcription and regulates the cell cycle ( 43 , 44 ).…”

LncRNAs in Non-Small-Cell Lung Cancer

“…LncRNA HOXA transcript induced by transforming growth factor (TGF)-β (HIT) was shown to interact directly with E2F1 and modulate E2F1 promoter binding to increase expression of its target genes to enhance NSCLC cell proliferation [48]. LINC00461 also led to E2F1 upregulation by sponging miR-4478, where E2F1 could also bind to the promoter of LINC00461 to induce its transcription and initiate a positive feedback loop for NSCLC progression [57]. LncRNA FLVCR1 antisense gene 1 (FLVCR1-AS1) upregulated E2F3 by acting as a ceRNA for miR-573, promoting NSCLC proliferation and progression [44].…”

“…ZEB1 can also bind to the promoter of ZEB-AS1 to increase its expression, acting in a positive feedback loop to regulate EMT [98]. This is a similar mechanism to E2F1 feedback on LINC00461 expression to regulate cell-cycle progression and proliferation [57]. HIT can interact directly with ZEB1, increasing its stability and binding to the CDH1 promoter to repress E-cadherin, a marker of EMT [49].…”