Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression

Abstract

BackgroundOct4, a key stemness transcription factor, is overexpressed in lung cancer. Here, we reveal a novel transcription regulation of long non-coding RNAs (lncRNAs) by Oct4. LncRNAs have emerged as important players in cancer progression.MethodsOct4 chromatin-immunoprecipitation (ChIP)-sequencing and several lncRNA databases with literature annotation were integrated to identify Oct4-regulated lncRNAs. Luciferase activity, qRT-PCR and ChIP-PCR assays were conducted to examine transcription regulation of lncRNAs by Oct4. Reconstitution experiments of Oct4 and downstream lncRNAs in cell proliferation, migration and invasion assays were performed to confirm the Oct4-lncRNAs signaling axes in promoting lung cancer cell growth and motility. The expression correlations between Oct4 and lncRNAs were investigated in 124 lung cancer patients using qRT-PCR analysis. The clinical significance of Oct4/lncRNAs signaling axes were further evaluated using multivariate Cox regression and Kaplan-Meier analyses.ResultsWe confirmed that seven lncRNAs were upregulated by direct binding of Oct4. Among them, nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and urothelial carcinoma-associated 1 (UCA1) were validated as Oct4 transcriptional targets through promoter or enhancer activation. We showed that lung cancer cells overexpressing NEAT1 or MALAT1 and the Oct4-silenced cells reconstituted with NEAT1 or MALAT1 promoted cell proliferation, migration and invasion. In addition, knockdown of NEAT1 or MALAT1 abolished Oct4-mediated lung cancer cell growth and motility. These cell-based results suggested that Oct4/NEAT1 or Oct4/MALAT1 axis promoted oncogenesis. Clinically, Oct4/NEAT1/MALAT1 co-overexpression was an independent factor for prediction of poor outcome in 124 lung cancer patients.ConclusionsOur study reveals a novel mechanism by which Oct4 transcriptionally activates NEAT1 via promoter and MALAT1 via enhancer binding to promote cell proliferation and motility, and led to lung tumorigenesis and poor prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0674-z) contains supplementary material, which is available to authorized users.

LncRNA DGCR5 promotes lung adenocarcinoma (LUAD) progression via inhibiting hsa‐mir‐22‐3p

“…A growing number of studies have indicated that lncRNAs can determine some cellular processes in cancer, including proliferation, metastasis, and differentiation (Eades et al, ; Jiang et al, ). Many earlier studies have presented that lncRNAs are associated with carcinogenesis, metastasis, prognosis, and diagnosis, and function as oncogenes or cancer suppressor genes (Chen et al, ; Jen et al, ; Nie et al, ). Herein, more studies are required to elucidate the biological and molecular mechanisms of lncRNAs on cancer.…”

High expression of long non-coding RNA MALAT1 in breast cancer is associated with poor relapse-free survival

“…The MALAT1 gene is highly conserved across mammals, suggesting that it may have important biological implications [9]. Evidence suggests that MALAT1 may act like an oncogene in several malignancies, including lung cancer [17, 24], pancreatic cancer [19], liver cancer [20], bladder cancer [25], prostate cancer[26], colon cancer [27, 28], renal cell carcinoma [18], and oral squamous cell carcinomas [29, 30]. Lowering MALAT1 expression in hepatocellular carcinoma cells resulted in reduced cell proliferation and colony formation [20].…”

Long Non-Coding RNA LINC01260 Inhibits the Proliferation, Migration and Invasion of Spinal Cord Glioma Cells by Targeting CARD11 Via the NF-κB Signaling Pathway

“…Moreover, lncRNAs might contribute to brain development, and some specific differentially expressed lncRNAs might exert strong effects on the pathogenesis of glioblastoma [25]. Furthermore, specific lncRNAs may serve as tumor inhibitors or oncogenes, which have similar functions [26]. For example, expression of Maternally Expressed Gene 3 (MEG3) is markedly reduced in glioma tissues compared to adjacent normal tissues, and MEG3 was found to enhance apoptosis and impair proliferation of U87 and U251 glioma cells [27], which was consistent with the results of the present study.…”