STAT1-induced upregulation of LINC00467 promotes the proliferation migration of lung adenocarcinoma cells by epigenetically silencing DKK1 to activate Wnt/β-catenin signaling pathway.

Long non-coding RNAs (lncRNAs) have been reported as essential regulators in human cancers, including lung adenocarcinoma (LUAD). In the present study, we found that lncRNA long intergenic non-protein coding RNA 467 (LINC00467) was expressed higher in TCGA LUAD samples and predicted poor prognosis in LUAD patients. High expression of LINC00467 was further detected in LUAD cell lines. Functionally, high expression level of LINC00467 promoted LUAD cell proliferation and migration, indicating that LINC00467 exerted oncogenic functions in LUAD progression. Considering the upregulation of LINC00467 in LUAD, we further detected the activator of LINC00467 promoter. Combining with bioinformatics analysis and mechanism experiments, we determined that LINC00467 was activated by STAT1 in LUAD. Moreover, high expression of LINC00467 was found to be associated with the activation of Wnt/β-catenin signaling pathway. Rescue assays demonstrated that dickkopf WNT signaling pathway inhibitor 1 (DKK1; an inhibitor of Wnt/β-catenin signaling pathway) and Wnt/β-catenin signaling involved in DKK1-mediated LUAD cell proliferation and migration. Furthermore, LINC00467 was located in the nucleus of LUAD cell lines and negatively regulated DKK1 in LUAD cells. Mechanistically, we determined that LINC00467 epigenetically silenced DKK1 by recruiting enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) to DKK1 promoter. Collectively, we determined that STAT1-induced upregulation of LINC00467 promoted LUAD progression by epigenetically silencing DKK1 to activate Wnt/β-catenin signaling pathway.

Yang J ，Liu Y ，Mai X ，Lu S ，Jin L ，Tai X ... -  《-》

EGR1-induced upregulation of lncRNA FOXD2-AS1 promotes the progression of hepatocellular carcinoma via epigenetically silencing DKK1 and activating Wnt/β-catenin signaling pathway.

Lei T ，Zhu X ，Zhu K ，Jia F ，Li S ... -  《-》

CircRNA has_circ_0006427 suppresses the progression of lung adenocarcinoma by regulating miR-6783-3p/DKK1 axis and inactivating Wnt/β-catenin signaling pathway.

Recently, circular RNAs (circRNAs) are identified as a novel class of noncoding RNAs playing important roles in human malignant tumors. However, the regulatory function of circRNA in lung adenocarcinoma (LUAD) is still largely unknown. Present study aimed to explore the role of circ_0006427 in LUAD progression. Firstly, the downregulation of circ_0006427 in LUAD tissues and cell lines was revealed by microarray analysis and qRT-PCR analysis. And we also confirmed the circ_0006427 as a prognostic target in LUAD patients. Functionally, overexpression of circ_0006427 effectively suppressed cell proliferation, migration and invasion. Mechanistically, circ_0006427 was found to be predominantly located in the cytoplasm of LUCA cell, and was further revealed to positively regulate DKK1 in LUAD by sponging miR-6783-3p. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and western blot analysis revealed that circ_0006427 inactivated Wnt/β-catenin signaling pathway by upregulating DKK1. At last, rescue assays proved the function of circ_0006427/miR-6783-3p/DKK1 axis in LUAD progression. In conclusion, our study revealed that circ_0006427 suppressed lung adenocarcinoma progression through regulating miR-6783-3p/DKK1 axis.

Yao Y ，Hua Q ，Zhou Y 《-》

Long Noncoding RNA SNHG7 Activates Wnt/β-Catenin Signaling Pathway in Cervical Cancer Cells by Epigenetically Silencing DKK1.

Chi C ，Li M ，Hou W ，Chen Y ，Zhang Y ，Chen J ... -  《-》

HIF-1ɑ-regulated miR-1275 maintains stem cell-like phenotypes and promotes the progression of LUAD by simultaneously activating Wnt/β-catenin and Notch signaling.

Rationale: Cancer stem cells (CSCs) are considered to be essential for tumorigenesis, recurrence, and metastasis and therefore serve as a biomarker for tumor progression in diverse cancers. Recent studies have illustrated that specific miRNAs exhibit novel therapeutic potential by controlling CSC properties. miR-1275 is upregulated in lung adenocarcinoma (LUAD) and enhances its stemness. However, the underlying mechanisms have not been elucidated. Methods: miRNA expression microarray of LUAD and adjacent nontumor tissues was used to identify miRNAs involved in LUAD malignant progression. miR-1275 expression level was determined using quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH), and its correlation with clinicopathological characteristics was analyzed in LUAD specimens. The upstream regulator of miR-1275 was validated by chromatin immunoprecipitation (ChIP). The biological functions and underlying mechanisms of miR-1275 were investigated both in vitro and in vivo. Results: MiR-1275 was highly upregulated in lung cancer cell lines and LUAD tissues. Overexpression of miR-1275 in lung cancer patients was associated with shorter overall- and recurrence-free-survival. Proto-oncogene HIF-1ɑ was identified as the transcription mediator of miR-1275. Activation of Wnt/β-catenin and Notch signaling by miR-1275 was found to enhance the stemness of LUAD cells, while antagonizing miR-1275 or suppressing Wnt/β-catenin and Notch pathways potently reversed miR-1275-induced pathway co-activation and stemness. Enhanced stemness dramatically promoted tumorigenicity, recurrence, and metastasis. miR-1275 directly targeted multiple antagonists of Wnt/β-catenin and Notch pathways, including DKK3, SFRP1, GSK3β, RUNX3, and NUMB, respectively, which resulted in signaling activation. Conclusions: Our findings identified miR-1275 as a potential oncogene in LUAD that exerts its tumorigenic effect through co-activating Wnt/β-catenin and Notch signaling pathways. Thus, HIF-1ɑ-regulated miR-1275 might be a potential therapeutic target for LUAD.

Jiang N ，Zou C ，Zhu Y ，Luo Y ，Chen L ，Lei Y ，Tang K ，Sun Y ，Zhang W ，Li S ，He Q ，Zhou J ，Chen Y ，Luo J ，Jiang W ，Ke Z ... -  《Theranostics》