LncRNA DHRS4-AS1 Inhibits the Stemness of NSCLC Cells by Sponging miR-224-3p and Upregulating TP53 and TET1.

Fei Yan,Lin Shi,Chenchen Li,Xiaoyou Li,Siwen Liu,Yuan Wu,Xiaoyue Xu,Wei Zhao

doi:10.3389/fcell.2020.585251

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. This study aimed to examine the roles of DHRS4-AS1/miR-224-3p signaling in the cancer cell stemness of NSCLC. Real-time PCR showed that DHRS4-AS1 was downregulated in cancerous tissues, and bioinformatics analysis revealed that high DHRS4-AS1 expression indicated a good prognosis for NSCLC patients. Sphere and colony formation assays showed that DHRS4-AS1 overexpression significantly suppressed NSCLC cell colony formation and stem cell-like properties. DHRS4-AS1 also abrogated the expression of OCT4, SOX2, CD34, and CD133, markedly inhibited the expression of epithelial-mesenchymal transition (EMT)-related factors, N-cadherin, ZEB1, and Vimentin, and increased E-cadherin expression in spheres. Furthermore, luciferase reporter assays and real-time PCR analysis demonstrated that DHRS4-AS1 and miR-224-3p were antagonistically repressed in NSCLC cells. RNA immunoprecipitation (RIP) analysis revealed that DHRS4-AS1 interacted with miR-224-3p. DHRS4-AS1 partially reversed the miR-224-3p-decreased TP53 and TET1, resulting in the inhibition of tumor growth in vivo. Finally, TP53 and TET1 were antagonistically regulated by DHRS4-AS1 and miR-224-3p in NSCLC cells. In conclusion, TP53- and TET1-associated DHRS4-AS1/miR-224-3p axis is an essential mechanism by which NSCLC modulates cancer cell stemness.

Highlights

Lung cancer is the most common cancer worldwide and causes the death of many patients (Chen et al, 2016; Siegel et al, 2020)
To explore the relationship between DHRS4-AS1 expression and Non-small cell lung cancer (NSCLC) patients survival, the survival rate was analyzed in GEPIA, which base on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) samples, high DHRS4AS1 expression indicated a good overall survival outcome of patients with NSCLC (Figure 1A)
Real-time PCR analysis demonstrated that DHRS4-AS1 expression was lower in NSCLC cell spheres than in parental cells (Figure 1E)

Summary

Introduction

Lung cancer is the most common cancer worldwide and causes the death of many patients (Chen et al, 2016; Siegel et al, 2020). Non-small cell lung cancer (NSCLC) is a common type of lung cancer, accounting for up to 85% of all lung cancer cases, and the 5-year survival rate of NSCLC patients remains poor (Boolell et al, 2015). Effective treatment has been achieved for NSCLC patients in the clinic, most cancers recur after surgery or radiotherapy (Wood et al, 2015; Duma et al, 2019). To produce better therapeutic strategies, it is essential to elucidate the DHRS4-AS1 Inhibits NSCLC Stemness signaling pathways of metastasis and recurrence of NSCLC progression. The recurrence of NSCLC is associated with cancer stem cells. Cancer stem cells are potentially responsible for cancer cell self-renewal, initiation, proliferation, and differentiation, can produce aggressive and metastatic tumors, as well as multidrug resistance (Kusoglu and Biray Avci, 2019)

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