Chang Ruimin, Xiao Xiaoxiong, Fu Yao, Zhang Chunfang, Zhu Xiaoyan, Gao Yang
Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China.
Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha, China.
Front Cell Dev Biol. 2021 Mar 4;9:631259. doi: 10.3389/fcell.2021.631259. eCollection 2021.
Lung adenocarcinoma (LUAD) is the main histological type of lung cancer, which is the leading cause of cancer-related deaths. Long non-coding RNAs (lncRNAs) were recently revealed to be involved in various cancers. However, the clinical relevance and potential biological roles of most lncRNAs in LUAD remain unclear. Here, we identified a prognosis-related lncRNA ITGB1-DT in LUAD. ITGB1-DT was upregulated in LUAD and high expression of ITGB1-DT was correlated with advanced clinical stages and poor overall survival and disease-free survival. Enhanced expression of ITGB1-DT facilitated LUAD cellular proliferation, migration, and invasion, and also lung metastasis . Knockdown of ITGB1-DT repressed LUAD cellular proliferation, migration, and invasion. ITGB1-DT interacted with EZH2, repressed the binding of EZH2 to promoter, reduced H3K27me3 levels at promoter region, and therefore activated expression. Through upregulating ITGB1, ITGB1-DT activated Wnt/β-catenin pathway and its downstream target MYC in LUAD. The expressions of ITGB1-DT, ITGB1, and MYC were positively correlated with each other in LUAD tissues. Intriguingly, ITGB1-DT was found as a transcriptional target of MYC. MYC directly transcriptionally activated ITGB1-DT expression. Thus, ITGB1-DT formed a positive feedback loop with ITGB1/Wnt/β-catenin/MYC. The oncogenic roles of ITGB1-DT were reversed by depletion of ITGB1 or inhibition of Wnt/β-catenin pathway. In summary, these findings revealed ITGB1-DT as a prognosis-related and oncogenic lncRNA in LUAD via activating the ITGB1-DT/ITGB1/Wnt/β-catenin/MYC positive feedback loop. These results implicated ITGB1-DT as a potential prognostic biomarker and therapeutic target for LUAD.
肺腺癌（LUAD）是肺癌的主要组织学类型，肺癌是癌症相关死亡的主要原因。长链非编码RNA（lncRNAs）最近被发现与多种癌症有关。然而，大多数lncRNAs在LUAD中的临床相关性和潜在生物学作用仍不清楚。在此，我们在LUAD中鉴定出一种与预后相关的lncRNA ITGB1-DT。ITGB1-DT在LUAD中上调，其高表达与晚期临床分期以及较差的总生存期和无病生存期相关。ITGB1-DT的表达增强促进了LUAD细胞的增殖、迁移和侵袭，以及肺转移。敲低ITGB1-DT可抑制LUAD细胞的增殖、迁移和侵袭。ITGB1-DT与EZH2相互作用，抑制EZH2与启动子的结合，降低启动子区域的H3K27me3水平，从而激活表达。通过上调ITGB1，ITGB1-DT激活了LUAD中的Wnt/β-连环蛋白通路及其下游靶点MYC。在LUAD组织中，ITGB1-DT、ITGB1和MYC的表达相互呈正相关。有趣的是，发现ITGB1-DT是MYC的转录靶点。MYC直接转录激活ITGB1-DT的表达。因此，ITGB1-DT与ITGB1/Wnt/β-连环蛋白/MYC形成了一个正反馈环。ITGB1或Wnt/β-连环蛋白通路的抑制可逆转ITGB1-DT的致癌作用。总之，这些发现揭示了ITGB1-DT通过激活ITGB1-DT/ITGB1/Wnt/β-连环蛋白/MYC正反馈环，是LUAD中一种与预后相关的致癌lncRNA。这些结果表明ITGB1-DT是LUAD潜在的预后生物标志物和治疗靶点。
