Analysis of Survival-Related lncRNA Landscape Identifies A Role for LINC01537 in Energy Metabolism and Lung Cancer Progression.

Wei Gong,Mingzhu Lin,Fuman Qiu,Yifeng Zhou,Yuanyuan Wang,Li Liu,Yingyi Feng,Lei Yang,Jianfeng Xian,Jiachun Lu

doi:10.3390/ijms20153713

Wei Gong, Mingzhu Lin + Show 8 more

Open Access

https://doi.org/10.3390/ijms20153713

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Abstract

Many long non-coding RNAs (lncRNAs) have emerged as good biomarkers and potential therapeutic targets for various cancers. We aimed to get a detailed understanding of the lncRNA landscape that is associated with lung cancer survival. A comparative analysis between our RNA sequencing (RNA-seq) data and TCGA datasets was conducted to reveal lncRNAs with significant correlations with lung cancer survival and then the association of the most promising lncRNA was validated in a cohort of 243 lung cancer patients. Comparing RNA-seq data with TCGA ones, 84 dysregulated lncRNAs were identified in lung cancer tissues, among which 10 lncRNAs were significantly associated with lung cancer survival. LINC01537 was the most significant one (p = 2.95 × 10−6). Validation analysis confirmed the downregulation of LINC01537 in lung cancer. LINC01537 was observed to inhibit tumor growth and metastasis. It also increased cellular sensitivity to nilotinib. PDE2A (phosphodiesterase 2A) was further identified to be a target of LINC01537 and it was seen that LINC01537 promoted PDE2A expression via RNA–RNA interaction to stabilize PDE2A mRNA and thus echoed effects of PDE2A on energy metabolism including both Warburg effect and mitochondrial respiration. Other regulators of tumor energy metabolism were also affected by LINC01537. These results elucidate a suppressed role of LINC01537 in lung cancer development involving tumor metabolic reprogramming, and we believe that it might be a biomarker for cancer survival prediction and therapy.

Highlights

Molecular targeted therapy (MTT) has been one of the most popular modes of cancer treatment for several years, which works by blocking the growth of cancer cells via interfering with specific molecules that play essential roles in cancer development
BLAST analysis showed that 84 long non-coding RNAs (lncRNAs) were overlapping in three differential lncRNAs expression profiles (Figure 1b, Supplementary Figure S1c,d)
Further univariate cox model revealed 10 lncRNAs to be significantly associated with lung cancer survival (Figure 1c), among which LINC01537 was the most significant one (p = 2.95 × 10−6)

Summary

Introduction

Molecular targeted therapy (MTT) has been one of the most popular modes of cancer treatment for several years, which works by blocking the growth of cancer cells via interfering with specific molecules that play essential roles in cancer development. Only 10–20% of cancer patients respond well to these existing targeted drugs. Another problem that is often experienced is that once the primary tumorous clones are treated by targeted drugs, the secondary clones that are not sensitive to the drugs gain a growth advantage and cause recurrence of cancer and metastasis [2]. These challenges encouraged us to explore the molecular landscape for cancer and exploit comprehensive biomarkers that can aid in development of new MTT drugs

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