Lung cancer (LC) is the most common cause of global cancer-related death with an approximate 5-year survival rate of 16.6% all over the world [
1]. Recently, although great advance has been made in clinical treatment for LC, the overall survival time of LC patients has not improved dramatically and a critical problem for that is the lack of valuable molecular biomarkers. Thus, a good understanding of the molecular mechanism underlying LC progression and metastasis is urgent to improve the diagnosis and effective therapy at the onset of the disease. Long non-coding RNAs (lncRNAs) as one of the non-protein coding transcripts are commonly defined as longer than 200 nucleotides in length [
2] and have recently attracted increasing attention. LncRNAs served as important players have been implicated in a variety of physiological and pathological processes, and the majority, so far, studied are implicated in gene regulation either at the transcriptional or posttranscriptional level [
3]. In cancer, abnormal expression and mutations of lncRNAs as important regulators can contribute to tumor development and progression through pathophysiological activities such as cell growth, apoptosis, invasion, and metastasis [
4‐
8]. As an emerging hot spot of cancer research, numerous cancer-specific lncRNAs have been identified, among which several have been validated as biomarkers for metastasis or metabolism, such as metastasis associated long antisense transcript 1 (MALAT-1) [
9], prostate cancer gene expression marker 1 (PCGEM1) [
10] and HOX transcript antisense RNA (HOTAIR) [
11]. Here, we found an lncRNA termed insulin-like growth factor binding protein 4–1 (IGFBP4–1) located in the upstream region of IGFBP4 gene by bioinformatics analysis. IGFBPs is a kind of multifunctional cell proliferation regulation factor, which play an important role in tumor metabolic processes via competing with insulin-like growth factor receptor (IGFR) to combine with insulin-like growth factors (IGFs) and regulate the biological function of the IGFs eventually [
12,
13]. IGFBP4 is an important core member of the IGFBPs family, which can mediate its main functions through inhibiting IGF-induced cellular growth and thus regulate the tumor metabolic processes [
14]. Several studies have found that overexpression of IGFBP4 inhibited the cell growth in some cancers including prostatic cancer [
15], colon cancer [
16] and breast cancer [
17]. It has been found that higher amounts of IGFBP4 mRNA in normal lung than in tumor tissues derived from lung cancer patients, and the expression level of IGFBP4 is in association with tumor differentiation, the poorly differentiated adenocarcinoma cells often lost their IGFBP-4 expression [
18‐
20]. Given this, recent research therefore planned to emphasize mechanisms mediated by this lncRNA in cancer progression.
Conceptual progress has made us to better understand that the chronic and uncontrolled cell proliferation and metastasis are representative of the essence of LC involves not only deregulated control of cell proliferation but also making corresponding adjustments of energy metabolism in order to accelerate cell growth and division. Reprogrammed energetic metabolism as a result of increased glycolysis and glucose uptake to facilitate cell growth and proliferation was recently pointed out as an emerging hallmark of cancer [
21]. Most cancer cells employ aerobic glycolysis coupling with reduced mitochondrial oxidative phosphorylation for energy instead of oxidative phosphorylation, even in sufficient oxygen state. This phenomenon is called “Warburg effect”, increasing uptake of glucose and glutamine; synthesis of more ATP, amino acids, nucleic acids, and lipids; and lead to changes in the activity of relevant enzymes in the process of glucose metabolism [
22]. To compensate for the consequent decrease in ATP production, cancer cells adopt corresponding mechanisms to increase glucose uptake and utilization. One mechanism underlying the regulation of glucose transporters, especially GLUT1, is responsible for increase glucose uptake in the cytoplasm [
23,
24]. Here we focus on a highly possible mechanism mediated by lncRNA IGFBP4–1 to promote proliferation and metastasis through reprogramming glucose metabolism in LC.
Evidence from other studies demonstrates that lncRNA is involved in tumor metabolic regulation process. LncRNA PCGEM1 functioned as a unique target to regulate energy metabolism for prostate-cancer therapy [
10]. Lnc-UCA1 plays a positive role in cancer cell glucose metabolism through the cascade of mTOR-STAT3/microRNA143-HK2, and reveal a novel link between lncRNA and the altered glucose metabolism in cancer cells [
25]. Given that lncRNA may be functioned as an important regulator of cancer energy metabolism that promotes to improve biosynthetic processes, supporting proliferative advantages for rapid cancer cell growth. Thus, more comprehensive assessment of the impact of lnc-IGFBP4–1 on the metabolic features of LC cells may shed new light on the molecular mechanism how lnc-RNA exerts influence to regulate metabolic programming to facilitate the cancer cell growth and metastasis. In the present study, we observed that lnc-IGFBP4–1 is up-regulated in LC tissues compared with corresponding non-tumor tissues and that its expression level is significantly correlated with TNM stage and lymph node metastasis. Subsequently, we found lnc-IGFBP4–1 could regulate cell growth and metastasis both in vitro and in vivo. In addition, we found that lnc-IGFBP4–1 negatively correlated to the gene IGFPB4 and IGFBP4 expressiong levels was decreased in lnc-IGFBP4–1-overexpressing cells. Moreover, lnc-IGFBP4–1 was determined to be as an important regulator in the process of ATP production and enzymatic activities in LC.