AL355338 acts as an oncogenic lncRNA by interacting with protein ENO1 to regulate EGFR/AKT pathway in NSCLC

Abstract

Background Non-small cell lung cancer (NSCLC) is a malignancy with considerable morbidity and mortality. Abnormal metabolism is a hallmark of cancer; however, the mechanism of glycolysis regulation in NSCLC progression is not completely understood. Recent studies suggest that some dysregulated long non-coding RNAs (lncRNAs) play important roles in tumor metabolic reprogramming. Methods To identify glycolysis-associated-lncRNAs in NSCLC, we compared RNA-sequencing results between high 18F-fluorodeoxyglucose (FDG)-uptake NSCLC tissues and paired paratumor tissues. The transcript abundance of AL355338 in 80 pairs of clinical samples was evaluated by quantitative real-time PCR assay and fluorescence in situ hybridization. The biological role of AL355338 on NSCLC cells were evaluated by functional experiments in vitro and in vivo. Moreover, RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP) assays were used to identify the protein interacted with AL355338. Co-immunoprecipitation, in situ proximity ligation assays and western blotting were applied to define the potential downstream pathways of AL355338. Results AL355338 was an upregulated glycolysis-associated lncRNA in NSCLC. Functional assays revealed that AL355338 was critical for promoting aerobic glycolysis and NSCLC progression. Mechanistic investigations showed that AL355338 directly bound with alpha-enolase (ENO1) and enhanced the protein’s stability by modulating its degradation and ubiquitination. A positive correlation was observed between AL355338 and ENO1 in NSCLC, and ENO1 was subsequently confirmed to be responsible for the oncogenic role of AL355338. Furthermore, AL355338 was capable of modulating ENO1/EGFR complex interaction and further activating EGFR-AKT signaling. Conclusions This study indicates that AL355338 confers an aggressive phenotype to NSCLC, and targeting it might be an effective therapeutic strategy.

miR-199a: A Tumor Suppressor with Noncoding RNA Network and Therapeutic Candidate in Lung Cancer

“…The up-regulation of glycolysis levels has been observed in many cancers, including primary and metastatic cancers, and aerobic glycolysis is the most commonly used and preferred mechanism of glucose metabolism in cancer cells [ 54 ]. Previous studies [ 55 , 56 , 57 , 58 , 59 , 60 , 61 ] showed that signaling pathways such as Akt, Myc, ERK, and NF-κB play an important regulatory role during glycolysis. In NSCLC, high levels of glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) promoted glucose uptake by lung cancer cells, which was the initial step of glucose metabolism [ 62 , 63 ].…”

Long Noncoding RNAs and Circular RNAs in the Metabolic Reprogramming of Lung Cancer: Functions, Mechanisms, and Clinical Potential

“…AL355338, functioning as an oncogenic lncRNA, was identified as highly expressed in NSCLC tissues and predicted unfavorable prognosis. Mechanistically, AL355338 was demonstrated to specifically bind to ENO1 and prevent its ubiquitin-mediated degradation to enhance its stability, further facilitating the Warburg effect and other aggressive phenotypes in NSCLC cells [ 36 ].…”

“…The circRNAs comprise circMYLK, circMAGI3, circAGFG1, circSLC25A16, circ-MEMO1, circDCUN1D4, circ-ERBB2, circTADA2A, circ-PGC, circPUM1, circ_0000517, circ-PITX1, circ_0006677, circNFIX, circ-ENO1, circ-LDLRAD3, and circ_0003028 [ 20 , 24 , 29 , 30 , 32 , 39 – 48 , 52 , 55 ]. In fact, some of them were also shown to have potential as prognostic indicators in patients with LC; they included DUXAP8, LINC00243, AC020978, LINC01123, HOXA11-AS, ABHD11-AS1, AL355338, circMYLK, circMAGI3, circAGFG1, circSLC25A16, circ-MEMO1, circDCUN1D4, circ-PGC, circPUM1, circ_0000517, circ_0006677, circNFIX, CCAT1, and MINCR [ 20 , 22 , 24 , 26 , 29 – 36 , 39 , 42 – 44 , 46 , 47 , 50 , 53 ]. Besides, two other lncRNAs, LINC01537 and ARHGAP10, were only found to have potential as prognostic indicators [ 19 , 38 ].…”

“…Clinically, the expression of IGFBP4-1, ABHD11-AS1, circMAGI3, circSLC25A16, circDCUN1D4, and circPUM1 in LC tissues was associated with TNM stage; the expression of DUXAP8, circ_0000517, and circ-LDLRAD3 correlated with TNM stage and LNM; while the expression of AC020978, HOXA11-AS, circ-PGC, and circ_0006677 was associated with TNM stage, LNM, and tumor size [ 22 – 24 , 26 , 30 , 33 , 35 , 39 , 42 – 44 , 46 , 52 ]. In addition, CRYBG3 expression correlated with distant metastasis; CCAT1 expression correlated with clinical stage; circNFIX expression was associated with TNM stage and distant metastasis; circ-MEMO1 expression correlated with clinical stage and LNM; circMYLK was associated with TNM stage and tumor size; LINC01123 expression was associated with TNM stage, T stage, and LNM, while AL355338 expression was associated with TNM stage, T stage, LNM, and distant metastasis [ 20 , 28 , 31 , 32 , 36 , 47 , 50 ].…”

Emerging Role of Noncoding RNAs in EGFR TKI-Resistant Lung Cancer

“…Lung cancer, the foremost malignancy in terms of mortality rate, can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) [ 1 , 2 ]. NSCLC, accounting for approximately 85% of lung cancers, is mainly composed of lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD) and large cell lung cancer [ 2 ].…”