In this study, we found that AC00393986.3 expression was positively related to patient age and pathological grade in gliomas, and was an independent risk factor for patient survival. Functional prediction revealed that this gene might play important roles in regulating tumor cell metabolism through TWIST1. These results demonstrated that AC003986.3 was a potential target for gene therapy in gliomas.
Despite substantial progress in understanding the genetic mechanism in tumorigenesis, the treatment for gliomas remains difficult and challenging. One responsible reason is the high heterogeneity of the tumor. Further analysis of DNA, RNA, and proteins might further refine what should be targeted and lead to novel clinical trials.[8] Long noncoding RNAs (lncRNAs) are a variety of RNA transcripts longer than 200 nucleotides and lack of protein-encoding capacity.[9] Previously, lncRNAs were deemed as spurious wastes without function during transcription.[10] Recently, lncRNAs were recognized to play widespread roles in gene regulation and other cellular processes. [9] LncRNAs have also been implicated in cancer progressions, such as stemness, proliferation, angiogenesis and drug resistance.[11] Many lncRNAs have been identified as regulators in glioma progression. For example, HOXA11-AS could regulate cell cycle progress and was closely related to glioma grade and poor prognosis.[12] Similar functions were found with another lncRNA of HOTAIR.[13] In this study, we found the expression of the novel lncRNA AC003986.3 increased with of glioma malignancy (P < 0.001, Fig. 1C), and AC003986.3 expression was an independent risk factor for predicting patient survival irrespective of patient age and tumor pathological grade (HR = 1.975, 95% CI 1.312–2.966, P = 0.001, Fig. 3). Patients with higher AC003986.3 expression suffered a poorer survival than those with low expression (P < 0.001, Fig. 2). Prediction accuracy with only AC003986.3 expression surpassed 0.70 for 1, 2, 3 and 5 years survivals (Fig. 5A), and the accuracy reached even higher (nearly 0.90) when combined with tumor pathological grade, age and other clinical features (Fig. 5B). These results suggest that AC003986.3 may be a novel potential treatment target for gliomas.
The functions of AC003986.3 have not been reported. Interaction target prediction with Ensemble Browser revealed that this novel lncRNA might interact with TWIST1 and regulate its degradation and function. TWIST1 is a well-known regulator of epithelial-mesenchymal transition, tumorigenesis, and invasion in gliomas,[14–16] and is a predictor of prognosis for the patients.[17] Not only in gliomas, but TWIST1 was also a key regulator in a variety of cancers such as breast, lung, prostate, gastric, bladder, pancreatic, and so on, in tumor initiation, progression, metastasis, apoptosis, the resistance of chemotherapy, and cancer stem cell formation.[18, 19] TWIST1 is also an important node in the intracellular signaling transduction network and linked to a variety of key signaling pathways such as FGF, TGF-β, NF-κB, and Notch, all of which were vital for both normal biological and pathological processes. All these results further confirmed the priceless potential of AC003986.3 for gene therapy.[19, 20]
KEGG gene set enrichment analysis revealed that AC003986.3 related genes were enriched in Biosynthesis of unsaturated fatty acids, Butanone metabolism, Fatty acid metabolism, Glycolysis gluconeogenesis, Lysine degradation, Pentose phosphate pathway, Peroxisome, Propanoate metabolism, and valine leucine and isoleucine degradation (Fig. 6B), demonstrating that AC003986.3 was mainly involved in cell energetic and synthetic metabolism. The tumor is hallmarked by reprogrammed pathways of nutrient acquisition and metabolism to meet the high demand for aggressive biological properties.[21] The reprogrammed metabolism activities always improved tumor cell adaption to provide a selective advantage during tumorigenesis, and some were potential for tumor control.[21] Tumor cell metabolism targeted therapies have been reported both in animal models and clinical practice.[22, 23] Similar to KEGG analysis, GO enrichment analysis also indicated the potential role of AC003986.3 in tumor cell metabolism (Fig. 6C). These results suggest AC003986.3 may be a potential target for tumor metabolism-targeted treatment.
How AC003986.3 was involved in reprogrammed tumor metabolism was is unclear. As the interactor of AC003986.3, TWIST1 has been reported as a key regulator for metabolism.[24–27] Pan et al reported that TWIST1 was selectively expressed in adipose tissue, and was recruited to suppress mitochondrial metabolism and uncoupling, maintaining the of energy homeostasis.[24] Furthermore, TWIST1 was also reported to take part in glucose metabolism [26] and mitochondrial oxidative metabolism.[27] Along with our findings from the Ensemble Browser (Fig. 6A), we can infer that it is TWIST1 that mediates the regulation of AC003986.3 in glioma cell metabolism. Future experimental studies were needed to further elucidate the mechanism of how AC003986.3 regulates tumor cell metabolism and to validate the feasibility of utilizing AC003986.3 as the gene therapy target for gliomas.
Limitations
There are some limitations in this manuscript. First, other clinical features such as chemotherapy, radiology were not considered in this study, and these features would influence patient survival to some extent. Second, only bioinformatics analysis was conducted in this manuscript, molecular experiments were needed to further elucidate the function of AC003986.3.Third, only the TCGA dataset was analyzed in this manuscript, external validation was absent.