Role of Metabolic Reprogramming of Long non-coding RNA in Clear Cell Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC), one of the most frequent cancers, is a "classical" malignancy characterized by metabolic reprogramming. Clear cell renal cell carcinoma (ccRCC) is its most common histopathological subtype. Long-stranded non-coding ribonucleic acids (LncRNAs) are regulatory RNA molecules with limited protein-coding capacity and evolutionary conservation. Recent studies have revealed that lncRNAs can broadly regulate the metabolic reprogramming of ccRCC and its malignant transformation. However, there are few studies on lncRNAs regulating the metabolism of ccRCC, and the specific mechanisms are unknown. Therefore, this paper summarizes the regulatory mechanisms of lncRNAs in the metabolism of ccRCC, especially in the pathways of glycolysis, mitochondrial function, glutamine and lipid metabolism, cellular mechanisms, interactions with other molecules, specific scientific and clinic implications and applications to provide a basis for early clinical diagnosis, prediction and treatment. We also discuss the clinical application and challenges of targeting lncRNAs in ccRCC metabolism.

Keywords: LncRNAs; metabolic reprogramming; renal clear cell carcinoma.

Figure 1

ccRCC cell metabolism. With the changes of intracellular metabolism of ccRCC, intermediates and metabolic enzymes of related pathways also showed significant changes.

Figure 2

Glycolysis and the TCA cycle are involved in metabolic reprogramming in ccRCC. In this figure, the red word represents the molecule with high expression in ccRCC cells, while the green word represents the molecule with low expression in ccRCC cells. a-KG, α-ketoglutarate; GSH, glutathione; FA, fatty acid; GLUT‑1, glucose transporter 1; G6P , glucose‑6‑phosphate; HK, hexokinase; LDH-A, lactate dehydrogenase A; ROS, reactive oxygen species; SDH, succinate dehydrogenase; ASS1, Arginine succinate synthase 1; FASN, Fatty acid synthase.

Figure 3

Lipid metabolism reengineering involves several aspects, such as increased lipid uptake , FAS and FAO. In this figure, the red word represents the molecule with high expression in ccRCC cells, while the green word represents the molecule with low expression in ccRCC cells. HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; AA-PI, arachidonic acid containing PI; LPI, lysophosphatidylinositol; MBOAT7, Membrane bound O-acyltransferase domain 7; ACOT8, acyl-coenzyme A thioesterases; PIPs, phosphatidylinositol phosphate; ER, endoplasmic reticulum; LDs, lipid droplets; CPT1A, carnitine palmityl transferase 1A; PLIN2, Perisolipoprotein 2; HIF, hypoxia-inducible factor; MUFA, single-chain unsaturated fatty acids; YB-1, Y box binding protein 1; LXRα,liver X receptor α; FASN, atty acid synthase; ACC, acetyl-CoA carboxylase; SCD1, stearoyl-coA desaturase-1; SR-B1, scavulant receptor Class B type 1; CA V1; cellulin 1.

Figure 4

SIRT4 is involved in glutamine metabolism. Glutamine metabolism is another important mode of energy metabolism in ccRCC cells. SIRT4, as a novel molecule, has been shown to be involved in alternate metabolism of glutamine and regulation of tumor microenvironment. SIRT4, Sirtuin 4; HO-1, Heme oxygenase-1.

Figure 5

Biological function of lncRNAs. In the nucleus, the gene specificity of lncRNAs enables their relocalization at the synthesis site to affect gene regulation or transcription, and thus regulate the expression of adjacent genes and play a cis-regulatory role. In cytoplasm, lncRNAs decay mRNA and regulate mRNA stability or translation, induction of miRNAs and proteins and influence gene regulation.

Figure 6

IncRNAs is involved in different pathways or mechanisms of ccRCC metabolic reprogramming. MultipleIncRNAs participate in the metabolic reprogramming pathway of ccRCC and regulate the biological behavior of ccRCC cells. Metabolic reprogramming of ccRCC includes glycolysis, TCA cycle, lipid metabolism and amino acid metabolism. In the figure, the blue boxes represent IncRNAs acting as ceRNA, the green boxes represent proteins interacting with IncRNAs (enhancers) and the pink boxes represent other molecules interacting with IncRNAs. ROS, reactive oxygen species; ASS1, Arginine succinate synthase 1; FA, fatty acid; MICU1, Mitochondrial calcium uptake 1; mTORC1, Rapamycin complex; IGFBP, Insulin-like growth factor-binding protein-1; VLCAD, Very long chain acyl CoA dehydrogenase.