"Molecular pigeon" network of lncRNA and miRNA: decoding metabolic reprogramming in patients with lung cancer

Abstract

In recent years, with the advancement of RNA analysis techniques, such as single-cell RNA sequencing, noncoding RNAs have demonstrated substantial potential in regulating gene expression, encoding peptides and proteins, constructing the cellular microenvironment, and modulating cell function. They can serve as potential therapeutic targets and diagnostic markers for various diseases, offering novel avenues for diagnosis and treatment. Among them, long noncoding RNAs (lncRNAs) represent a principal component. Through the competing endogenous RNA mechanism, lncRNAs sequester microRNAs (miRNAs), interact with metabolic enzymes or transcription factors, regulate gene expression, and participate in the metabolic communication network within the tumor microenvironment. This process significantly promotes the growth, proliferation, and metastasis of lung cancer cells by reprogramming core metabolic pathways-including glucose utilization, lipid homeostasis, and amino acid flux. This article reviews the key roles of lncRNAs and miRNAs in the metabolic reprogramming of patients with lung cancer, elucidates the complex lncRNA-miRNA network involved, and provides mechanistic insights into metabolic vulnerabilities and translational opportunities for targeted interventions in the diagnosis and treatment of lung cancer.

Keywords: NSCLC; lncRNA; lung cancer; metabolic reprogramming; miRNA.

Figure 1

Regulatory mechanism of LncRNAs. The picture mainly describes the four main gene expression regulation mechanisms of LncRNAs in tumors, which are: As a ceRNAs “molecular sponge”, it adsorbs miRNAs, affects the enrichment level of specific proteins, promotes the degradation of target mRNAs, and regulates TME metabolic reprogramming, thereby mediating complex and accurate regulatory mechanisms and significantly promoting the growth, proliferation and metastasis of lung cancer cells. The image is created with Figdraw.

Figure  2

Glucose metabolism. The chart illustrates the regulation mechanism of different LncRNAs on glucose metabolism in lung cancer cells. These lncRNAs influence the abundance of glucose metabolic enzymes, glucose uptake, and the expression of related transcription factors through various pathways, in order to adapt to their rapid growth, metastasis and immune escape. The following is a supplement to the specific mechanisms in the figures: CYB561-5: Interacts with Bsg protein and stimulates the expression of HK2 and PFK1; DUXAP8 & FAM83A-AS1: Upregulate HIF-1α and glycolysis-related enzymes, and target miR-203-3p to boost HK2 expression; AL355338: Binds with ENO1 to enhance cellular glycolysis and drive malignant evolution of NSCLC via EGFR - AKT.; BC200 & HOXA11-AS: Function as a molecular sponge for miR-148b-3p to promote PKM2 expression; LINC00243: Sequesters miR-507 to enhance PDK4 expression; lnc-IGFBP4-1: Mainly localizes in the nucleus, regulates the transcription of glycolysis - related genes like GLUT1, PKM2, and HK2, and increases the expression of glycolysis - associated enzymes; SNHG14: Acts as a molecular sponge for miR-206, upregulates G6PD expression, and helps tumor cells combat oxidative stress, participate in antioxidant synthesis, and generate free radicals; KIMAT1 & LncCRYBG3: Activate mTOR to promote MYC transcription, and bind with LDH; LINC01123 competes with miR-199a-5p to relieve the suppression of c-Myc mRNA, and also participates in the progression of lung adenocarcinoma via the ZEB1/LINC01123/miR-499b-5p/NOTCH1 axis; MetaLnc9: Forms a NONO/CRTC/CREB1 complex in the nucleus to interfere with transcription, and binds with PGK1 in the cytoplasm to prevent its degradation and activate the Akt/mTOR pathway; AC020978: Under the regulation of HIF-1α binding site in the upstream region, it is inversely regulated by hypoxic conditions and HIF-1α . It binds to and stabilizes PKM2, modulates the interaction between PKM2 and HIF-1α to enhance the transcriptional activity of HIF-1α , and also binds to MDH2 to activate the PI3K-AKT pathway; LINC01537, mainly located in the cytoplasm, stabilizes PDE2A mRNA, enhancing its expression, and thus inhibits mitochondrial respiration and the Warburg effect. When its expression is down - regulated in lung cancer cell mitochondria, PDE2A expression decreases correspondingly, regulating mitochondrial biological activity and the Warburg effect. The image is created with Figdraw.

Figure 3

Lipid metabolism. This chart shows the regulatory mechanism of different LncRNAs in the reprogramming of lipid metabolism in tumor cells. These lncRNAs promote the progression of lung cancer by modulating lipid metabolism-related proteins such as FABP5, regulating the expression levels of ferroptosis-related transcription factors such as FOSL2 and NRF2, or facilitating intercellular interactions among tumor cells. The image is created with Figdraw.

Figure  4

Glutamine metabolism. The chart shows the regulatory mechanism of different LncRNAs in glutamine metabolic reprogramming of tumor cells. LncRNAs can mediate mesenchymal-tumor cell interaction in TME, up-regulate glutamine uptake by cells, or affect the enrichment level of metabolic enzyme GLS to meet the high addiction tendency of lung cancer cells to glutamine. The following is a supplement to the specific mechanisms in the figures: OGFRP1: Indirectly promotes SLC38A1 expression by inhibiting miR-299-3p, alleviating intracellular lipid peroxidation and ferroptosis; FEZF1-AS1: Functions as a “ molecular sponge” to sequester miR-32-5p, enrich GLS, and promote cisplatin resistance in cells; LINC01614: Released from cancer - associated fibroblast exosomes, it interacts with ANXA2 and P65 to activate NF - κ B signaling and initiate the transcription of the glutamine transporters SLC38A2 and SLC7A5; NR2F1-AS1: Highly expressed in non-small cell lung cancer, its silencing reduces HK2 and GLS expression, suppressing glycolysis and glutamine metabolism. Mechanistically, it binds with miR-363-3p to enrich SOX4, promoting glycolysis and glutamine metabolism, and accelerating tumor malignancy. The image is created with Figdraw.

Figure 5

Glycine/serine/tryptophan metabolism. This chart describes the regulatory mechanism of different LncRNAs in the reprogramming of glycine/serine/tryptophan metabolism in tumor cells. Similar to its role in glutamine metabolism, lncRNA also affects the expression level of metabolic enzymes in glycine/serine/tryptophan, maintains the balance of glycine/serine concentration inside and outside the cell, and mediates fibroblast-tumor cell interaction in TME, which also provides novel insights for clinical diagnosis and treatment of lung cancer. The following is a supplement to the specific mechanism shown in the figure: the xc(-) system comprises the SLC3A2 and SLC7A11 subunits; The lnc T-UCR Uc.339/miR-339/SLC7A11 axis serves as a factor influencing ferroptosis in lung adenocarcinoma and promotes the proliferation, migration, and invasion of tumor cells; LncRNA UCA1 targets miR-495 to indirectly regulate NRF2 expression in cisplatin-resistant NSCLC cells; LncRNA MEG8 drives NSCLC progression in vivo via the miR-15a/b-5p/PSAT1 axis; In lung cancer cells, lncRNA Gm15290 mediates serine - to - glycine conversion via SHMT2 and is regulated by lncRNA Gm15290 as a downstream target; ITGB2-AS1 is aberrantly expressed in the tumor tissue and cisplatin-resistant tissue of NSCLC patients. It regulates NAMPT expression by interacting with transcription factor FOSL2 and affects the production of ferroptosis - related proteins, including GPX4 and SLC7A11, by targeting p53 downstream; In NSCLC, LncRNA MEG3 is low - expressed. It can bind miR - 543 as a ceRNA and affects autophagy of lung cancer cells by regulating the IDO pathway; LncRNA ROR1-AS1 exists in cancer-associated fibroblast (CAF) exosomes, interacts with the N6-methyladenosine (m6A) reader IGF2BP1 to enhance SLC7A11 mRNA stability, and suppresses ferroptosis. The image is created with Figdraw.