Non-Coding RNAs in Lung Tumor Initiation and Progression

Abstract

Lung cancer is one of the deadliest forms of cancer affecting society today. Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), through the transcriptional, post-transcriptional, and epigenetic changes they impose, have been found to be dysregulated to affect lung cancer tumorigenesis and metastasis. This review will briefly summarize hallmarks involved in lung cancer initiation and progression. For initiation, these hallmarks include tumor initiating cells, immortalization, activation of oncogenes and inactivation of tumor suppressors. Hallmarks involved in lung cancer progression include metastasis and drug tolerance and resistance. The targeting of these hallmarks with non-coding RNAs can affect vital metabolic and cell signaling pathways, which as a result can potentially have a role in cancerous and pathological processes. By further understanding non-coding RNAs, researchers can work towards diagnoses and treatments to improve early detection and clinical response.

Keywords: RNA editing; RNA modifications; cancer metabolism; immortalization; long non-coding RNA; lung cancer; microRNA; oncogene; tumor initiation; tumor progression.

Figure 1

Non-coding RNAs involved in lung cancer initiation and progression along with the hallmark they affect. ↑, upregulation; ↓, downregulation; →, promotion; ┤, inhibition. Abbreviations: Apoptotic peptidase activating factor 1/2 (APAF1/2), BCL-2-like protein 11 (BIM), bromodomain-containing protein 4 (BRD4), cyclin E1 (CCNE1), E-cadherin (CDH1), cyclin dependent kinase 4 (CDK4), cyclin dependent kinase inhibitor 1A (CDKN1A), C-X-C motif chemokine receptor 4 (CXCR4), endoribonuclease Dicer (DICER), epidermal growth factor receptor (EGFR), endothelial PAS domain protein 1 (EPAS1), Erb-B2 receptor tyrosine kinase 4 (ERBB4), enhance of zeste 2 polycomb repressive complex 2 subunit (EZH2), F-box and WD repeat domain containing 7 (FBXW7), forkhead box O3 (FOXO3A), hypoxia inducible factor 1 alpha (HIF-1α), homeobox A3 (HOXA3), homeobox A5 (HOXA5), inhibitor of DNA binding 1 (ID1), interferon regulatory factor 2 (IRF2), Jumonji and AT-rich interaction (JARID2), minichromosome maintenance complex component 7 (MCM7), methyltransferase like 3 (METTL3), SMAD Family Member 3 (SMAD3), mechanistic target of rapamycin kinase (mTOR), metallothionein 1G (MT1G), protein tyrosine phosphatase receptor type U (PTPRU), programmed cell death 1 ligand 1 (PD-L1), programmed cell death 4 (PDCD4), phosphatidylinositol-3-kinase regulatory subunit 3 (PIK3R3), phosphatase and tensin homolog (PTEN), protein kinase C epsilon (PKC-ε), tumor necrosis factor ligand superfamily member 11 (RANKL), Ras p21 protein activator (RASA1), retinoblastoma-like protein 2 (RBL2), succinate dehydrogenase (SDH), sprouty related EVH1 domain containing 1/2 (SPRED1/2), sprouty 1 (SPRY1/3/4), SRC proto-oncogene non-receptor tyrosine kinase (SRC), signal transducer and activator of transcription 3 (STAT3), SUZ12 polycomb repressive complex 2 subunit (SUZ12), Simian virus 40 small T antigen (SV40 ST), transforming growth factor beta 1 (TGFβ), tissue inhibitor of metalloproteinases 2 (TIMP2), tumor protein 21 (TP21), tumor protein 53 (TP53), telomerase reverse transcriptase (TERT), vascular endothelial growth factor A (VEGFA), von Hipper-Lindau tumor suppressor (VHL), yes associated protein 1/tafazzin (YAP1/TAZ), Y-Box binding protein 1 (YBX1), zinc finger protein X-linked (ZFX).

Figure 2

Interactions among cell signaling pathways and non-coding RNAs. →, promotion; ┤, inhibition; ↷/⤾, guanine nucleotide exchange reactions. Abbreviations: AKT serine/threonine kinase (AKT), adenomatous polyposis coli (APC), BH3-interacting domain death agonist (BID), cyclin B1 (CCNB1), casein kinase I (CKI), DEAD-box helicase 3 X-linked (DDX3), disheveled (DVL), epidermal growth factor receptor, frizzled class receptor 2 (FZD2), frizzled class receptor 8 (FZD8), glycogen synthase kinase 3 (GSK3), hypoxia inducible factor 1 subunit alpha (HIF1α), hypoxia inducible factor 1 subunit alpha inhibitor (HIF1AN), IκB kinase (IKK), matrix metallopeptidase 9 (MMP9), MET proto-oncogene receptor tyrosine kinase (MET), mechanistic target of rapamycin kinase (mTOR), neurofibromin 1 (NF1), nuclear factor kappa-light-chain-enhancer of activated B (NF-κB), phosphoinositide-dependent protein kinase-1 (PDK1), sirtuin 1 (SIRT1), son of sevenless homolog 2 (SOS2), wingless-type (WNT).

Figure 3

Metabolic pathways including glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, and lipid synthesis with target non-coding RNAs. →, promotion; ┤, inhibition; ⟳, metabolic reactions of the tricarboxylic acid cycle. Abbreviations: 3-Phosphoglyceric acid (3PG), AKT serine/threonine kinase (AKT), ATP citrate lyase (ACLY), aconitase (ACO), ⍺-Ketoglutarate dehydrogenase (⍺-KGDH), citrate synthase (CS), fructose 6-phosphate (F6P), fructose bisphosphatase (FBP), fumarase (FH), glucose 6-phosphate (G6P), glucose-6-phosphate dehydrogenase (G6PD), histone deacetylase 4 (HDAC4), glucose transporter 1 (GLUT1), hexokinase 2 (HK2), isocitrate dehydrogenase (IDH), lactate dehydrogenase A (LDHA), malate dehydrogenase (MDH), nuclear factor erythroid-2-related factor 2 (NRF2), phosphoenolpyruvate (PEP), phosphofructokinase-1 (PFK), phosphogluconate dehydrogenase (PGD), pyruvate kinase M1/2 (PKM2), pentose phosphate pathway (PPP), succinyl-CoA synthetase (SCS), succinate dehydrogenase (SDH), transketolase (TKT), wingless-type (WNT).