Long Non-Coding RNAs in Colorectal Cancer: Navigating the Intersections of Immunity, Intercellular Communication, and Therapeutic Potential
Abstract
:1. Introduction
2. The Fundamentals of Long Non-Coding RNAs
3. Interplay of lncRNAs and Consensus Molecular Subtypes (CMSs) in CRC
4. The Role of Immunity and Inflammation in CRC Tumor Stroma
5. The Role of LncRNAs in Tumor–Stroma Immune Interplay via Extracellular Vesicles and Exosomes
6. Unraveling the Complexity: The Interplay of lncRNAs and Other ncRNAs in Cell-to-Cell Communication within the CRC Microenvironment
7. Exploring Strategies for Manipulating lncRNAs to Enhance Anti-Tumor Immunity in CRC Patients
7.1. Potential Methodologies for Manipulating Extracellularly Released lncRNAs
7.2. Immune Processes That We Can Regulate via lncRNAs
8. Conclusions: Future Perspectives on Long Non-Coding RNAs in CRC
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Classification | Description |
---|---|
Sense lncRNAs | Transcribed from the same strand as a protein-coding gene and may overlap entirely or partially with the gene [12]. |
Antisense lncRNAs | Transcribed from the opposite strand of a protein-coding gene and may overlap with exons or introns [13]. |
Intronic lncRNAs | Located within the introns of a protein-coding gene but transcribed independently [14]. |
Intergenic lncRNAs | Situated between protein-coding genes and do not overlap with them. Also known as long intergenic non-coding RNAs (lincRNAs) [15]. |
Bidirectional lncRNAs | Transcribed in close proximity to a protein-coding gene but in the opposite direction [16]. |
Enhancer lncRNAs (eRNAs) | Associated with enhancer regions and may regulate the activity of enhancers, influencing gene expression [17]. |
Broad Function | Specific Mechanism | Description |
---|---|---|
Gene Expression Regulation | Transcriptional Control | Involves the activation/repression of transcription, enhancer activity, RNA polymerase interference, chromatin remodeling, histone modification, and DNA methylation [18,19,20]. |
Post-transcriptional Control | Includes the regulation of splicing, mRNA stability, and translation [21,22]. | |
RNA Interactions | miRNA Sponging | lncRNAs may sequester miRNAs away from their target mRNAs [23]. |
RNA-RNA Interactions | Includes base pairing with other RNAs, affecting function or stability [24]. | |
RNA–Protein Interactions | Scaffolding and Sequestration | lncRNAs can act as scaffolds for protein complexes or sequester proteins away from functional locations. May overlap with gene expression regulation and RNA interactions [25,26]. |
Structural Roles | Nuclear Architecture | Contributes to the organization of nuclear structures. May have indirect effects on gene regulation [27]. |
Signaling Regulation | Pathway Modulation | Involves interactions with signaling molecules or pathway components, potentially impacting various cellular processes, including gene expression, growth, and stress [28,29]. |
CMS Subtype | Typical Molecular Genetic Alterations |
---|---|
CMS1 (MSI Immune) | High microsatellite instability (MSI-H), DNA mismatch repair (MMR) deficiency, hypermutated phenotype, and a high neoantigen load. |
CMS2 (Canonical) | Chromosomal instability, a high level of somatic copy number alterations, the activation of the WNT and MYC signaling pathways, and mutations in APC and TP53. |
CMS3 (Metabolic) | Microsatellite stable (MSS), metabolic dysregulation, KRAS mutations, and involvement in the PI3K/AKT signaling pathway and possibly others that affect metabolism, such as CDK2 signaling. |
CMS4 (Mesenchymal) | Stromal invasion and involvement in the RAS/MAPK, Rb/E2F, CDK8/β-catenin, and Raf/ERK pathways. There is a focus on the epithelial-to-mesenchymal transition (EMT) and the regulation of pathways related to cell growth and migration. |
lncRNA | CMS Subtype | Main Characteristics | References |
---|---|---|---|
HOTAIR | CMS1 (MSI Immune) | Antisense lncRNA. Gene expression regulation. Oncogenic. Interacts with PRC2 and LSD1 to modulate H3K27 methylation, affecting gene silencing. Consequences: PTEN methylation, PI3K/p-AKT/p-MDM2/p53, and PI3K/AKT/mTOR pathways in tumorigenesis; regulates ASTN1, PCDHA1, and MUC5AC in metastasis. | [49,50,53,54] |
LINK-A (LINC01139) | CMS1 (MSI Immune) | Intergenic lncRNA. Pathway modulation. Oncogenic. Facilitates crosstalk between the PIP3 and GPCR pathways, attenuating PKA activity on TRIM71, leading to the degradation of PLC and tumor suppressors Rb and p53. Directly binds to phosphatidylcholine, AKT, and PIP3, causing AKT hyperactivation and tumorigenesis. | [55,56,57,58] |
CCAT1 | CMS2 (Canonical) | Intergenic lncRNA. Nuclear architecture; scaffolding. Oncogenic. Mediates chromosome looping with CTCF, affecting c-Myc promoter and promoting c-Myc expression. Acts as a ceRNA; serves as a scaffold for epigenetic complexes, with chromosome looping central to interaction. | [59,60] |
CRNDE | CMS2 (Canonical) | Intergenic lncRNA. miRNA sponging; pathway modulation; transcriptional control. Oncogenic. Molecular sponge for miRNAs; promotes cell growth. Activates/inhibits the Wnt/β-catenin, PI3K/AKT/mTOR, Ras/MAPK, and Notch1 signaling pathways. Binds to EZH2. | [61,62,63] |
lncRNA-ATB | CMS3 (Metabolic) | Intergenic lncRNA. miRNA sponging. Oncogenic. Interacts with miR-141-3p and miR-200c, influencing the CDK2 pathway, affecting EMT process, and contributing to cancer progression. | [64,65,66,67] |
RP11-462C24.1 (RPL34-DT) | CMS3 (Metabolic) | Intergenic lncRNA. Pathway modulation; transcriptional control. Oncosuppressive. Upregulates HSP70; inhibits the PI3K/AKT signaling pathway. | [68,69] |
H19 | CMS4 (Mesenchymal) | Intergenic lncRNA. RNA interactions; pathway modulation. Oncogenic. Promotes CRC progression by targeting RB with miR-675, sponging miR-200a and miR-138, leading to HMGA2 upregulation. Activates the RAS/MAPK, Rb/E2F, CDK8/β-catenin, and Raf/ERK pathways. | [70,71,72,73,74] |
lincRNA-p21 (TP53COR1) | CMS4 (Mesenchymal) | Intergenic lncRNA. RNA–RNA interactions; RNA–protein interactions. Oncosuppressive. Interacts with the JUNB and CTNNB1 mRNAs, reducing translation. Antagonism via HuR. mTOR/lincRNA-p21 involved in carcinogenesis, progression, metastasis. Part of the p53 network. | [75,76,77,78] |
Mechanism | Key Components | Effect | Key Details |
---|---|---|---|
The secretion of pro-inflammatory cytokines | CAFs and TAMs | Induces inflammation | CAFs and TAMs secrete IL-6 and TNF-α, which can foster chronic inflammation, paradoxically promoting tumor progression. |
The secretion of immunosuppressive factors | CAFs and TAMs | Immunosuppression | CAFs and TAMs secrete TGF-β, IL-10, and PD-L1, which inhibit T cells and promote Tregs. |
T cell exhaustion | T cells | Immunosuppression | Chronic exposure to tumor antigens and inflammatory signals can lead to a state of T cell dysfunction characterized by sustained expression of inhibitory receptors (PD-1 and CTLA-4). |
The recruitment of regulatory immune cells | MDSCs and Tregs | Immunosuppression | The tumor stroma can attract immunosuppressive cell types like MDSCs and Tregs, which suppress cytotoxic T cells and NK cells. |
Metabolic reprogramming | Tumor cells and stromal cells | Immunosuppression | Tumor cells and stromal cells can alter the metabolic landscape of the TME, creating conditions like hypoxia and nutrient deprivation that negatively impact immune cell function. |
The modulation of extracellular matrix (ECM) | CAFs | Creates a physical barrier | CAFs can remodel the ECM, creating a physical barrier that hinders immune cell infiltration and access to tumor cells. |
Cell polarization | TAMs, CD4+ T cells, MDSCs, and DCs | Immunosuppression | TAMs adopt an M2 polarization state, CD4+ T cells can be polarized into Tregs, MDSCs suppress T cell function, and DCs can become tolerogenic. |
lncRNA Name (Genome Type) | Mechanism of Action | Effect on Cancer Progression | Interaction with Tumor Microenvironment |
---|---|---|---|
CCAT1 (Intergenic) | Influences inflammation, angiogenesis, and immune regulation via the microRNA-138-5p–HMGA1 axis in exosomes. Promotes immune cell polarization and pro-inflammatory cytokine release. | Promoting | Mediates angiogenesis and influences immune interactions in CRC. |
CCAT2 (Sense) | Facilitates progression via PI3K/AKT/mTOR signaling. Enhances growth and metastasis via interactions with TAF15 to stimulate RAB14 transcription, triggering AKT/GSK3β signaling. Modulates the hsa-miR-145-5p/AKT3/mTOR axis in MCF7 cells. | Promoting | Plays a role in tumor–stroma immune interplay. |
CRNDE (Intergenic) | Influences inflammation and immune evasion by releasing immunosuppressive factors, inducing T cell exhaustion, and recruiting regulatory immune cells. Activates NF-κB and JAK/STAT signaling. Participates in Th17 differentiation via CRNDE-h isoform interactions with RORγt. | Promoting | Mediates tumor–stroma immune interplay. |
H19 (Intergenic) | Guides inflammation, pro-inflammatory cytokine release, and extracellular matrix remodeling via the upregulation of TNF-α. Involved in the STAT3 pathway. | Promoting | Facilitates interactions with immune cells in CRC. |
HOTAIR (Antisense) | Connected with tumor grade and prognosis. Influences B cells toward a regulatory role via PDL1, suppressing CD8+ T cell activity. May stimulate pro-inflammatory cytokines and extracellular matrix remodeling. | Promoting | Suppresses CD8+ T cell activity. |
HULC (Antisense) | Influences immune response, enhancing EZH2-H3K27me3 enrichment, and targets miR-613 and miR-488, promoting cell proliferation and suppressing p53 expression, which may facilitate tumor growth and metastasis. | Promoting | Influences immune response, promotes tumor growth and metastasis. |
LINC00461 (Intergenic) | Mixed effects on CRC development and immunity. Promotes tumor growth and proliferation via the miR-323b-3p/NFIB axis. Acts as a competitive endogenous RNA (ceRNA) for PHLPP2, a colon cancer tumor suppressor. | Mixed | Influences cell migration, invasion, and transition, and the epithelial–mesenchymal transition. |
lnc-ATB (Intergenic) | Involved in cancer progression, particularly in CRC, stimulating the release of pro-inflammatory cytokines and enhancing metastasis through pathways involving CDK2 and miR-200c. | Promoting | Enhances cancer metastasis and induces the EMT. |
lnc-EGFR or EGILA (Antisense) | Facilitates immune evasion in CRC through the EGFR signaling pathway, potentially inducing T cell exhaustion and enhancing Treg differentiation. | Promoting | Enhances tumor immune escape. |
MALAT1 (Intergenic) | Modulates T cell function, induces pro-inflammatory cytokines, and plays roles in immune evasion and inflammation in various cancers, potentially impacting NF-κB signaling. | Promoting | Suppresses innate and adaptive immune responses. |
NEAT1 (Intergenic) | Contributes to immunosuppression and stemness maintenance through the regulation of ALDH1 and c-Myc. NEAT1 also influences metabolic and mitochondrial homeostasis, Fosters immune evasion through its expression in M2-polarized tumor-associated macrophages. | Promoting | Promotes immune evasion. |
PCAT-1 (Antisense) | Enhances pro-inflammatory cytokine secretion and affects cellular processes like proliferation, invasion, and apoptosis by targeting miR-149-5p. | Promoting | Fosters an inflammatory tumor microenvironment. |
SNHG1 (Intergenic) | Promotes pro-inflammatory cytokine secretion, cell proliferation, migration, and the EMT. It is linked with the Wnt/β-catenin pathway and molecules like MYC and SLC3A2, affecting immune responses and tumor progression. | Mixed | Influences immune response and induces the EMT. |
SNHG14 (Sense) | Promotes CRC progression by negatively regulating EPHA7 through an EZH2-dependent pathway, enhancing methylation on the EPHA7 promoter and stabilizing EZH2 mRNA by interacting with FUS and freeing it from miR-186-5p-induced silence. | Promoting | Regulator of the immune response. |
SOX2OT (Sense) | Related to inflammation and oncogenesis. It regulates pro-inflammatory cytokines and is linked with SOX2. Its silencing suppresses CRC cell growth and alters miR-194-5p | Mixed | Affects cell behavior in the TME. |
TUG1 (Intergenic) | Interacts with the miR-138-5p/ZEB2 axis, promoting the EMT and, on the other hand, an immunosuppressive environment. | Mixed | Affects cancer cell behavior in the TME. |
GAS5 (Antisense) | Downregulates IL-10 and VEGF-A via the NF-κB and Erk1/2 pathways. By inhibiting these cytokines, GAS5 suppresses tumor cell proliferation and promotes the tumor-suppressive function of M1 macrophages | Inhibiting | Reduces tumor immune escape, potentially reducing angiogenesis. |
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Shakhpazyan, N.K.; Mikhaleva, L.M.; Bedzhanyan, A.L.; Sadykhov, N.K.; Midiber, K.Y.; Konyukova, A.K.; Kontorschikov, A.S.; Maslenkina, K.S.; Orekhov, A.N. Long Non-Coding RNAs in Colorectal Cancer: Navigating the Intersections of Immunity, Intercellular Communication, and Therapeutic Potential. Biomedicines 2023, 11, 2411. https://doi.org/10.3390/biomedicines11092411
Shakhpazyan NK, Mikhaleva LM, Bedzhanyan AL, Sadykhov NK, Midiber KY, Konyukova AK, Kontorschikov AS, Maslenkina KS, Orekhov AN. Long Non-Coding RNAs in Colorectal Cancer: Navigating the Intersections of Immunity, Intercellular Communication, and Therapeutic Potential. Biomedicines. 2023; 11(9):2411. https://doi.org/10.3390/biomedicines11092411
Chicago/Turabian StyleShakhpazyan, Nikolay K., Liudmila M. Mikhaleva, Arcady L. Bedzhanyan, Nikolay K. Sadykhov, Konstantin Y. Midiber, Alexandra K. Konyukova, Andrey S. Kontorschikov, Ksenia S. Maslenkina, and Alexander N. Orekhov. 2023. "Long Non-Coding RNAs in Colorectal Cancer: Navigating the Intersections of Immunity, Intercellular Communication, and Therapeutic Potential" Biomedicines 11, no. 9: 2411. https://doi.org/10.3390/biomedicines11092411