Long Non-Coding RNAs in Colorectal Cancer: Navigating the Intersections of Immunity, Intercellular Communication, and Therapeutic Potential

Abstract

This comprehensive review elucidates the intricate roles of long non-coding RNAs (lncRNAs) within the colorectal cancer (CRC) microenvironment, intersecting the domains of immunity, intercellular communication, and therapeutic potential. lncRNAs, which are significantly involved in the pathogenesis of CRC, immune evasion, and the treatment response to CRC, have crucial implications in inflammation and serve as promising candidates for novel therapeutic strategies and biomarkers. This review scrutinizes the interaction of lncRNAs with the Consensus Molecular Subtypes (CMSs) of CRC, their complex interplay with the tumor stroma affecting immunity and inflammation, and their conveyance via extracellular vesicles, particularly exosomes. Furthermore, we delve into the intricate relationship between lncRNAs and other non-coding RNAs, including microRNAs and circular RNAs, in mediating cell-to-cell communication within the CRC microenvironment. Lastly, we propose potential strategies to manipulate lncRNAs to enhance anti-tumor immunity, thereby underlining the significance of lncRNAs in devising innovative therapeutic interventions in CRC.

Keywords: colorectal cancers (CRCs); immune cells; long non-coding RNAs (lncRNAs); tumor environment (TME).

Figure 1

Tumor microenvironment and intercellular communications. (A) A colorectal cancer tumor is a complex, multicellular, and multi-dimensional entity. The tumor microenvironment encompasses not only tumor cells originating from the intestinal epithelium but also various components that help regulate metabolism, nutrition, and immune responses. These components include an extracellular matrix, a diverse population of tumor-infiltrating lymphocytes (TILs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs), along with blood and lymphatic vessels. Another characteristic aspect of colorectal cancer is the presence of gut-associated lymphoid tissue (GALT). Additionally, bacteria play an essential role within the microenvironment. All these components interact to maintain a balance, thereby establishing a conducive environment for tumor growth. Among other forms of interaction, intercellular communication involving long non-coding RNAs (lncRNAs) is noteworthy. (B) The signaling mechanism of the long non-coding RNA (lncRNA) HOTAIR can serve as an example of intercellular communication through an lncRNA. In the nucleus of the tumor cell, the transcription and primary modification of the HOTAIR gene RNA occur (1), after which the mature lncRNA HOTAIR moves to the cytoplasm (2). Here, via a loader mechanism, HOTAIR is incorporated into a multivesicular body (MVB) where exosome particles loaded with HOTAIR are formed (3). These exosomes are then released into the extracellular environment (4). Their content is subsequently absorbed by macrophages via pinocytosis (5). Nuclear transport proteins guide HOTAIR into the macrophage’s nucleus (6), where this RNA interacts with the Polycomb Repressive Complex 2 (PRC2) chromatin remodeling complex (7). The HOTAIR-PRC2 complex identifies specific genomic regions (8), leading the PRC2 complex to methylate histones and silence a series of genes, thereby altering the gene expression profile of the macrophage. This results in a switch in macrophage polarization from M1 (anti-tumor) to M2 (pro-tumor), helping to sustain an environment conducive to tumor growth.

Figure 2

Extracellular vesicle biogenesis and lncRNA uptake: inhibition strategies in cancer Cells. This illustration provides a view of the interaction between a cancer cell and a recipient cell, focusing on extracellular vesicles (EVs) and long non-coding RNAs (lncRNAs). Within the cancer cell, the processes of transcription, multivesicular body (MVB) formation, and exosome biogenesis are depicted, leading to the release of lncRNA-packed exosomes into the extracellular environment. A rectangle marked “EV Inhibitors” signifies the inhibition of exosome biogenesis and release. The recipient cell is shown absorbing the lncRNAs contained within the exosomes, a process that is represented as being inhibited by a rectangle marked “Uptake Inhibitors”. The entire figure integrates these components to illustrate the complex mechanisms of EV formation, release, and uptake, and the potential therapeutic strategies of inhibiting these processes.

Figure 3

Principles of ASOs/RNAi for lncRNA silencing in colorectal cancer tumor cells. The illustration offers a step-by-step visual guide of the process involving ASOs/RNAi-based gene silencing, beginning from the in vitro production of therapeutic molecules to their eventual interaction and impact within colorectal cancer tumor cells. “ASOs/RNAi Preparation”: displayed as a lab flask containing miniature, colored strands of DNA or RNA, this section represents the synthesis of antisense oligonucleotides (ASOs) or RNA interference molecules (RNAi). “Loading into Microparticles”: this stage is portrayed by these small strands being encapsulated into larger, sphere-like structures. This represents the loading of ASOs/RNAi into microvesicles or microparticles. Additionally, these microparticles could be engineered to carry a specific antibody to facilitate targeted binding to specific cells. “Targeted Delivery”: delivery poses a significant challenge in this process. The microparticles carrying the therapeutic molecules are depicted entering the complex cellular environment of a colorectal tumor, which is composed of a myriad of different cell types. “mRNA Cleavage or Translation Inhibition and M1-Polarisation”: within the tumor cells, the microparticles discharge the ASOs or RNAi. These molecules are illustrated as binding to their long non-coding RNA (lncRNA) targets (depicted as strands of varying colors within the cells), leading to the degradation of the lncRNA, effectively “silencing” them. This step includes the RNA-induced silencing complex (RISC) mechanism, which allows for either mRNA cleavage or translation inhibition, leading to the silencing of the target genes.

Figure 4

Conceptual model of engineering CAR macrophages through lncRNA HOTAIR targeting and PRC2 knockout for cancer immunotherapy. The illustration outlines a hypothetical framework for enhancing cancer immunotherapy through genetic engineering. It begins with the isolation of a monocyte from a patient’s blood sample for in vitro cultivation. Within this controlled setting, Chimeric Antigen Receptor (CAR) structures are hypothetically engineered onto the monocyte. Following this, a targeted knockout of the protein PRC2, which is associated with lncRNA HOTAIR, is performed. This theoretical modification could transform the monocyte into a CAR macrophage, a change depicted by a clear alteration in the cell’s appearance. The final stage of the model demonstrates the potential reintroduction of the enhanced CAR macrophage into the patient’s body, encapsulating an innovative concept for the future development of cancer treatment strategies.