The incidence of colorectal cancer (CRC) in people aged ≥65 in high-income countries has declined since 2012. However, in people <55 years of age, the incidence has increased by 1–2% per year. The death rates in men and women decreased by 1.8% per year from 2012-2021, according to the latest report. Despite these improvements, CRC remains the 3rd most common type of cancer worldwide and the second leading cause of cancer-related deaths globally (1). The survival rate of patients with CRC is significantly influenced by the stage at which the tumor is detected, with an overall 5-year survival rate of ~65% (2). Common diagnostic methods for CRC include the fecal occult blood test (FOBT), the fecal immunochemical test (FIT), colonoscopy and computed tomography (CT) colonography. FOBT and FIT are non-invasive screening methods; the former detects hidden blood in the stool, whereas the latter detects human hemoglobin in the stool. However, neither method can reveal the exact location of the lesions, and they have relatively high false-positive and false-negative rates (3). Colonoscopy is the gold standard for diagnosing CRC, providing direct visualization and allowing for pathological analysis. Although highly accurate, it is invasive, expensive, and requires bowel preparation and anesthesia, which poses some risks (4). CT colonography generates a 3D image of the colon via CT scans. Although it is non-invasive, its resolution and detection sensitivity have limitations (5). The diagnosis of CRC usually begins with a preliminary screening with the FOBT and FIT, followed by imaging tests such as CT scans and magnetic resonance imaging to assess the spread of the cancer. The most effective method of diagnosis is endoscopy, as the lesions can be directly observed through colonoscopy and the cancer can be confirmed by biopsy (6–8). CRC is classified into 4 stages on the basis of the TNM system as follows: i) Stage I, the cancer is confined to the intestinal wall and has not spread to the lymph nodes or beyond; ii) stage II, cancer invades deeper into the intestinal wall or adjacent structures but does not spread far; iii) Stage III, cancer spreads to regional lymph nodes without distant metastasis; and iv) stage IV, the cancer has spread to a distant organ or site. ‘Advanced’ CRC usually refers to stages III and IV (9,10). Owing to the absence of distinct early-stage symptoms and limitations in early diagnostic methods, most patients with CRC are diagnosed at an advanced stage. In total, ~50% of the patients with CRC develop metastases, with the liver being the primary metastatic site and the most frequent cause of death (11). Recurrence patterns differ by location: 20% of right-sided colon cancer recurrences exhibited peritoneal dissemination, 42% of left-sided colon cancer recurrences were liver metastases and 33% of rectal cancer recurrences were local (12). CRC is unique in that it can be prevented and cured through the early identification and removal of high-risk adenomas (13). Therefore, implementing early detection screening programs is crucial for reducing the incidence and mortality of this disease. Early detection increases the likelihood of successful treatment and improves patient health outcomes (14). Colonoscopy is a widely accepted and effective screening method for CRC detection, despite certain risks, such as bleeding during sampling or polyp removal, and other potential complications (15). In recent years, advanced molecular techniques have played a significant role in the early diagnosis and treatment of various cancers, including CRC, by revealing the genetic mechanisms underlying CRC (16). Understanding these molecular mechanisms is crucial for addressing colon cancer. Non-coding RNAs (ncRNAs) have been shown to be involved in the onset and progression of colon cancer (17,18). These ncRNAs, which are mostly not translated into proteins, play significant roles in various cellular and physiological processes (19). Long non-coding RNAs (lncRNAs), which are longer than 200 nucleotides, participate in numerous biological processes, including cell proliferation, differentiation, development, apoptosis and metastasis. They often act as competitive endogenous RNAs (ceRNAs) to regulate the expression of specific miRNAs, thereby targeting molecules downstream of these miRNAs (20). lncRNAs can interact with RNA, DNA and proteins to form RNA-RNA, RNA-DNA and RNA-protein complexes that regulate gene expression through by affecting transcription, mRNA stability and translation (21,22). Numerous studies suggest that lncRNAs are crucial in cancer-related biological processes, including apoptosis, cell proliferation, cell invasion and metastasis (23–25).

In 1984, Pachnis et al (26) discovered the first eukaryotic lncRNA in mice and named it H19. This lncRNA was identified as a highly abundant fetal transcript in mice. Initially, scientists focused primarily on mRNAs, which encode proteins, whereas ncRNAs were dismissed ‘noise’ or ‘byproducts’. However, as technology has advanced and research has progressed, it has become clear that ncRNAs play crucial roles in gene regulation, epigenetics and disease development. The research on lncRNAs can be traced back to a series of groundbreaking studies in the late 20th and early 21st centuries. In 2002, researchers identified a lncRNA associated with gene silencing on the X chromosome (27). Subsequently, Guttman et al (19) discovered HOTAIR, a lncRNA that significantly influences gene locus regulation. In 2009, Rinn et al (28) identified HOTTIP, a different lncRNA located in the HOX gene cluster, noting its crucial involvement in gene locus regulation. Additionally, lncRNAs have been reported to play essential roles in embryonic development (29). Previous studies have also highlighted the involvement of lncRNAs in tumor initiation and progression, sparking intense research into their roles in cancer (20,30,31).

lncRNAs can be found in the cytoplasm (32), nucleus (33), nucleolus (34) and other subcellular regions and vesicles (such as nucleoli and exosomes). The localization of these proteins is associated with their molecular functions (32,35). Certain sequence motifs in their primary sequences are associated with subcellular localization (36). Investigating the localization of lncRNAs is crucial for understanding their roles in gene regulation, disease development and cellular functions. Compared with mRNAs, a greater proportion of lncRNAs are localized in the nucleus. An analysis of the overall characteristics of lncRNAs and mRNAs revealed that lncRNA genes are less evolutionarily conserved, contain fewer exons, and are expressed at lower levels (37–41). Different polyadenylation signals within lncRNAs can also influence their subcellular localization. For example, the CCAT1 lncRNA gene produces two isoforms: The long isoform (CCAT1-L) is expressed in the nucleus and includes an internal polyadenylation site that corresponds to the 3′ end of the short isoform (CCAT1-S), which is expressed in the cytoplasm (42). Nuclear lncRNAs can play a regulatory role in gene expression; for example, Xist RNA located on the X chromosome achieves X chromosome inactivation by silencing genes on the X chromosome (43). Numerous lncRNAs in the nucleus interact with chromatin modification complexes, affecting chromatin structure and gene expression; for example, HOTAIR binds to polycomb reactive complex 2 (PRC2), promoting the formation of H3K27me3 marks (29). NEAT1 is an lncRNA located in the nucleolus that plays an important role in paraspeckle formation and mRNA maturation (44). NEAT1 and MALAT1 are well-known nucleolar lncRNAs that play roles in maintaining nucleolar structure and RNA processing (45). Certain lncRNAs regulate mRNA stability and translation efficiency by binding to the target mRNAs in the cytoplasm. For instance, the lncRNA Linc-ROR protects mRNAs from degradation by binding to miRNAs, thereby influencing protein synthesis (46). Cytoplasmic lncRNAs can also act as molecular sponges, sequestering miRNAs and preventing them from binding to their target miRNAs. For example, the lncRNA PTENP1 regulates the expression of PTEN genes by binding to miRNAs, thus impacting the PI3K/Akt signaling pathway (47). H19, located on the cell membrane, is involved in the signal transduction process of the cell membrane, affecting cell proliferation and differentiation (48). Techniques for studying the localization of lncRNAs include in situ hybridization (49), RNA immunoprecipitation (50), RNA-seq (51), single-cell RNA sequencing (52) and fluorescence in situ hybridization-flow cytometry (53), among others.

According to a genomic database [Ensembl Release 96 (April 2019); https://www.ensembl.org/info/website/archives/index.html?redirect=no], human lncRNAs are categorized into several types, including 3′ overlapping ncRNA, antisense lncRNA, long interspersed ncRNA, retained intron, sense intronic, sense overlapping and macro lncRNAs. Intronic lncRNAs are transcribed from the introns of protein-coding genes; however, they do not encode proteins themselves (54). Antisense lncRNAs overlap with the antisense strand of coding genes and can influence gene expression by forming double-stranded RNA structures with coding regions through complementary base pairing (55,56). Intergenic lncRNAs are located between two coding genes and may regulate the expression of nearby genes (26). Sense lncRNAs overlap with the sense strand of protein-coding genes containing exons (57). Messenger lncRNAs can act as regulatory factors involved in modulating the expression of specific genes (29). Structural lncRNAs may play crucial roles in regulating the physical structure of cells or the chromosomal architecture within the nucleus (58). The classifications of lncRNAs are shown in Table I.

Although lncRNAs are functionally important, most lncRNA sequences exhibit low conservation across different species, making it challenging to identify the same lncRNA in different species through sequence similarity. This low degree of conservation is considered to reflect the diversity and specificity of lncRNA functions, as well as their rapid evolution (41). Despite their low sequence conservation, some lncRNAs exhibit a degree of structural and functional conservation across different species. These lncRNAs may maintain similar three-dimensional structures or play roles in the same gene expression regulation pathways across species (58,59). Moreover, numerous lncRNAs exhibit strong species specificity; that is, they are expressed in certain species but not expressed in others. This species specificity suggests that lncRNAs may play specialized roles in the development and adaptation processes of specific species (41,60). The conservation level of lncRNA promoters is comparable to that of protein-coding genes (37,61).

Ease of acquisition and detectability are essential criteria for diagnostic biomarkers. For patients that may have early-stage CRC, the option of performing a colonoscopy to obtain tissue samples might be strongly resisted. A genome-wide analysis of lncRNA stability by Clark et al (62) revealed that most lncRNAs exhibit high stability, with some having a half-life exceeding 16 h. Additionally, lncRNAs demonstrate greater stability room temperature and greater tolerance to repeated freeze-thaw cycles, making them suitable for clinical applications. Given the long length of lncRNAs, stem-loop primers used for microRNA detection are unnecessary for lncRNA amplification (63). Therefore, biomarkers that can be detected in blood or other body fluids are ideal for broader clinical applications. Over the past decade, numerous studies have demonstrated that lncRNAs are stable in the bloodstream and possess diagnostic potential, making them promising candidates for non-invasive diagnostic tests in CRC (64–67). In certain situations, lncRNAs may not be detectable in blood. These circumstances include improper sample handling (such as insufficient centrifugation, repeated freeze-thaw cycles and prolonged exposure to room temperature), inadequate storage conditions (such as failing to promptly freeze samples or maintain them at appropriate temperatures), and the use of inappropriate anticoagulants (such as heparin), leading to lncRNA degradation. Additionally, insufficient technical sensitivity and specificity can result in undetectable lncRNA levels. Furthermore, the expression levels of lncRNAs can be influenced by the stage of disease, with early-stage diseases potentially having lncRNA levels below the detection limit (63,68,69). lncRNAs are present in various body fluids, such as blood and urine, because they can traverse cellular membranes. This characteristic allows their detection in non-invasive diagnostic tests (70). lncRNAs in body fluids directly reflect the expression levels of certain genes and can distinguish between patients with cancer and healthy individuals (71). Additionally, a key feature of circulating lncRNAs is their ability to resist degradation by RNase enzymes (68,72). Apoptotic bodies, microvesicles and exosomes are vesicles encapsulated by a phospholipid bilayer containing DNA, RNA, lipids, proteins, polysaccharides and metabolites. These vesicles are released into the human circulatory system to facilitate the transfer of materials between cells (73–75). Owing to its notable sensitivity and specificity, reverse transcription-quantitative PCR is frequently employed to detect circulating lncRNAs (76). CCAT1 and HOTAIR were the first lncRNA markers reported to be present at significantly higher levels in the plasma of patients with CRC than in that of healthy individuals (77). lncRNAs also exhibit CRC specificity, which is reflected mainly in the difference in the expression of certain lncRNAs in the blood of patients with CRC compared with healthy individuals or those with other gastrointestinal diseases (78–80). Furthermore, these lncRNAs may be involved in key biological processes such as cell proliferation, invasion and metastasis in CRC. These findings not only contribute to understanding the molecular mechanisms of CRC but also provide new potential targets for the clinical diagnosis of CRC (81–83). Numerous other circulating lncRNAs have also been identified as potential biomarkers for detecting CRC (Table II) (64,77–79,80,84–108).

lncRNAs can serve as diagnostic markers for CRC, and changes in their expression can also predict patient prognosis. lncRNAs play multifaceted roles in CRC, impacting various biological processes, including cell cycle control, cell proliferation, epithelial-mesenchymal transition, migration, invasion, drug resistance, apoptosis and cellular stemness (109). These processes influence the malignancy of the tumor and ultimately affect patient prognosis. This section summarizes lncRNAs related to the prognosis of CRC and highlights their associated regulatory signaling pathways, enhancing our understanding of their mechanistic impact on the pathophysiology of CRC (Table III) (79,81–83,110–158).

CRC poses significant global health challenges and is characterized by high mortality rates, particularly when it is diagnosed at advanced stages. Improving treatment success and patient survival hinges on the development of reliable early detection biomarkers. In recent years, researchers have increasingly explored the potential of lncRNAs as non-invasive molecular biomarkers in CRC.

lncRNAs exhibit diverse functions in CRC, influencing processes such as cell cycle regulation, proliferation, apoptosis and metastasis. By acting as ceRNAs, they modulate the expression of specific miRNAs and downstream targets while also exerting control over gene expression through mechanisms such as transcriptional regulation, mRNA stability and translation. Interactions with RNA, DNA and proteins enable lncRNAs to form complex regulatory networks that impact CRC initiation and progression.

Owing to their stability in blood and potential for early detection, lncRNAs represent promising non-invasive biomarkers for CRC. Research highlights their pivotal roles in regulating pathological processes associated with CRC, including the modulation of cancer cell aggressiveness and metastatic potential through specific regulatory axes.

In conclusion, the study of lncRNAs offers novel insights into the molecular mechanisms of CRC and has potential to guide the development of innovative diagnostic and therapeutic approaches. Further investigations are essential for delineating their precise functions in CRC and exploring their clinical applications with the ultimate goals of increasing treatment efficacy and improving survival outcomes for patients with CRC.