A glimpse of research cores and frontiers on the relationship between long noncoding RNAs (lncRNAs) and colorectal cancer (CRC) using the VOSviewer tool

Abstract As lncRNAs are essential participants in colorectal carcinogenesis. This study aimed to use the VOSviewer tool to access the research cores and frontiers on the relationship between lncRNAs and CRC. Our findings showed that the mechanism of lncRNA in the occurrence and development of CRC was the core theme of the field. (1) Immunotherapy and immune microenvironment of CRC and lncRNAs, (2) CRC and lncRNAs in exosomes and (3) CRC and lncRNA-targeted therapy might represent three research frontiers. A comprehensive understanding of their existing mechanisms and the search for new regulatory paradigms are the core topics of future research. This knowledge will also help us select appropriate targeting methods and select appropriate preclinical models to promote clinical translation and ultimately achieve precise treatment of CRC.


Introduction
Colorectal cancer (CRC) is the third most common tumor in men and the second most common tumor in women globally, causing more than 900,000 death every year [1]. With the aging population and the improvement of living standards, the incidence of CRC worldwide is increasing year by year, especially in developing countries. In addition, the incidence of CRC is gradually showing a younger trend [2,3]. Although some progress has been made in the treatment of CRC in recent decades, the overall survival rate of patients with advanced or metastatic CRC is still less than 50% [4,5]. Therefore, in this case, it is urgent to clarify the mechanism of the occurrence and progression of CRC to develop new markers and treatment strategies. In recent years, the contribution of long noncoding RNA (lncRNAs) in the occurrence and development of CRC has gradually attracted the attention of researchers. LncRNA is a type of RNA with a length of more than 200 nucleotides, which participates in various biological processes, such as transcription regulation, cell metabolism, RNA shearing and protein transport [6][7][8]. In CRC, they participate in the occurrence and development of CRC by acting as tumor suppressor genes and oncogenes, or interacting with DNA, RNA and proteins [9].
Numerous studies have demonstrated the potential value of lncRNAs for improving CRC diagnosis, prognosis, and treatment, but more studies are still needed to further determine the overall extent of these values and facilitate clinical translation. Mastering the development trend in this field will provide a theoretical basis for further research. Besides, this information can provide policy guidance to policymakers. However, few studies summarize and describe trends in this field from a bibliometric perspective.
Bibliometrics is the quantitative analysis of published literature on specific topics [10]. It can conduct an in-depth analysis of corresponding documents and references, qualitatively and quantitatively evaluate literature and reveal research trends [11][12][13]. In addition, its visualization technology can also display valuable information intuitively. Therefore, bibliometric analysis has been used in many fields [14][15][16]. Its systematic, transparent and repeatable review process also helps overcome the subjective bias of narrative literature reviews.
Therefore, in this study, we will perform a bibliometric analysis of the articles related to the relationship between lncRNAs and CRC, and briefly describe the research cores and frontiers based on our results.

Data source and search strategy
In this study, to ensure the high quality and timeliness of the literature, we chose the Web of Science: Science Citation Index Expanded (SCIE) and Social Sciences Citation Index (SSCI) as the data source. The search strategy was Topic (TS) ¼ ((((colorectal) OR (colo-rectal) OR (colonic) OR (colon) OR (rectum) OR (rectal)) AND ((neoplasm) OR (neoplasia) OR (malignancy) OR (tumor) OR (tumor) OR (carcinoma) OR (cancer) OR (adenoma) OR (adenocarcinoma) OR (adenomatous))) AND ((lncRNA) OR (lincRNA) OR (long non-coding RNA) OR (long untranslated RNA) OR (long non-protein-coding RNA) OR (long intergenic non-protein coding RNA))). The retrieval time was until 1 June 2022. All retrieval and data collection were completed within the same day to avoid the bias caused by the daily update of the database.

Eligibility criteria
After the preliminary search, two authors (J-H, WH-W) screened and reviewed the literature according to the following eligibility criteria: 1) The publication language is English.
2) The publication type is the article. 3) The subject of the publication must be CRC patients, CRC animal models or CRC cell models, and the relationship between lncRNAs and CRC should also be evaluated. Any contentious issues would be resolved through internal discussions and an eventual consensus would be formed.

Analysis tool
This research used VOSviewer version 1.6.18 (https://www. vosviewer.com/) as the primary tool for literature analysis. VOSviewer was integrated many analysis functions, such as network analysis, co-occurrence analysis, cluster analysis and coupling analysis, which helps identify patterns and trends in the publication in a specific field [17]. VOSviewer can automatically generate a scientific knowledge map in a specific field according to the plain text format literature data and the appropriate parameter settings [18]. The visual knowledge network map is generally composed of nodes and lines. The nodes in the network represent the unit, such as author, countries, keywords and cited references, and the lines between nodes represent cooperation, co-occurrence or co-citation relationships.
The data of this review was directly downloaded from public databases and did not directly involve the interaction between humans and animals, so the review by the Institutional review board was exempted.

Literature screening and keyword visualization
Based on our literature search, we located 3355 relevant publications. A total of 688 articles were excluded based on the type of literature and language of publication. Following the full-text evaluation of the remaining 2667 articles, 1281 articles were excluded. Finally, a total of 1386 publications were included in this study. The flow diagram of literature screening is shown in Figure S1.
The software VOSviewer was used to analyze and visualize co-occurrence frequencies and time trends of keywords across all publications. In total, all studies covered a total of 2702 keywords. The frequency of keyword occurrence was set to be at least twice, and we introduced a total of 764 keywords for analysis ( Figure 1). After excluding some subject terms, such as CRC, colon cancer and long non-coding RNA. Based on the size of the circle (the number of times the keyword appears) and the color of the circle in the graph (the color closer to yellow means that the keyword appears most recently), we found that the core theme in this field is the mechanism of lncRNA in the occurrence and development of CRC. Meanwhile, we also noticed three potential research frontiers: 1) Immunotherapy and immune microenvironment of CRC and lncRNAs. 2) CRC and lncRNAs in exosomes. 3) CRC and lncRNA-targeted therapy ( Figure 2).

A core theme
Lots of studies have focused on the specific mechanisms of lncRNA in the occurrence and development of CRC (such as proliferation, migration, epithelial-mesenchymal transition, metastasis, drug resistance and radioresistance). These studies have identified five functional paradigms of lncRNAs in CRC ( Figure 2).

Some lncRNAs function as signal molecules in CRC and
are directly involved in the regulation of transcription initiation. This functional paradigm of lncRNA has strong temporal and spatial specificity and can play a role in transcriptional silencing or enhancement. LncRNA H19 has been proven to promote CRC proliferation by upregulating CDK4 and CCND1 and increasing the activity of the b-catenin signaling pathway by reducing the expression of CDK8 via interacting with macroH2A [19]. Besides, lncRNA H19 can also form a complex with eIF4A3 to induce up-regulation of cell cycle gene expression and participate in tumorigenesis [20]. LINC01021 has been reported to be related to the chemosensitivity of CRC, and the molecular mechanism is that it can bind to the MER61C LTR promoter of p53 and regulate the DNA damage response of CRC cells [21]. In CRC, lncRNA SATB2-AS1 was found to acetylate H3K27 and H3K9 at the SATB2 promoter to up-regulate STAB2, then it recruits HDAC1 to the Snail promoter to down-regulate Snail and inhibits the invasion and metastasis [22]. There was also research report that HOXD-AS1 has been shown to down-regulate HOXD3 by hijacking PRC2 to accumulate H3K27me3 at the HOXD3 promoter, thereby inhibiting the MAPK/AKT signaling pathway [23]. Besides, lncRNA PVT1 has been reported to act as an epigenetic enhancer of MYC to promote CRC progression [24]. 2. Some lncRNAs act as molecular repressors in CRC. This type of lncRNA is often considered to be a negative regulator that binds to the target. LncRNA LUCAT1 has been shown to antagonize NCL function in the nucleus to regulate MYC expression [25]. LncRNA MALAT1 and PANDAR have also been shown to act as molecular repressors. These repressors often play different roles in subcellular domains, and their functions are directly related to their targets. 3. Some lncRNAs act as intermediaries in CRC. Some studies have shown that lncRNA can regulate gene expression by acting as a miRNA precursor. For example, LncRNA H19 can be used as a miR-675 precursor, thereby reducing the level of RB [26]. Other studies have shown that lncRNA can bind to proteins to regulate downstream signaling pathways. It has been reported that LncRNA FEZF1-AS1 can bind and increase the stability of pyruvate kinase 2 (PKM2) protein and further activate STAT3 in CRC [27]. There was reported that LINC01413 could bind to hnRNP-K and induce YAP1/ TAZ1 nuclear translocation to regulate the expression of ZEB1 in CRC cells [28]. lncRNA CASC11 has been reported to target heterogeneous ribonucleoprotein K (hnRNP-K) to activate WNT/b-catenin signaling in CRC cells [29]. An interesting study also reported that the lncRNA CYTOR could form heterotrimers with NCL and Sam68 to activate the NF-jB pathway and EMT to promote CRC progression [30]. Besides, lncRNA SLCO4A1-AS1 was also reported to act as a molecular scaffold to enhance the interaction between Hsp90 and Cdk2 to promote Cdk2 stability [31]. 4. The most frequently reported function of lncRNA in CRC is RNA-RNA interaction to regulate gene expression. It has been reported that lncRNAs can regulate the stability of mRNA in CRC. LINC00460 directly interacts with IGF2BP2 and DHX9 and binds to the 3' UTR of HMGA1 mRNA, thereby increasing the stability of HMGA1 mRNA [32]. It has also been reported that FOXC2-AS1 can positively regulate the neighboring gene FOXC2 and stabilize FOXC2 mRNA by forming RNA duplexes [33]. Besides, some lncRNAs contain multiple binding sites for miRNAs and are called competitive endogenous RNAs (ceRNA). Many lncRNAs function as ceRNAs in CRC.
There was reported that lncRNA NEAT1 could act as a ceRNA and inhibit the miR-34a/SIRT1 axis to promote the Wnt/b-catenin signaling pathway in CRC [34]. It has been proposed that MALAT1 could promote tumorigenesis through different axes, including MALAT1/miR-145/ SOX9, MALAT-miR-203-DCP1A and miR-363-3p/EZH2 [35][36][37]. Besides, lncRNA LINC00152 has been reported to promote cell proliferation, metastasis and confers 5-FU resistance in CRC by inhibiting miR-139-5p [38]. LncRNA UCA1 was also found to enhance CRC 5fluorouracil resistance by inhibiting miR-204-5p [39]. It is worth noting that some studies have found that the interaction between lncRNA and miRNA can form a circular signaling pathway and feedback regulate the expression of lncRNA in CRC [40]. 5. Recent studies have also revealed an emerging functional paradigm of lncRNA in CRC: encoding tumorassociated functional peptides. It has been reported that lncRNA HOXB-AS3 could encode a conserved 53-aa peptide (HOXB-AS3 peptide). Mechanistically, HOXB-AS3 peptide competitively binds to arginine residues in the RGG motif of hnRNP A1, ensuring the formation of lower PKM2 and inhibiting reprogramming of glucose metabolism, ultimately acting as a tumor suppressor [41]. LINC00675 is another discovered gastrointestinal tractspecific lncRNA, which encodes a small conserved protein (FORCP) consisting of 79 amino acids and is thought to inhibit proliferation, clonogenicity and tumorigenesis in CRC [42].

Three potential research frontiers
Immunotherapy and immune microenvironment of CRC and lncRNAs In recent years, immunomodulatory therapies targeting immune checkpoints have shown promising results in many cancers. However, CRC exhibits high resistance and inefficiency to this therapy, which may be related to its immune microenvironment [43]. Therefore, some studies have begun to explore whether lncRNAs can be used as immune-related markers of CRC to judge the tumor immune-related status and prognosis of patients. Sun et al. constructed a new signature using immune-related lncRNAs, which can predict the infiltration status of specific immune cells in CRC to a certain extent [44]. Some studies have also identified potential lncRNAs related to CRC immune infiltration through the ceRNA network, such as lncRNA MIR4435-2HG and lncRNA ELFN1-AS1 [45]. Besides, a considerable number of studies have achieved good results in judging the prognosis of CRC patients by using traditional statistical models or machine learning models constructed by immune-related lncRNAs [46][47][48].
There are also some studies trying to find the mechanism by which lncRNAs control the interaction between CRC and the immune microenvironment. In Table 1, we summarized how lncRNAs mediate the interaction between CRC cells and the immune microenvironment. These studies suggest that lncRNAs can induce the formation of CRC immunosuppressive microenvironment through various molecular mechanisms, such as acting as signaling molecules or RNA sponge adsorption, leading to immune escape of tumor cells and promoting metastasis.

CRC and lncRNAs in exosomes
Exosomes are nanoscale vesicles secreted by most types of cells, with a diameter of 30-150 nm [58]. Current evidence suggests that exosomes can regulate the physiology and function of various diseases by transporting nucleic acids including mRNA, microRNA and lncRNA as intercellular communication mediators [59]. Therefore, researchers have begun to explore the function and significance of exosomerelated lncRNAs in CRC. Table 2 summarizes the evidence of exosome-associated lncRNAs in CRC. In addition to their ability to mediate crosstalk between tumor cells and the immune microenvironment (LncRNA RPPH1, LncRNA HLA-F-AS1, LncRNA KCNQ1OT1, lncRNA CRNDE-h and lncRNA SNHG10 in Table 1), these exosome-associated lncRNAs can also act as regulators affect progression, metastasis, stemness and drug resistance in CRC (Table 2). Besides, other studies have explored the potential of exosome-associated lncRNAs as diagnostic and prognostic biomarkers for CRC [60][61][62]. Table 1. The mechanisms by which lncRNAs mediate the interaction between CRC cells and the immune microenvironment.

LncRNA
Function or significance Molecular mechanism

CRC and lncRNA-targeted therapy
Accumulating evidence demonstrated that lncRNA plays an essential role in cancer pathogenesis. Therefore, lncRNA-targeted therapies may represent a promising approach to cancer treatment. Given the diversity of their potential regulatory modes, lncRNAs can be targeted by multiple approaches, including pre-transcriptional targeting and post-transcriptional targeting. On the one hand, we can repress the promoter or use gene-editing techniques, such as CRISPR/Cas9 to manipulate the expression of lncRNAs prior to transcription. On the other hand, lncRNAs can also be targeted post-transcriptionally using a variety of approaches: (1) antisense oligonucleotides (ASOs) can be used to target RNAs for degradation through RNase Hdependent mechanisms; (2) using siRNA mediated by Dicer and Argonaute-dependent cleavage pathways; (3) lncRNA function loss can also be achieved by small molecules that prevent lncRNA secondary structure formation or cause steric inhibition.
Recently, researchers have begun to explore lncRNAtargeted therapy in CRC model animals. A study reported that a new type of primate-specific lncRNA FLANC was highly upregulated in CRC cells and promoted tumor metastasis, while the treatment with siRNA FLANC could reduce the number of large metastases and the tumor burden in the liver [71]. There was also a study using synergistic therapeutic strategy of self-assembled nanoparticles-mediated lncRNA CCAT1 silencing (siRNA) and curcumin in a subcutaneous xenograft model of CRC, showing good biosafety and compatibility [72]. Studies have also explored the use of ASOs to target key lncRNAs to reverse the malignant phenotype in animal models of CRC. For example, Wu et al. reported that the lncRNA MNX1-AS1 could promote the progression of CRC by stabilizing YB1, and the use of ASO targeting lncRNA MNX1-AS1 in combination with oxaliplatin demonstrated a better tumor inhibitory effect than oxaliplatin alone [73]. The lncRNA ELFN1-AS1 was also considered to be closely related to the occurrence of CRC and oxaliplatin resistance, and the use of ASO targeting lncRNA ELFN1-AS1 can inhibit tumor growth and reduce oxaliplatin resistance in animal models. Besides, another study showed that LINC00152 could promote CRC cell proliferation, invasion and migration, and miRNA-based therapy could reverse this effect in the xenograft nude mouse mode [74].

Discussion
Determining the mechanism of lncRNAs in the occurrence and development of CRC remains a core topic in the future. Because the expression of lncRNAs is usually highly speciesspecific, tissue-cell-specific and time-specific [75,76], accurate identification of candidate lncRNAs related to CRC is the basis for further exploration of their mechanisms. Highthroughput sequencing technologies, such as RNA-seq, which can explore the expression profiles behind phenotypic differences, identify new transcripts and other alternative spliceosomes of known transcripts have made it possible to obtain CRC-related lncRNAs on a large scale. However, interpatient variability and high spatial heterogeneity are essential characteristics of CRC [77]. Typical RNA-seq usually determines the average response of multiple cell populations and cannot resolve the heterogeneity of each cell population. This inevitably affects the precise identification of CRCrelated lncRNAs, especially since lncRNAs were generally lower expressed [78]. Single-cell sequencing technology can perform a comprehensive and unbiased analysis of the cell diversity in CRC masses [79]. Therefore, the single-cell transcriptome will be a more rigorous method to identify lncRNAs related to the specific phenotype of CRC. Besides, the whole functions of individual cells in multicellular organisms can be fully elucidated by determining their exact location [80]. Spatial transcriptome technology includes a series of methods of assigning each cell population to the exact location in the tissue section [81]. This will provide additional valuable insights for exploring lncRNAs spatially related to CRC.
Rapid and accurate screening of potentially valuable CRCrelated lncRNAs is the premise of further exploring their specific molecular mechanisms. Novel high-throughput sequencing technology allows us to obtain many lncRNA candidates. Although a small number of well-defined lncRNAs have proven that they play a role in various biological functions, such as chromatin modification and posttranscriptional regulation, the functional annotations of most lncRNAs are not explicit [6]. This phenomenon might be caused by many reasons, including the lack of a unified resource for annotating lncRNAs, and the lack of conservation of lncRNAs [82,83]. Therefore, in the future, the development of rapid bioinformatics tools to perform functional annotation and structural prediction of lncRNAs with  [70] reasonable accuracy, and the construction of the lncRNAs database in CRC will help quickly screen CRC-related lncRNAs with a potential value from a large number of candidates. For those potentially valuable lncRNAs, exploring their mechanisms in CRC will lay the foundation for clinical translation and precision medicine. This study summarizes five functional paradigms of lncRNAs in CRC, including acting as signal molecules, acting as molecular repressors, acting as intermediaries, involving in RNA-RNA interactions and encoding tumor-associated peptides. However, these classifications are not wholly exclusive, and most well-studied lncRNAs function in multiple mechanisms under the same functional paradigm, or even multiple functional paradigms, such as lncRNA XIST, lncRNA CRNDE [84][85][86][87]. Besides, some lncRNAs also played a double-sided role in carcinogenesis or cancer suppression in CRC, such as H19 [88,89], SNHG6 [90,91] and BANCR [92,93]. However, this difference might also be caused by not being under the same experimental conditions. These evidences demonstrate the complexity of the mechanisms of lncRNAs in CRC. It is worth noting that most these studies focus on cell lines and tissues, and further animal models to illustrate the mechanism are still necessary. Overall, the study of new functional paradigms of lncRNAs in CRC and the comprehensive characterization of their mechanisms remain the future focus.
Current clinical evidence suggests that immunotherapy has a therapeutic effect in the mismatch repair deficient (MMRd)/microsatellite instable (MSI) subgroup of CRC. However, most patients with MMR or microsatellite stable (MSS) tumors cannot benefit from immunotherapy [94]. Therefore, there is an urgent need to develop novel predictive biomarkers and explore the mechanisms underlying the interaction between CRC and the immune microenvironment. Immunotherapy and immune microenvironment of CRC and lncRNAs was a potential emerging trend identified in this study. We first reviewed lncRNAs as biomarkers related to the immune microenvironment of CRC and the corresponding predictive models. Then, the mechanisms by which lncRNAs mediate the interaction between CRC cells and the immune microenvironment were summarized. These studies demonstrated the important potential of lncRNAs in CRC immunotherapy. However, these studies on biomarkers or predictive models were almost retrospective designs with small sample sizes, which may introduce bias and confounding factors. Therefore, multi-center and large-sample prospective studies are still needed to verify the application value. Second, testing costs are also worth considering, and a corresponding cost-benefit analysis is required. Obviously, exploring the mechanisms of lncRNAs in the immune microenvironment of CRC remains a top priority in the future.
In the tumor microenvironment, exosomes are derived from different types of cells, such as tumor cells, fibroblasts and immune cells, and can modulate the tumor microenvironment by autocrine, paracrine or endocrine. As a novel mode of action, lncRNAs can be selectively sorted into exosomes and act as signaling messengers in intercellular communication, which are critical for tumor proliferation, metastasis, angiogenesis, immunosuppression and chemoresistance [95]. This study identified CRC and lncRNAs in exosomes as a potential emerging trend. We summarized the mechanisms of exosome-associated lncRNAs in CRC progression, metastasis, stemness and drug resistance, and reviewed the studies of exosome-associated lncRNAs as CRC biomarkers. Exosome-associated lncRNAs provide us with a new perspective on the generation and development of CRC. However, some key questions remain to be resolved, such as the mechanism that initially drives the sorting of lncRNAs into exosomes and the relevance of CRC progression remains unclear. Second, the results of many studies were obtained only from in vitro experiments and in vivo experiments in established animal models, which mean that there may be differences from the actual pathophysiology. Furthermore, as with any other novel biomarkers, large multicenter and prospective clinical studies are needed to assess clinical reliability in the future. Besides, due to the low abundance of lncRNAs in exosomes, in addition to considering clinical costeffectiveness in clinical applications, rapid and sensitive detection methods need to be developed. Many studies have shown that lncRNAs may be involved in regulating tumor cell proliferation, invasion, migration, stemness maintenance, drug resistance and remodeling of the microenvironment. More interestingly, many lncRNAs also showed cell-and/or tissue/tumor-specific expression. These make lncRNAs excellent candidates for precision cancer therapy. Our study indicated that CRC and lncRNAtargeted therapy was an emerging trend in the field of lncRNA in CRC. We described interventions when lncRNAs are potential therapeutic targets, and reviewed studies on lncRNAs as therapeutic targets in CRC. Currently, lncRNAs can be targeted by methods including siRNA, ASO, CRISPR-Cas9 and lncRNA steric repression.
Numerous studies have demonstrated the feasibility of using canonical siRNA to interfere with lncRNAs in cell lines [96]. However, the direct use of siRNA in vivo (animal) experiments is a huge challenge, mainly due to the lack of an ideal polymer carrier for carrying siRNA. Developing a carrier with good biocompatibility, low cytotoxicity, low immunogenicity and tumor enrichment is the key to using siRNA to target lncRNA. In addition, the material of the carrier and the construction process should not be complicated. Otherwise, it will affect the subsequent clinical transformation. This shows the importance of collaboration between materials science researchers and biomedical researchers. It is worth noting that although there are some reports that siRNAs can be transported into the nucleus when transfecting cells, the more common view is that they accumulate in the cytoplasm [97]. In addition to functioning in the cytoplasm, lncRNAs can also function in the nucleus [6]. Therefore, a detailed understanding of the mechanisms of lncRNAs in CRC is essential before carrier construction.
ASO is another promising approach for targeting lncRNAs. After binding to the target, ASO can invoke an RNase H-dependent cleavage mechanism, resulting in endonucleolytic cleavage of the target RNA [98]. Besides, some modified ASOs also can modulate RNA splicing patterns by affecting enhancers or repressors [99]. In addition to the ASOs mentioned in this article for targeting lncRNAs in CRC, this technique has also achieved good results in animal models of breast cancer and lung cancer [100,101]. Mastering the detailed mechanism of lncRNA in CRC will help us to design more targeted ASOs.
CRISPR-Cas9 can directly knock out the DNA sequence of lncRNA, while dead-Cas9 can trigger transcriptional silencing of lncRNA genes [102]. Because of the direct manipulation of DNA sequence by CRISPR-Cas9, in order to avoid some additional effects, we need to clearly grasp the regulatory mechanism of lncRNA in CRC, especially other hidden roles of lncRNA gene sequence. A study reported that after CRISPR-Cas9 knocked out the DNA sequence of lncRNA lockd, the expression of the target gene Cdkn1b decreased, but blocking the transcription of lncRNA lockd did not affect the expression of the target gene. The reason was that the DNA of the lncRNA lockd contacted with the promoter of Cdkn1b and acted as an enhancer [103]. Other studies have also found that using CRISPR-Cas9 to intervene at the DNA site of lncRNA, the effect on the target gene did not necessarily come from the lncRNA itself, but might originate from the additional regulatory effect of its sequence [104].
Repressing the spatial conformation of lncRNAs also represents a potential approach, especially for those lncRNAs involved in complex formation. With the development of RNA structure analysis methods, it has become possible to map the secondary and tertiary structures of lncRNAs accurately [105]. The development of new small-molecule inhibitors targeting the spatial concept of lncRNAs may have interesting therapeutic effects in CRC, although substantial work is required to confirm. A variety of approaches to targeting lncRNAs have brought light to the precise treatment of CRC. However, given the species specificity of lncRNAs, it is challenging to conduct preclinical tests in common animal models. Therefore, the development of new preclinical models, and comprehensive use of existing models, such as genetically engineered mouse models, xenograft models and organoids will help fully evaluate the therapeutic value of lncRNAs in CRC.
Our research also has some limitations, which should be considered when interpreting our research results. Publications were only from the SCIE and SSCI databases, which may lead to incomplete literature searches. However, the SCIE and SSCI databases have a strict evaluation of publications, which guarantees the high quality of literature. Therefore, this ensures that we reveal the research trends of lncRNAs in CRC to a certain extent.

Conclusion
As lncRNAs are essential participants in colorectal carcinogenesis, a comprehensive understanding of their existing mechanisms and the search for new regulatory paradigms are the core topics of future research. This will lay the foundation for improving immunotherapy resistance in CRC and understanding how lncRNAs in exosomes mediate crosstalk between CRC and the microenvironment. In addition, fully understanding the molecular mechanism of lncRNAs in CRC will also help us select appropriate targeting methods and select appropriate preclinical models to promote clinical translation and ultimately achieve precise treatment of CRC.