Liver cancer, predominantly hepatocellular carcinoma (HCC), is a gastrointestinal malignancy characterized by its insidious onset, rapid progression, restricted therapeutic efficacy, and dire prognosis. In 2020, liver cancer ranked as the sixth most prevalent cancer globally, with an incidence surpassing 900,000 new diagnoses (1). It also stood as the third leading cause of cancer-related mortality, accounting for over 830,000 deaths annually (1). Remarkably, China bore nearly half of the global liver cancer mortality burden (2, 3). Although the past decade has seen progress in liver cancer therapeutics (4), the long-term prognosis remains bleak, as evidenced by the low 5-year survival rate of 12.1% in China (5), and similarly unsatisfactory rates in affluent nations such as the United States of America (17.4%) (6). Therefore, unraveling the molecular intricacies of HCC and identifying new molecular markers and therapeutic avenues are of paramount importance.

Long noncoding RNAs (lncRNAs) are transcripts defined by their length—typically over 200 nucleotides—and limited protein-coding potential (7, 8). The biogenesis of lncRNAs is complex; they are transcribed by RNA Polymerase II, sharing certain characteristics with mRNAs, yet they also exhibit unique features such as less evolutionary conservation, fewer exons, and lower expression levels (9–11). Some lncRNAs are inefficiently spliced and terminate transcription independently of polyadenylation signals, resulting in nuclear retention and degradation mediated by the RNA exosome (12). Factors including transcriptional regulation, processing, and specific sequence motifs that recruit nuclear factors influence their nuclear localization. U1 small nuclear ribonucleoprotein (snRNP) binding sites and repeat elements play roles in lncRNA localization (13). A significant fraction of lncRNAs is exported to the cytosol via the Nuclear RNA export factor 1 (NXF1) pathway (14), where they undergo sorting processes, potentially associating with ribosomes for translation or localizing to mitochondria or exosomes, broadening their functional diversity. In essence, lncRNA biogenesis involves transcription, splicing, and sequence motifs, governing their nuclear retention and cytoplasmic export (15).

LncRNAs are classified based on their genomic location (intergenic, intronic, sense, and antisense) and size (small, medium, large) (16). Pioneering research has unveiled their crucial roles in various physiological processes, modulating gene expression at the epigenetic (17, 18), transcriptional (19–21), and post-transcriptional levels (20–22). LncRNAs interact with DNA, RNA, and proteins, influencing chromatin structure, gene transcription, RNA splicing, stability, and translation (15). They can serve as scaffolds for protein interactions, guide chromatin modifiers to specific genomic loci, or compete with microRNAs to regulate mRNA expression. Exploring the complexities of lncRNAs is poised to uncover new dimensions of gene regulation and cellular function.

Emerging data highlight the significant role of lncRNAs in human pathologies (23–25), especially in malignant tumors (26–29). Dysregulation of lncRNAs has been closely linked to tumor growth, metastasis, and resistance to chemotherapy (30–34), radiotherapy (35–38), and immune responses (39–41), underscoring their crucial involvement in cancer development.

Homo sapiens long intergenic non-protein-coding RNA 1134 (LINC01134), also known as TLNC1, is a lncRNA gene located on Chromosome 1p36.32 ( Figure 1A ). This gene, consisting of four exons and spanning a sequence length of 15,044 nucleotides, plays a pivotal role in various biological processes (42–44). To provide context to the significance of LINC01134, it’s essential to consider its neighboring genes, which include C1orf174, LINC01346, LINC02780, and DFFB, as illustrated in Figure 1B . Understanding the genomic context of LINC01134 sheds light on its potential functional importance and its role in gene regulation. Recently, LINC01134 has gained attention for its role in the progression of HCC (42, 45). and it has been identified as a prognostic indicator for HCC patients (42–44). In addition, LINC01134 has been linked to an unfavorable prognosis in ovarian cancer (46), and signatures related to LINC01134 have shown superior predictive value for prognosis in low-grade glioma (47) and gastric cancer (48). Altered expression of LINC01134 has been observed in HCC tissues and cell lines, implicating it in the progression of HCC (42–45, 49–51).

To compile pertinent literature for a comprehensive analysis of LINC01134’s involvement in cancer biology and its prospective clinical relevance, we conducted a thorough systematic search across multiple databases. These databases included PubMed, Web of Science, ScienceDirect, Embase, SpringerLink, and Google Scholar, as well as Chinese databases such as China National Knowledge Infrastructure (CNKI), Weipu Information (VIP), and Wanfang Database. Our search utilized the keywords ‘LINC01134’ and ‘TLNC1’. We considered peer-reviewed articles published in English or Chinese up to October 1, 2023. The inclusion criteria were predefined, focusing on original studies that explored LINC01134’s expression, clinicopathological associations, and biological functions in human tumors.

In this review, we provide a comprehensive analysis, addressing aberrant expression patterns, molecular mechanisms, and the clinical significance of LINC01134 in HCC. This review aims to establish a theoretical foundation for potential future clinical applications, predict the functions and regulatory mechanisms of LINC01134, and delineate both the current research gaps and future directions.

Research underscores the pivotal roles of LINC01134 in hepatocarcinogenesis and progression. LINC01134 functions through diverse mechanisms, including interactions with DNA promoters, decoy proteins, mRNA binding, and acting as a miRNA sponge, regulating malignant cellular behaviors, and contributing to tumor therapy resistance ( Figure 2 ). It has also been identified as a promising prognostic and diagnostic tumor marker, along with its potential as a therapeutic target in hepatoma ( Figure 2 ). In the following sections, we reviewed the multifaceted role of LINC01134 in HCC progression, metastasis, and its impact on chemo- and radiotherapy resistance. In addition, we examine the clinical applications of LINC01134 in HCC, focusing on prognosis, diagnosis, and therapy.

In recent times, bioinformatics has significantly advanced the discovery and annotation of lncRNAs. Mainstream technologies for sequencing and lncRNA profiling include RNA-seq and microarray, which prominently feature in repositories like The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). This advancement in bioinformatics is crucial for deeper explorations into lncRNAs. Currently, in silico methods, backed by bioinformatic analyses, stand out as powerful tools. Numerous databases are available that can be instrumental in annotating and predicting potential lncRNA functions, such as LncBook 2.0 (73) and RNAInter (74). To enrich this review, we tapped into several online lncRNA databases and high-throughput data, aiming to predict the clinical significance, functional dynamics, and pathway involvement of LINC01134 in tumorigenesis and HCC progression. These insights may provide invaluable guidance for future studies.

In our investigation of LINC01134’s diagnostic potential in HCC samples, we analyzed data from the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. Our analysis revealed that LINC01134 exhibits good accuracy in distinguishing between normal and HCC tissues, as evidenced by an area under the curve (AUC) value of 0.833 ( Figure 7 ). Furthermore, LINC01134 demonstrates diagnostic value in distinguishing between N0 and N1 HCC samples (AUC = 0.716) and between M0 and M1 HCC patients (AUC = 0.604) ( Figure 7 ). Turning our attention to the potential of LINC01134 as a minimally invasive diagnostic tool, we initiated an analysis of extracellular vesicle lncRNA expression in blood samples. Notably, exosomes represent a subpopulation of extracellular vesicles with an average diameter of 100 nm (75). Exosomal lncRNAs are currently recognized as promising tumor diagnostic tools (76–79). Utilizing exoRBase (http://www.exorbase.org/), a repository of extracellular vesicle long RNAs derived from RNA-seq data analyses (80), we observed a significant upregulation of LINC01134 expression in the blood of individuals with various cancers, including HCC, when compared to healthy donors ( Figure 8 ). These findings underscore the potential of LINC01134 as a highly promising diagnostic marker for HCC. The prospect of utilizing LINC01134 as a novel circulating oncological biomarker opens up an exciting avenue for future research.

LncRNAs play crucial roles in modulating chromatin architecture and function, regulating transcription, and influencing RNA processing and stability (81, 82). They achieve these functions through targeting DNA, binding to RNAs, and recruiting proteins (81, 82). Here we found the top significant 25 RNA-DNA interactions, RNA-RNA interactions, and RNA-protein interactions related to LINC01134 ( Figure 9 ), using RNAInter (http://www.rnainter.org/), an RNA interactome database. Accumulating evidence suggests that lncRNAs can behave like competing endogenous RNAs (ceRNAs), and compete with microRNAs to communicate with mRNAs (83–86). LncRNA-associated ceRNA regulation has been implicated in cell-fate determination and tumorigenesis (87–90). Here, we used the LnCeCell database (91) to predict lncRNA-associated ceRNA networks at single cancer cell resolution. We displayed the LINC01134-associated ceRNA-network ( Figure 10A ) and also identified LINC01134-associated ceRNA-related cancer hallmarks, such as self-sufficiency in growth signals, evading apoptosis, enduring angiogenesis, and tissue infiltration and metastasis ( Figure 10B ). Furthermore, we conducted an analysis to identify the top 10 enriched functions of LINC01134-associated ceRNA ( Figure 10C ). The findings indicate that ceRNAs associated with LINC01134 play a role in crucial tumor-related biological processes, such as the “G2-M transition of the mitotic cell cycle”, “maintenance of cellular protein localization” and “MAP kinase activity”. Furthermore, these ceRNAs are linked to several cancer-associated pathways, including the “Aurora B pathway”, “phosphoinositide 3-kinase pathway” and “Wnt non-canonical pathway”. It’s worth noting that these pathways are closely related to the onset and progression of various tumors (92–94), including HCC (95–98).

Moreover, we investigated the role of LINC01134 in immunotherapy. We obtained liver cancer datasets from UCSC (https://xenabrowser.net/) for analysis. Our findings revealed a significant negative correlation between LINC01134 gene expression and immune infiltration scores (including stromal, immune, and ESTIMATE scores) ( Figure 11A ). This suggests a potential inverse association between LINC01134 and immune infiltration, hinting at its involvement in the immune evasion mechanisms in HCC. However, more experiments and mechanistic studies are required. Additionally, we analyzed the correlation between LINC01134 and 60 key genes related to inhibitory and stimulatory immune checkpoint pathways ( Figure 11B ). The identification of LINC01134-related regulatory networks enhances our understanding of its role in tumor pathology and aids precision medicine. These predictions offer insights into potential tumor-related mechanisms, requiring further validation.

In this review, we elucidated the biological function and regulatory mechanism of LINC01134 in hepatocellular carcinoma and highlighted its potential as a diagnostic and prognosis marker, as well as a therapeutic target for HCC. However, it is imperative to emphasize that investigations into LINC01134 are at a nascent stage, and its involvement in most human tumors remains largely unexplored. Currently, LINC01134 has only been reported in the context of liver cancer, While the existing reports are limited in number, this review’s synthesis of LINC01134 research in liver cancer can serve as a valuable foundation and inspiration for future investigations in other human tumors.

Based on an in-depth analysis of previous studies, there are still some significant questions regarding the role of LINC01134 in HCC that warrant further investigation. This includes a need for further research into the biological impact of LINC01134 on other RNA-binding proteins (RBPs) (42). Furthermore, the oncogenic role of LINC01134 in HCC requires a thorough assessment through genetic knockout mouse models. Moreover, further exploration is warranted to understand the role and functions of LINC01134 in tumor stem cells of HCC (45).

Additionally, to elucidate LINC01134’s role in tumor pathogenesis, particularly in the context of drug and radiotherapy resistance, and immunotherapy impact, in-depth experimental studies of its functional and biological mechanisms are required. Furthermore, it is also necessary to investigate the expression profiles of homologous protein-coding genes associated with LINC01134. Given the significant role of endogenous siRNAs (esiRNAs) in regulating RNA silencing (99–101), future research should also focus on unraveling the interactions between esiRNAs derived from LINC01134 and their target genes. Moreover, there is a need to investigate LINC01134’s expression profiles in both tumor tissues and body fluids, aiming to assess its diagnostic potential using minimally invasive samples such as serum, which could facilitate distinguishing cancer patients from healthy individuals. Extensive research is also warranted to evaluate the prognostic value of LINC01134 across diverse populations and various pathological stages of different tumors. Undertaking these research initiatives will provide invaluable insights, paving the way for personalized cancer management in terms of diagnosis, risk stratification, and therapeutic interventions.

In conclusion, our study emphasizes LINC01134 as a multifaceted oncogenic lncRNA exerting a substantial impact on HCC growth, metastasis, and therapy resistance. We recognize its potential as a promising biomarker and therapeutic target in hepatoma, offering a valuable avenue for targeted interventions. However, it is imperative to recognize that further experimental investigations are necessary to comprehensively unravel the underlying roles and mechanisms of LINC01134 in hepatocarcinogenesis, progression, resistance, and immunotherapy, establishing a robust theoretical foundation. To enhance the clinical relevance of LINC01134, future clinical studies focused on this lncRNA are essential for uncovering innovative ideas and approaches in HCC diagnosis, risk stratification, and treatment.

YY: Visualization, Data curation, Formal Analysis, Writing – original draft. JW: Visualization, Writing – original draft, Data curation, Formal Analysis. QG: Writing – original draft. HL: Visualization, Conceptualization, Supervision, Writing – review & editing.