1 Introduction

Non-coding RNAs (ncRNAs) are a broad class of RNA molecules that play essential regulatory roles in cells despite not encoding proteins [1, 2]. Using their length, structure, and function, ncRNAs can be classified into various types, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs) [3], circular RNAs (circRNAs) [4, 5], and Piwi-interacting RNAs (piRNAs) [6]. Each ncRNA type has distinct cellular functions and can regulate different aspects of gene expression. Among them, lncRNAs are defined as non-coding transcripts that are longer than 200 nucleotides and transcribed by RNA polymerase II [7]. With advances in epigenetics, the regulatory roles of lncRNAs in tumors have become increasingly clear, drawing significant research attention [8]. By competitively binding to miRNAs or directly interacting with protein-coding gene transcripts, lncRNAs can regulate the splicing, translation, and methylation of target genes, thereby modulating the expression levels and activity of their corresponding proteins [8]. One such lncRNA is LINC00922, which has a locus at 16q21. LINC00922 has attracted considerable interest because of its pivotal regulatory function. It is highly expressed in various cancer types and plays a critical role in tumor progression.

LINC00922 has eight alternative splicing variants, with LINC00922-203 being the representative transcript [9]. This lncRNA features a complex secondary structure, potentially serving as a binding site for target messenger RNA (mRNA) interaction or influencing cancer cell resistance mechanisms [10]. In various cancer cell lines, LINC00922 is predominantly localized in the cytoplasm, although a small portion is also found in the nucleus [11]. Extensive experimental evidence has confirmed that LINC00922 is abnormally expressed in numerous cancer types, with data from the GDC database further supporting this finding. LINC00922 operates within a complex gene regulatory network. The upstream factor TFAP2C binds to the promoter region of the gene encoding LINC00922, promoting its transcription. Additionally, LINC00922 can regulate the expression of downstream factors at both the pre-transcriptional and post-transcriptional levels, including NKD2, ETS1, and six competing endogenous RNA (ceRNA) axes. Interestingly, LINC00922 participates in a positive feedback loop, promoting its own accumulation in cancer cells via the LINC00922/miR-424-5p/TFAP2C axis in osteosarcoma (SaOS) cells [12].

In both in vitro and in vivo experiments, LINC00922 has been shown to promote several malignant processes, including tumor cell proliferation, the epithelial-mesenchymal transition (EMT), invasion, metastasis, and apoptosis. Furthermore, numerous independent studies have demonstrated that overexpression of LINC00922 is significantly associated with increased cancer cell resistance to chemotherapeutic drugs [12, 13]. Clinical data from patient follow-up evaluations confirm that high LINC00922 expression levels are correlated with poor cancer patient prognosis.

As an emerging focus of ncRNA research, LINC00922 has been found to play a pivotal role in cancer progression, holding significant potential for clinical applications in cancer diagnosis and treatment. The differential expression of LINC00922 across various cancers also positions it as a promising diagnostic biomarker. Additionally, its regulatory network influences multiple malignant processes, making LINC00922 a potential target for therapeutic intervention. In this review, we provide a comprehensive summary of the current research on LINC00922, highlighting its role in cancer biology, while also identifying existing gaps in knowledge. These insights will serve as a valuable resource for future studies and offer new perspectives for the clinical translation of LINC00922-based therapies.

2 LINC00922 Gene Characteristics

As illustrated in Figure 1a, LINC00922 is located at 16q21. A search of the Ensembl database (https://asia.ensembl.org/index.html, accessed August 17, 2024) revealed that LINC00922 has eight alternative splicing variants, with LINC00922-203 serving as the representative transcript [14]. Figure 1b shows the secondary structure prediction for LINC00922, as obtained from the lncHUB2 database (https://maayanlab.cloud/lncHUB2/, accessed August 17, 2024). The structure comprises multiple lncRNA-specific modules, including internal loops, stacked loops, multi-branched loops, hairpin loops, protruding loops, and external loops. Previous studies have demonstrated that such structures enable lncRNAs to regulate cancer cell behavior, including cell survival and drug resistance [15]. The complex LINC00922 secondary structure likely contributes to the regulation of malignant cancer behaviors.

LINC00922 is distributed in both the cytoplasm and nucleus. Subcellular fractionation and RT-PCR or fluorescent in situ hybridization (FISH) analysis of three different cancer cell lines have confirmed its cytoplasmic distribution in SaOS [12], ovarian cancer (OC) cell lines (ES-2 and SKOV3) [16], and gastric cancer (GC) cell lines (MKN-45 and HGC-27) [17]. However, FISH analysis of the breast cancer (BrC) cell line MCF-7 [18] and colorectal cancer (CRC) cell line HCT116 [19] revealed LINC00922 localization to be predominantly nuclear. To further clarify the distribution pattern, we consulted the lncLocator database, which confirmed that LINC00922 is predominantly cytoplasmic with some presence in the nucleus, as shown in Figure 1c [11].

Although LINC00922 has garnered attention as a newly discovered lncRNA, a deeper understanding of its genetic characteristics remains elusive. The nucleic acid properties of LINC00922 and its interactions with neighboring genes have yet to be fully characterized. Furthermore, the LINC00922 subcellular localization requires further experimental validation, with its nucleotide structure, secondary structure, and cellular distribution needing additional investigation to clarify its functional role in cancer progression.

3 Abnormal LINC00922 Expression in Multiple Cancer Types

As shown in Table 1, LINC00922 is significantly overexpressed in cancer samples compared with their corresponding normal tissues. LINC00922 is overexpressed in four cancer cell lines, including lung cancer (LC) [20], SaOS [12], OC [16, 25], and GC [17, 24]. Moreover, LINC00922 expression levels are significantly higher in highly invasive CRC cell lines compared with less invasive CRC cell lines [19], suggesting that LINC00922 contributes to the invasive ability of CRC cells. At the tissue level, LINC00922 is highly expressed in seven cancers: LC [20], SaOS [12], BrC [18, 26], bladder cancer (BC) [21], hepatocellular carcinoma (HCC) [22], OC [16, 25], and GC [17, 23, 24].

These findings, confirmed by multiple independent studies, highlight that LINC00922 is overexpressed in various cancer types. To further explore the relationship between LINC00922 and cancer, we conducted bioinformatic analyses using The Cancer Genome Atlas (TCGA) and TARGET datasets [27] from the UCSC database (https://xenabrowser.net/, accessed August 7, 2024). This work revealed that LINC00922 is significantly overexpressed in seven tumor types, including BrC, acute lymphoblastic leukemia, pancreatic adenocarcinoma (PAAD), sarcoma (SARC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and ovarian serous cystadenocarcinoma (OV) (Supporting Information S1: Figure S1). In the breast invasive carcinoma dataset, the experimental results corroborated each other, showing significant overexpression of LINC00922. Conversely, LINC00922 was significantly underexpressed in four cancer types, including LUAD, LUSC, neuroblastoma, and testicular germ cell tumors (TGCT). These findings provide additional insights into the role of LINC00922 in cancer (for detailed information, see supplementary material).

4 Complex Regulatory Mechanism of LINC00922

As shown in Table 2, LINC00922 exhibits a complex regulatory mechanism and can modulate multiple genes at both the pre-transcriptional and post-transcriptional levels. At the pre-transcriptional level, LINC00922 can interact with DNA methyltransferases (DNMTs) and Sirtuin 3 (SIRT3), inhibiting the transcription of downstream proteins. At the post-transcriptional level, as illustrated in Figure 2a, LINC00922 suppresses the expression of several miRNAs, thereby promoting cancer progression. The binding sites of four miRNAs in LINC00922 are shown in Figure 2b. Additionally, Figure 3 demonstrates how LINC00922 can enhance its own expression levels in cancer cells through a positive feedback regulation mechanism [12].

5 LINC00922 in Wnt Signaling Pathway Regulation

The Wnt signaling pathway is a highly conserved and fundamental pathway involved in key cellular processes, such as proliferation, apoptosis, and stem cell differentiation [38]. This pathway is activated when Wnt proteins bind to specific surface receptors on the cell membrane [39]. The aggregation of Wnt and its receptors initiates the formation of a downstream destruction complex, which facilitates the nuclear translocation of β-catenin, driving the malignant progression of various cancers [39].

As illustrated in Figure 4, the classic Wnt pathway can be divided into two states: Wnt ON and Wnt OFF [40]. In the inactive state (Wnt OFF), a destruction complex composed of the scaffolding protein AXIN, tumor suppressor APC, and kinases CK1α and glycogen synthase kinase-3β(GSK-3β), binds to unphosphorylated β-catenin [40]. This complex facilitates β-catenin degradation rendering it inactive. In the activated state (Wnt ON), Wnt proteins bind to a protein heterodimer consisting of the transmembrane receptors frizzled (FZD) and LRP5/6, which triggers Wnt signaling pathway activation [40]. The activated FZD receptor binds to disheveled (DVL), leading to phosphorylation of LRP5/6. This results in the formation of the Wnt-FZD-LRP5/6 complex, which recruits AXIN1 and inhibits phosphorylation of β-catenin, promoting its nuclear translocation [40]. In the nucleus, β-catenin binds to transcription factors, driving the malignant progression of cancer cells [40]. In OC, LINC00922 inhibits miR-361-3p and activates the Wnt signaling pathway, which enhances β-catenin nuclear translocation and drives cancer cell proliferation [16]. NKD2, a tumor suppressor known to inhibit cell proliferation, invasion, and migration, has been shown to act as a negative regulator of the Wnt signaling pathway [18, 41]. In BrC, LINC00922 promotes Wnt signaling pathway activation by recruiting DNMT and reducing NKD2 gene expression [18]. Furthermore, Wnt signaling pathway activation facilitates the binding of nuclear β-catenin to transcription factors, which in turn drives c-Myc expression and promotes the EMT and tumor infiltration [18, 42].

6 LINC00922 Regulates Multiple Cellular Behaviors

As shown in Figure 5 and Table 3, both in vitro and in vivo experiments have confirmed that LINC00922 plays a key role in promoting malignant cancer progression. Through its involvement in various gene regulatory networks, LINC00922 can influence multiple cellular processes, including proliferation, the EMT, invasion, metastasis, and apoptosis. Additionally, tumor xenograft models have further validated the tumor-promoting effects of LINC00922.

7 LINC00922 Increases Cancer Cell Resistance to Chemotherapy Drugs

Chemotherapy is a cornerstone of cancer treatment, designed to inhibit tumor cell proliferation and systemic metastasis. However, the development of chemotherapy resistance in cancer cells significantly reduces the therapeutic efficacy of these drugs [51]. As shown in Figure 6, LINC00922 has been found to increase chemotherapy resistance in cell lines of two cancer types, SaOS [12] and GC [13], by participating in ceRNA networks.

TFAP2C, a member of the transcription factor AP-2 family, is associated with drug resistance in several cancers [30]. High TFAP2C expression levels are correlated with increased drug resistance in CRC cells [30]. GDPD5, a choline-producing enzyme, has been linked to resistance to 5-FU in CRC [52]. In SaOS, LINC00922 overexpression increases TFAP2C expression levels in the MG63 cell line via the LINC00922/miR-424-5p/TFAP2C axis, thus enhancing resistance to the chemotherapy drug doxorubicin (DXR) [12]. In vivo studies using BALB/c nude mice further confirmed that LINC00922 can boost DXR resistance in cancer cells through this ceRNA axis [12]. Similarly, in GC, LINC00922 overexpression elevates GDPD5 expression levels in the AGS and HGC-27 cell lines through the LINC00922/miR-874-3p/GDPD5 axis, thereby increasing resistance to DDP [13].

8 LINC00922 Increases Immune Cell Infiltration in Cancer Patients

Immune cell-based therapies are emerging as a promising approach for cancer treatment, providing new avenues for tumor management [53]. The presence and activity of various immune cell types in the tumor microenvironment are closely associated with cancer progression and metastasis [19]. Using the ssGSEA algorithm in the GSVA package, we observed that LINC00922 expression levels positively correlate with the infiltration of multiple immune cell types, including cytotoxic T cells, dendritic cells (DC), immature DCs, eosinophils, macrophages, mast cells, neutrophils, natural killer (NK) cells, plasmacytoid DCs, T follicular helper cells, γδ T cells, Th1 cells, and regulatory T cells (Treg) [23]. However, high LINC00922 expression levels were negatively correlated with Th17 cell infiltration [23]. Further analysis revealed significant differences in immune cell infiltration patterns between high- and low-expression LINC00922 GC samples, reinforcing the association between LINC00922 expression levels and immune cell content in these patients.

To further confirm the relationship between LINC00922 and immune cells, we analyzed the TCGA Pan-Cancer dataset extracting LINC00922 expression data across samples from 30 different cancer types. Using the EPIC method to assess immune cell infiltration, we found a positive correlation between LINC00922 expression levels and immune cell infiltration in multiple cancer types (Supporting Information S1: Figure S2).

9 High LINC00922 Expression Levels Predict Poor Prognosis

As shown in Table 4, increased LINC00922 expression levels are strongly associated with poor prognosis in various cancer types. Prognostic analyses have revealed that patients with elevated LINC00922 expression levels tend to exhibit advanced pathological features, such as later tumor-node-metastasis (TNM) stages, higher T stages, poorer histological grades, larger tumors, and more frequent lymph node metastasis. High LINC00922 expression levels are also linked to worse overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) in numerous cancers, such as LC [20], SaOS [12], BrC [18], OC [16], GC [17, 23, 24], CRC [19], and BC [21].

In LC, LINC00922 expression patterns can predict poor OS, with higher levels correlating with later TNM stages, larger tumor size, and increased lymph node metastasis [20]. In SaOS, LINC00922 expression levels are linked to poor OS [12]. In BrC, high LINC00922 expression patterns correlate with poor OS, advanced TNM stages, and larger tumor size [18]. In OC, LINC00922 expression levels are predictive of poor OS [16]. In GC, LINC00922 expression can predict poor OS, DFS, and PFS, with higher expression levels associated with more advanced T and M stages, worse histological grades, and different histological types [23]. Additionally, other studies have shown that LINC00922 expression levels correlate with poor OS and DFS in GC [24] and are a predictor of poor OS in CRC [19].

Moreover, H3K27cr, a downstream factor of LINC00922, is highly expressed in tumors with more advanced stages and metastatic features, further confirming the prognostic significance of LINC00922 expression in predicting cancer progression [19].

10 Discussion

NcRNAs encompass a diverse range of molecules, including lncRNAs, miRNAs [3], circRNAs [4, 5], and piRNAs [6]. Previous studies have identified hundreds of ncRNAs involved in RNA maturation, transcriptional regulation, chromatin remodeling, and post-transcriptional modifications. Each ncRNA subtype plays a distinct regulatory role in gene expression and contributes to various aspects of cancer development. Over the past decade, lncRNA research has rapidly advanced, uncovering their remarkable properties. LncRNAs are now recognized as crucial players in numerous cellular processes, including the cell cycle, differentiation, and metabolism [8]. These molecules exert their functions through various mechanisms, such as regulating transcription, epigenetic modifications, controlling protein and RNA stability, and influencing the translation and post-translational modifications of RNA or proteins [54]. Consequently, targeting lncRNAs has emerged as a promising strategy for cancer therapy [55].

The gene encoding LINC00922, a recently discovered lncRNA, is located on chromosome 16 at 16q21. LINC00922 is predominantly localized in the cytoplasm, with smaller amounts found in the nucleus, ribosomes, and exosomes. Clinical data have shown that high LINC00922 expression levels are closely associated with various pathological features of malignant tumors and poor patient prognosis. Studies comparing normal and cancerous tissues at both the cellular and tissue levels have confirmed that LINC00922 expression levels are significantly elevated in many cancers, indicating that this molecule is strongly correlated with cancer development. Our pan-cancer analysis using data from the GDC database further supports this observation, revealing significant LINC00922 expression differences across diverse cancer types. However, current studies have mainly performed single-cell and tissue analyses, with limited research on LINC00922 expression patterns in common clinical body fluids. Currently, there is a lack of clinical data and experimental validation to confirm the feasibility and accuracy of LINC00922 as a potential therapeutic target and nuclear diagnostic biomarker in clinical applications. Future studies should aim to collect more comprehensive clinical datasets and integrate larger, diverse databases to analyze LINC00922 expression differences between cancer patients and healthy individuals across various tissues, cells, blood, and body fluids. This approach will help further validate the reliability of using LINC00922 as a clinical biomarker for cancer diagnosis. Thus, although LINC00922 holds promise as a clinical target and biomarker, further experiments are needed to fully assess its potential.

LINC00922 can regulate cancer cell functions by participating in complex gene regulatory networks. LINC00922 is known to be regulated by the activating protein TFAP2C in cancer cells [12]. Interestingly, it forms a positive feedback loop via the LINC00922/miR-424-5p/TFAP2C axis, continuously elevating LINC00922 expression levels in cancer cells, thereby promoting malignant progression [12]. Additionally, LINC00922 can directly target NKD2 [18] and five miRNAs, inhibiting their expression patterns. NKD2 is a negative regulator of Wnt signaling that is crucial for controlling activation of this pathway [18, 56]. By suppressing NKD2, LINC00922 can promote Wnt pathway activation. LINC00922 can also indirectly enhance the expression of the telomerase regulator ETS1 by recruiting H3K27cr in the nucleus, thereby facilitating cancer cell invasion and metastasis [19]. However, the downstream regulatory mechanisms of LINC00922 are still incompletely understood, as its upstream regulatory factors remain largely unexplored. LINC00922 has been shown to suppress the expression of multiple miRNAs, thereby modulating cancer cell proliferation, invasion, and metastasis through several ceRNA axes. Additionally, experimental evidence has indicated that LINC00922 can activate the Wnt signaling pathway by inhibiting its downstream targets, NKD2 and miR-361-3p, though the exact regulatory mechanism remains unclear. Future studies using CRISPR technology or western blot analysis may help clarify this pathway. While TFAP2C has been identified as an upstream factor, other proteins involved in regulating LINC00922 remain unidentified. LncRNAs exhibit complex regulatory mechanisms with diverse and intricate upstream factors [57]. Future studies should focus on elucidating these regulatory mechanisms through more detailed experiments. For future exploration of upstream regulators of LINC00922, ChIP-seq technology could be employed to identify transcription factors, along with methylation analysis and promoter region variation studies. Additionally, epigenetic modifications, such as DNA methylation and histone modifications, may be involved in regulating LINC00922 expression.

Moreover, LINC00922 is involved in key cellular processes, such as proliferation, the EMT, invasion, metastasis, and apoptosis regulation. Both in vivo and in vitro experiments have shown that LINC00922 can regulate cancer cell behavior by participating in five ceRNA axes and other mechanisms, significantly impacting the development of various cancers. In GC, multiple independent studies have confirmed that LINC00922 promotes malignant behavior in GC cell lines through different pathways. Although these findings have greatly expanded our understanding of the LINC00922 regulatory roles, the precise mechanisms by which this lncRNA contributes to cancer progression remain unclear. Although LINC00922 has been shown to promote cancer cell malignant behavior, the detailed regulatory pathways are still unknown.

Prior work has suggested that LINC00922 can promote cancer progression in multiple malignancies, such as GC, by participating in ceRNA axes [17]. However, its role in certain tumor types, including how it can promote lung metastasis in CRC, remains unclear [19]. Future research should investigate cancer-related tumor suppressors or oncogenic factors as entry points to better understand the full regulatory scope of LINC00922 using proteomics to explore its relationship with cancer-related cytokines. Numerous in vitro studies and some in vivo experiments have demonstrated the involvement of LINC00922 in various malignancies, with bioinformatics analyses using public datasets suggesting that LINC00922 is potentially related to cellular immunity across multiple cancer types. However, direct evidence supporting its role in inhibiting cancer progression remains insufficient. The precise function of LINC00922 in regulating tumor development and the underlying mechanisms through which it influences cancer progression warrant further investigation. Future research should prioritize the collection of broader and more robust clinical data and conduct in-depth integrative analyses using multiple databases. This will help elucidate the critical role of LINC00922 in cancer biology and assess its viability as a therapeutic target in clinical settings.

In cancer treatment, elevated LINC00922 expression levels are associated with increased cancer cell resistance to chemotherapy drugs [12, 13]. Data analysis has suggested that high LINC00922 expression levels correlate with extensive immune cell infiltration in GC tissues. To further explore the connection between LINC00922 and immunity, we analyzed data from the TCGA database, confirming that LINC00922 expression patterns are positively associated with immune cell infiltration in multiple cancer types. This suggests that LINC00922 may serve as a new target for both cancer chemotherapy and cellular immunotherapy. However, the precise relationship between LINC00922 and immune cell infiltration in cancer requires further experimental validation. Immune resistance and targeted drug resistance are common mechanisms of tumor immune evasion in clinical cancer treatment [58, 59]. However, the potential roles of LINC00922 in these processes have not yet been experimentally verified. Future studies should explore how this lncRNA is specifically involved in drug resistance mechanisms. Additionally, the impact of LINC00922 on immune cell-targeted therapies has yet to be verified, representing a potential avenue for future research. Targeted therapy and immunotherapy are key approaches in cancer treatment. A deeper understanding of the relationship between LINC00922 and targeted therapies will provide critical insights into its potential clinical applications [58, 59]. However, its roles in regulating immunotherapy resistance and targeted drug resistance have not yet been experimentally validated. Future studies should investigate the specific mechanisms underlying LINC00922-mediated drug resistance. Furthermore, clinical data and patient follow-up studies have shown that high LINC00922 expression levels can predict poor prognosis in several cancer types, suggesting that this lncRNA could serve as a novel prognostic biomarker for cancer patients. Although LINC00922 has been associated with poor prognosis in a limited number of cancers, its prognostic significance in other malignancies remains uncertain. While existing studies have confirmed its high expression patterns in multiple cancer types, there are insufficient data to establish a direct correlation between high LINC00922 expression levels and poor prognosis in cancer patients. Future research should incorporate extensive clinical data and correlation analyses to validate its prognostic potential.

In conclusion, this article summarizes the aberrant LINC00922 expression patterns in various cancers as well as explores its associated gene regulatory network and effects on various tumor cell biological behaviors. We also examined the impacts of LINC00922 overexpression on chemotherapy drug responses and its prognostic value. As a potential oncogenic lncRNA, LINC00922 is poised to become a new diagnostic biomarker and therapeutic target, warranting further in-depth investigation.

Author Contributions

Jiahua Si: conceptualization (equal), data curation (equal), formal analysis (equal), visualization (equal), writing – original draft (equal). Chenhao Liang: data curation (equal), formal analysis (equal), visualization (equal), writing – original draft (equal). Xueting Zhang: data curation (equal), visualization (equal), writing – original draft (equal). Hening Xu: visualization (equal), writing – original draft (equal). Xinming Su: writing – original draft (equal). Luqing Liu: writing – original draft (equal). Ruyi Yuan: writing – original draft (equal). Yuemin Ding: conceptualization (equal), supervision (equal), writing – review and editing (equal). Shiwei Duan: conceptualization (equal), funding acquisition (equal), project administration (equal), writing – review and editing (equal).

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.