A pan-cancer analysis of the prognostic value of long non-coding RNA LINC00662 in human cancers

Background: Numerous studies have revealed that the long non-coding RNA LINC00662 is irregularly expressed in various cancers, as well as is correlated with cancer development and progression. Nevertheless, the clinical value of LINC00662 remains controversial. Hence, we explored the correlation of LINC00662 with cancer prognosis through meta-analysis and bioinformatics analysis.

Methods: From the beginning through 12 March 2022, we searched for correlational studies on Web of Science, Embase, PubMed and The Cochrane Library. We used pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) to determine the significance of studies on survival outcomes and clinicopathological aspects in human cancers. Additionally, the Gene Expression Profiling Interactive Analysis (GEPIA) database was employed to confirm our findings.

Results: Our meta-analysis of 14 studies comprising a total of 960 cancer patients revealed that LINC00662 overexpression was correlated with poor overall survival (HR = 1.91, 95% CI 1.49–2.45, p < 0.001) in cancer patients and relapse-free survival (HR = 2.12, 95% CI 1.19–3.76, p = 0.010) in hepatocellular carcinoma patients. The correlation between LINC00662 and OS was further supported by the results of subgroup analyses according to cancer type, follow-up time, HR availability, and NOS score. In addition, LINC00662 overexpression predicted advanced tumor stage (OR = 4.23, 95% CI 2.50–7.17, p < 0.001), larger tumor size (OR = 1.49, 95% CI 1.11–1.99, p = 0.008), earlier lymph node metastasis (OR = 2.40, 95% CI 1.25–4.59, p = 0.008), and earlier distant metastasis (OR = 4.78, 95% CI 2.57–8.88, p < 0.001). However, there were no statistically significant differences in age (OR = 1.16, 95% CI 0.90–1.51, p = 0.246), gender (OR = 1.10, 95% CI 0.79–1.53, p = 0.578), or differentiation grade (OR = 1.53, 95% CI 0.71–3.33, p = 0.280).

Conclusion: LINC00662 expression upregulation is associated with poor prognosis and advanced clinicopathological features in patients with multiple tumors. LINC00662 may serve as a biomarker for the diagnosis and treatment of patients with tumors.

Introduction

Cancer is one of the leading causes of death globally, and the worldwide cancer burden is increasing (Sung et al., 2021). Despite considerable advancement in modern cancer treatments, such as surgical therapy and radiotherapy, many patients still progress to the advanced cancer stage, which results in a lousy prognosis (Chen et al., 2021). The lack of clear markers for tumor diagnosis is among the fundamental causes for this dismal prognosis (Avila et al., 2006). Consequently, finding new tumor indicators for diagnosis, prognosis, and treatment is crucial.

Long non-coding RNA (lncRNA) is over 200-nucleotide long, of which 55 nucleotides lack a specific open reading frame, rendering the encoded protein inactive (Xue et al., 2017). Although lncRNAs were initially considered transcriptional disruptions, they are recently implicated in various diseases (Renganathan and Felley-Bosco, 2017). Recently, an increasing amount of lncRNAs was found to be inappropriately expressed in cancer and was implicated in diverse pathophysiological processes, such as controlling gene expression through epigenetic, transcription, and post-transcription modification (Lin et al., 2021). Therefore, lncRNAs are potentially both tumorigenic and antitumorigenic (Huarte and Rinn, 2010). Because of their unique expression and functionality in multiple cancer types, lncRNAs act as promising cancer diagnostic, prognostic, and therapeutic biomarkers (Wang et al., 2021).

LINC00662, the long intergenic non-protein coding RNA 662, is located on chromosome 19q11 and is 2085-bp long (Zhong et al., 2021). Aberrant LINC00662 expression was first reported in lung tissues and cells (Gong et al., 2018). Many recent studies have found that LINC00662 is overexpressed in numerous tumors, and this overexpression implies poor prognosis, such as prostate cancer (PCa) (Li et al., 2019), colorectal cancer (CRC) (Wang et al., 2019; Cheng B. et al., 2020), bladder cancer (Ma et al., 2021), osteosarcoma (OSA) (Yu et al., 2021), hepatocellular carcinoma (HCC) (Guo et al., 2020; Tian et al., 2020), ovarian cancer (OC) (Wu et al., 2021), cervical cancer (CC) (Wei et al., 2020), glioma (Geng et al., 2020; Wu et al., 2020), and gastric cancer (GC) (Liu et al., 2018). Furthermore, elevated LINC00662 expression is usually linked to advanced clinicopathological features. For instance, in breast cancer (BC) (Cheng L. et al., 2020), high LINC00662 expression is related to the advanced tumor stage and positive lymph node metastasis (LNM). Moreover, LINC00662 could be engaged in tumor proliferation, apoptosis, invasion and migration (Cheng B. et al., 2020; Liu and Meng, 2020; Xu et al., 2021). Some studies have confirmed the critical link between LINC00662 and tumor-related signaling pathways (Liu Y. L. et al., 2021; Yu et al., 2021). Taken together, LINC00662 could be a prospective prognostic marker and therapeutic target for most human malignancies. However, most studies are restricted by the small sample size or scattered results, and the mechanism of action has not yet been entirely clarified. Therefore, we performed quantitative meta-analysis and bioinformatics analysis to estimate the combined role of LINC00662 in human cancers.

Materials and methods

Search strategy and literature collection

The registry was established with PROSPERO prior to the start of the research (registration number: CRD42021286741). A structured literature search of Web of Science, Embase, PubMed and The Cochrane Library was performed from their inception through 12 March 2022. “Long intergenic non-protein coding RNA 662,” “lncRNA LINC00662,” “LINC00662,” “neoplasm,” “cancer,” “malignancy,” “neoplasia,” “melanoma,” “tumor,” “sarcoma,” “carcinoma” or “adenoma” were the search terms. Relevant study citation lists were also thoroughly reviewed. To ensure accuracy and consistency, two investigators individually assessed the database search methodologies and debated the results.

Inclusion and exclusion criteria

The inclusion criteria were as follows: 1) discussing LINC00662 expression in cancer tissues; 2) in which patients were classified into two groups by the LINC00662 expression levels; 3) reporting the connection between LINC00662 expression and cancer prognosis or clinicopathological characteristics; and 4) in which hazard ratios (HRs) and 95% confidence intervals (CIs) for survival data were presented or could be obtained from survival curves.

The exclusion criteria were as follows: 1) conference reports, in vitro or in vivo experiments, and reviews; 2) duplicate publications; and 3) articles whose data could not be extracted and articles from non-English publications.

Data extraction and quality assessment

Two researchers separately explored and chose articles based on the aforementioned criteria, extracting the following data: first author’s name, publication year, country of study, types of cancer, number of patients, detection methods, cut-off criteria, clinical parameters, overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS), and progression-free survival (PFS). Studies were used immediately if they contained precise survival data. When publications supplied only Kaplan Meier (KM) curves without precise survival data, we used Engauge Digitizer V.4.1 software to obtain data from the KM curves and computed HRs and 95% CIs. Literature quality was evaluated using the Newcastle-Ottawa Scale (NOS). The study was graded on a nine-item scale, with one point assigned for each item completed. Aggregate scores varied from 0 to 9. The NOS score of 7 and above denoted high-quality research findings.

Validation by using public datasets

Gene Expression Profiling Interactive Analysis (GEPIA), an online web-based tool based on TCGA and GTEx data, is designed to verify the LINC00662 expression levels in pan-cancer. LINC00662-related survival analysis was conducted using the KM method and log-rank test.

Prediction of LINC00662 functions and pathways

The MEM-Multi Experiment Matrix database, which is based on the Affymetrix Gene Chip Human Genome U133 Plus 2.0 Array technology, was used to identify the relevant genes of LINC00662. Then, gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using R software. Finally, Cytoscape software was utilized for constructing the signaling pathway network.

Statistical analysis

Stata 12.0 was used to estimate all statistical data. To investigate the relationship between LINC00662 expression and survival outcome, HRs with 95%CIs were determined. To investigate the link between LINC00662 expression and clinicopathological features, researchers estimated pooled odds ratios (ORs) with 95% CIs. If heterogeneity was moderate (P_Q > 0.1, I² < 50%), a fixed-effects model was applied. Otherwise, a random-effects model was applied. Significant heterogeneity was addressed using methods such as subgroup analysis or sensitivity analysis. All data were presented in the form of Forest plots. Egger’s test and Begg’s funnel plot were used to determine possible publication bias, while sensibility analysis was employed to determine the causes of heterogeneity and to verify the stability of the results. p < 0.05 was considered statistically significant.

Results

Characteristics of studies

In total, 115 studies were initially obtained according to the search strategy (Web of Science = 35, Embase = 44, PubMed = 36, Cochrane = 0). After removing 38 duplicate studies, 45 articles were removed as extraneous papers by scanning the titles and abstracts. The remaining 32 studies were then carefully reviewed by reading the full article. Of them, 9 were eliminated due to the lack of eligible data, 9 were eliminated since they were physical experimental studies, and 14 studies (Gong et al., 2018; Li et al., 2019; Wang et al., 2019; Cheng B. et al., 2020; Cheng L. et al., 2020; Guo et al., 2020; Liu and Meng, 2020; Tian et al., 2020; Wei et al., 2020; Zhang et al., 2020; Ma et al., 2021; Wu et al., 2021; Yu et al., 2021; Wang et al., 2022) were finally included for meta-analysis. The study screening procedure is presented in Figure 1.

FIGURE 1

FIGURE 1. Flow diagram of this meta-analysis.

The 14 enrolled articles contained a total of 960 patients, with sample sizes between 39 and 105. All of these articles were conducted in China and published between 2018 and 2022. The above articles included ten tumors, including three cases of OSA (Liu and Meng, 2020; Yu et al., 2021; Wang et al., 2022), two cases of HCC (Guo et al., 2020; Tian et al., 2020), two cases of CRC (Wang et al., 2019; Cheng B. et al., 2020), one case of bladder cancer (Ma et al., 2021), one case of lung cancer (Gong et al., 2018), one case of CC (Wei et al., 2020), one case of ESCC (Zhang et al., 2020), one case of BC (Cheng L. et al., 2020), one case of PCa (Li et al., 2019), and one case of OC (Wu et al., 2021). Nine of these articles (Gong et al., 2018; Li et al., 2019; Wang et al., 2019; Cheng B. et al., 2020; Guo et al., 2020; Tian et al., 2020; Ma et al., 2021; Wu et al., 2021; Yu et al., 2021) reported OS, two (Guo et al., 2020; Tian et al., 2020) reported RFS, and all studies reported clinical parameters. Three (Li et al., 2019; Guo et al., 2020; Wu et al., 2021) OS data and one (Guo et al., 2020) RFS data were obtained directly from the original text, and six (Gong et al., 2018; Wang et al., 2019; Cheng B. et al., 2020; Tian et al., 2020; Ma et al., 2021; Yu et al., 2021) OS data and one (Tian et al., 2020) RFS data were extracted by KM curves. All studies employed real-time quantitative polymerase chain reaction (RT-qPCR) to detect the expression levels of LINC00662. The characteristics of the included articles are summarized in Table 1.

TABLE 1

TABLE 1. Characteristics of studies in this meta-analysis.

Association between LINC00662 expression and survival

Nine articles (Gong et al., 2018; Li et al., 2019; Wang et al., 2019; Cheng B. et al., 2020; Guo et al., 2020; Tian et al., 2020; Ma et al., 2021; Wu et al., 2021; Yu et al., 2021) including 689 cancer patients reported a relationship between abnormal LINC00662 expression levels and OS. A fixed-effects model was used because no obvious heterogeneity existed (I² = 0%, P_Q = 0.807). As shown in Figure 2A, the HR of the pooled OS was 1.91, indicating that LINC00662 overexpression was notably interrelated with poor OS. Furthermore, two articles (Guo et al., 2020; Tian et al., 2020), with a total of 156 patients with HCC, provided suitable data for RFS. A fixed-effects model was used as no obvious heterogeneity existed (I² = 25.7%, P_Q = 0.246). LINC00662 overexpression was markedly interrelated with shorter RFS in patients with HCC (HR = 2.12, 95% CI 1.19–3.76, p = 0.010) (Figure 2B).

FIGURE 2

FIGURE 2. Forest plots for association of LINC00662 expression with survival. (A) Overall survival. (B) Relapse-free survival.

In addition, we conducted a subgroup meta-analysis based on tumor type (digestive tract tumors and non-digestive tract tumors), follow-up time (≥60 months or <60 months), HR availability (reported in text and survival curve), and NOS score (NOS scores ≥7 or <7) to investigate further the correlation between LINC00662 expression levels and OS. According to all subgroup analyses, revealed that LINC00662 overexpression was notably interrelated with poor OS (Figure 3; Table 2). The aforementioned results imply that LINC00662 expression levels is probably a prognostic factor for OS in patients with tumors.

FIGURE 3

FIGURE 3. Forest plots for subgroup analysis of LINC00662 expression with overall survival. (A) Subgroup analysis stratified by cancer type. (B) Subgroup analysis stratified by follow-up time. (C) Subgroup analysis stratified by HR availability. (D) Subgroup analysis stratified by NOS score.

TABLE 2

TABLE 2. Subgroup meta-analysis of pooled HRs for OS.

Association between LINC00662 and clinicopathological parameters

In total, 14 articles (Gong et al., 2018; Li et al., 2019; Wang et al., 2019; Cheng B. et al., 2020; Cheng L. et al., 2020; Guo et al., 2020; Liu and Meng, 2020; Tian et al., 2020; Wei et al., 2020; Zhang et al., 2020; Ma et al., 2021; Wu et al., 2021; Yu et al., 2021; Wang et al., 2022) presented usable data regarding the link between LINC00662 expression levels and clinicopathological parameters, which included age, sex, tumor stage, tumor size, LNM, differentiation grade, and distant metastasis (DM). The analysis was conducted using ORs and their 95% CIs. According to the results, LINC00662 overexpression was notably interrelated with advanced tumor stage (OR = 4.23, 95% CI 2.50–7.17, p < 0.001), larger tumor size (OR = 1.49, 95% CI 1.11–1.99, p = 0.008), earlier LNM (OR = 2.40, 95% CI 1.25–4.59, p = 0.008), and earlier DM (OR = 4.78, 95% CI 2.57–8.88, p < 0.001). However, the differences in terms of age (OR = 1.16, 95% CI 0.90–1.51, p = 0.246), gender (OR = 1.10, 95% CI 0.79–1.53, p = 0.578), and differentiation grade (OR = 1.53, 95% CI 0.71–3.33, p = 0.280) were not statistically significant. The results were presented in Figure 4 and Table 3.

FIGURE 4

FIGURE 4. Forest plots for association of LINC00662 expression with clinicopathological features. (A) Age. (B) Gender. (C) Tumor stage. (D) Tumor size. (E) Lymph node metastasis. (F) Differentiation. (G) Distant metastasis.

TABLE 3

TABLE 3. Association of LINC00662 expression with clinicopathological features.

Sensitivity analysis

To assess the reliability of LINC00662 expression and OS relevance findings, we conducted sensitivity analysis. No single study was found to alter the results (Figure 5A), and therefore, high LINC00662 expression was reliably associated with poor OS. Meanwhile, we performed sensitivity analysis by using the results of clinicopathological parameters. The heterogeneity of the relevance of LINC00662 overexpression to the tumor stage (Figure 5B) was completely eliminated after excluding the study of Cheng et al. (Cheng B. et al., 2020) and Zhang et al. (Zhang et al., 2020) (P_Q = 0.427, I² = 1.2%), without affecting the results (OR = 3.84, 95% CI 2.76–5.35, p < 0.001). In a sensitivity analysis of LNM (Figure 5C), excluding the study of Wu et al. (Wu et al., 2021) significantly reduced heterogeneity (P_Q = 0.337, I ² = 12.2%), but did not affect the final results (OR = 3.02, 95% CI 2.02–4.50, p < 0.001). For the sensitivity analysis on differentiation grade (Figure 5D), heterogeneity was significantly reduced with the elimination of the studies of Wei et al. (Wei et al., 2020) and Zhang et al. (Zhang et al., 2020) (P_Q = 0.265, I ² = 22.5%), and a significant correlation was observed between high LINC00662 expression and the degree of tumor differentiation (OR = 2.29, 95% CI 1.49–3.52, p < 0.001). Furthermore, sensitivity analysis of the relevance of LINC00662 overexpression to DM (Figure 5E) displayed complete elimination of heterogeneity after the exclusion of the study of Cheng et al. (Cheng B. et al., 2020) (P_Q = 0.578, I² = 0.0%), but the results were not affected (OR = 3.54, 95% CI 2.25–5.56, p < 0.001).

FIGURE 5

FIGURE 5. Sensitivity analysis and Begg’s funnel plot of LINC00662. (A) Sensitivity analysis of pooled HR for overall survival. (B) Sensitivity analysis of pooled HR for tumor stage. (C) Sensitivity analysis of pooled HR for lymph node metastasis. (D) Sensitivity analysis of pooled HR for differentiation. (E) Sensitivity analysis of pooled HR for distant metastasis. (F) Begg’s funnel plot of LINC00662 for overall survival.

Analysis of publication bias

Additionally, we used Begg’s funnel plot and Egger’s regression test to analyze the publication bias of the included studies on the correlation between LINC00662 expression and OS. Neither Begg’s funnel plot (Figure 5F) nor Egger’s regression test (Pr > |t| = 0.307) found significant publication bias, suggesting that our results are plausible.

Validation of LINC00662 results in public databases

To further confirm the reliability of our results, we assessed the relationship between LINC00662 expression in pan-cancer and prognosis of cancer patients by using the GEPIA database. Regarding aberrant LINC00662 expression, LINC00662 was highly expressed in cholangiocarcinoma (CHOL), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), pheochromocytoma and paraganglioma (PCPG), skin cutaneous melanoma (SKCM), and thymoma (THYM) (|log₂FC| Cutoff: 1, p-value: 0.01, Figure 6A). Regarding the relationship between LINC00662 expression and prognosis, LINC00662 overexpression was notably interrelated with worse OS in adrenocortical carcinoma (ACC; Figure 6B), kidney chromophobe (KICH; Figure 6C), brain lower grade glioma (LGG; Figure 6D), liver hepatocellular carcinoma (LIHC; Figure 6E), sarcoma (SARC; Figure 6F), and thyroid carcinoma (THCA; Figure 6G), and shorter DFS in ACC (Figure 6H), KICH (Figure 6I), LGG (Figure J), and LIHC (Figure 6K).

FIGURE 6

FIGURE 6. Validation of the role of LINC00662 in human cancers based on the GEPIA cohort. (A) The expression of LINC00662 in human cancers (red box) and normal tissues (blue box) based on the TCGA and GTEx databases (|Log₂FC|>1 and p < 0.05). (B) OS plots of LINC00662 in ACC. (C) OS plots of LINC00662 in KICH. (D) OS plots of LINC00662 in LGG. (E) OS plots of LINC00662 in LIHC. (F) OS plots of LINC00662 in SARC. (G) OS plots of LINC00662 in THCA. (H) DFS plots of LINC00662 in ACC. (I) DFS plots of LINC00662 in KICH. (J) DFS plots of LINC00662 in LGG. (K) DFS plots of LINC00662 in LIHC. CHOL (cholangiocarcinoma), DLBC (lymphoid neoplasm diffuse large B-cell lymphoma), PCPG (pheochromocytoma and paraganglioma), SKCM (skin cutaneous melanoma), THYM (thymoma), OS (overall survival), ACC (adrenocortical carcinoma), KICH (kidney chromophobe), LGG (brain lower grade glioma), LIHC (liver hepatocellular carcinoma), SARC (sarcoma), THCA (thyroid carcinoma), DFS (disease-free survival).

LINC00662 function and pathway prediction

We screened 200 LINC00662-related genes from the MEM database for GO and KEGG pathway analyses (Figure 7; Table 4). The GO analysis revealed that these genes were remarkably correlated with the cellular amino acid biosynthetic process, mitochondrial matrix, and transaminase activity. Additionally, the KEGG pathway analysis demonstrated that these genes were strongly interrelated with amino acid metabolic pathways. Furthermore, we built a signaling pathway network with Cytoscape (Figure 8).

FIGURE 7

FIGURE 7. GO terms and the KEGG pathway. (A) Histogram presentation of GO enrichment of LINC00662-related genes in biological processes (BP), cellular components (CC) and molecular functions (MF) of top 10 terms; (B) Bubble chart of GO enrichment of LINC00662-related genes in the aspects of BP, CC, MF of top 10 terms; (C) Histogram presentation of top 10 significant pathways related to the LINC00662-related genes by the KEGG pathway analysis; (D) Bubble chart of top 10 significant pathways.

TABLE 4

TABLE 4. Gene ontology analysis of LINC00662-related genes.

FIGURE 8

FIGURE 8. LINC00662-related genes interaction network analysis. Green nodes represent target genes and sky blue nodes represent the related pathway. As indicated in red, LINC00662 localized at the center of the network. GO:0005759 (mitochondrial matrix); GO:0006563 (L-serine metabolic process); GO:0030170 (pyridoxal phosphate binding); GO:0005739 (mitochondrion); GO:0034599 (cellular response to oxidative stress); GO:0005829 (cytosol); GO:0046655 (folic acid metabolic process); GO:0035999 (tetrahydrofolate interconversion); GO:0006564 (L-serine biosynthetic process).

Molecular mechanisms of LINC00662 carcinogenesis in various cancers

The molecular mechanisms of LINC00662-related carcinogenesis are recapitulated as follows.

• In HCC, LINC00662 facilitated the progression of HCC and the polarization of M2 macrophages by binding miR-107, miR-15a and miR-16 competitively to upregulate WNT3A expression and secretion, thereby activating the Wnt/β-catenin signaling pathway (Tian et al., 2020). Additionally, LINC00662 also exerted tumorigenic effects through simultaneous regulation of intracellular S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM) levels resulting in altered methylation profiles (Guo et al., 2020).

• In lung cancer, LINC00662 affected lung cancer progression by modulating miR-320d/E2F1 and miR-145-5p/PAFAH1B2 axis (Lv et al., 2021; Xu et al., 2021).

• In CC, LINC00662 was involved in CC progression through regulation of miR-103a-3p/PDK4 and miR-497-5p/CDC25A (Wei et al., 2020; Liu Y. L. et al., 2021).

• In OSA, LINC00662 promoted OSA progression by sponging miR103a-3p and regulating SIK2 expression (Huang et al., 2021). In addition, LINC00662 could also affect OSA proliferation, invasion and migration by modulating miR-16-5p/ITPR1 and microRNA-15a-5p/Notch2 axis (Liu and Meng, 2020; Yu et al., 2021).

• In melanoma, LINC00662 promoted melanoma progression via sponging miR-890 to up-regulate ELK3 (Xia et al., 2020).

• In chordoma, LINC00662 facilitated chordoma progression via sponging miR-16-5p to activate RNF144B (Wang et al., 2020).

• In glioma, LINC00662 could be an oncogene by modulating the miR-107/HMGB1 and the miR-34a5p/LMAN2L axis (Geng et al., 2020; Wu et al., 2020).

• In CRC, LINC00662 facilitated colon cancer progression via binding miR-340-5p to upregulate CLDN8/IL22 expression and activating extracellular signal-regulated kinase (ERK) signaling pathway (Cheng B. et al., 2020). In addition, LINC00662 could also promote the development of CRC via modulating the miR497-5p/AVL9 axis (Wang et al., 2019).

• In OSCC, LINC00662 promoted the growth and metastasis of OSCC via miR-144-3p/EZH2 Axis (Liu P. et al., 2021). Besides, LINC00662 inflected the radiosensitivity of OSCC cells through hnRNPC-modulated AK4 (Chen Y. Z. et al., 2020).

• In OC, LINC00662 facilitated the survival and glycolysis of OC cells via miR-375 to modulate HIF-1α expression (Tao et al., 2020). In addition, LINC00662 promoted OC progression via activating the GRP78/P38 pathway (Wu et al., 2021).

• In PCa, LINC00662 promoted the metastasis and proliferation of PCa cells via modulating miR-34a (Li et al., 2019).

• In BC, LINC00662 facilitated the progression of BC cells through modulating the miR-497-5p/EglN2 axis (Cheng L. et al., 2020).

• In ESCC, LINC00662 promoted the progression of ESCC via sponging miR-3405p to activate HOXB2 (Zhang et al., 2020).

• In GC, LINC00662 accelerated GC progression via modulating the Hippo-YAP1 pathway (Liu et al., 2018). Additionally, LINC00662 facilitated the progression of GC progression via sponging miR-195-5p to up-regulate centrosomal protein 55 (Tao et al., 2022).

• In bladder cancer, facilitated bladder cancer progression via sponging miR-199a-5p (Ma et al., 2021).

Discussion

The field of lncRNAs had received a lot of press attention lately because of the accelerated advancement of high-throughput sequencing technologies (Müller et al., 2015). Numerous studies have demonstrated that lncRNAs are implicated in tumorigenesis and development and are closely related to the prognosis of patients with tumors (Ge et al., 2018; Hu et al., 2021). In previous meta-analyses, FOXP4-AS1 (Zhang et al., 2022b), SNHG15 (Chen C. et al., 2020) and SNHG17 (Zhang et al., 2022a) were all linked to the clinicopathological characteristics and prognosis of various malignancies. These findings suggested that lncRNA could be a distinct cancer prognostic biomarker and therapeutic target.

LINC00662, a potential new cancer-related lncRNA, has been found to be upregulated in various malignancies and considered to function as a novel oncogene in tumor development. This anomalous expression typically resulted in poor clinical outcomes such as shorter OS and RFS, positive LNM, advanced tumor stage, and earlier DM (Li et al., 2019; Liu and Meng, 2020; Ma et al., 2021). In many malignancies, LINC00662 was also engaged in cell biological processes, including cell proliferation, migration, invasion, cell cycle arrest, and apoptosis inhibition (He et al., 2021). LINC00662 could act as a molecular sponge for miRNAs that influence tumor progression, and these miRNAs include miR-497-5p, miR-30b-3p, miR-103a-3p, etc. (Wang et al., 2019; Liu Y. L. et al., 2021; Wang et al., 2022). As a whole, these papers suggested that LINC00662 was linked to carcinogenesis and progression.

Because of the usefulness of LINC00662 in various cancers remains disputed, we conducted a meta-analysis to investigate the prognostic value and clinicopathological significance of LINC00662 differential expression in cancer patients. Our results suggested that LINC00662 overexpression was remarkably interrelated with worse OS in cancer patients and shorter RFS in patients with HCC. Moreover, further subgroup analysis indicated that LINC00662 overexpression was remarkably interrelated with worse OS in all subgroups, irrespective of the tumor type, follow-up time, HR availability and NOS score. Furthermore, patients with LINC00662 overexpression were more likely to have advanced tumor stage, larger tumor size, earlier LNM, and earlier DM. In a word, LINC00662 has an oncogenic role in tumors and may be a promising prognostic indicator. In addition, we used a public database to further confirm our results. LINC00662 overexpression was discovered in CHOL, DLBC, PCPG, SKCM, and THYM. Elevated LINC00662 expression was interrelated with worse OS in ACC, KICH, LGG, LIHC, SARC, THCA, and shorter DFS in ACC, KICH, LGG, LIHC. Collectively, the findings indicated that LINC00662 may be used as a novel biomarker for prognosis in cancer patients.

LINC00662 mainly acts through the Wnt/β-catenin signaling pathway, SMD signaling pathway, the ERK signaling pathway, and Hippo signaling pathway (Liu et al., 2018; Cheng B. et al., 2020; Tian et al., 2020). Furthermore, bioinformatics databases were used to forecast the functional mechanisms of LINC00662. GO and KEGG analyses indicated that the main biological functions of LINC00662-related genes were the cellular amino acid biosynthetic process, mitochondrial matrix, and transaminase activity, and that these genes were mainly significantly associated with amino acid metabolic pathways. These findings act as a reference for future studies on the mechanism of action of LINC00662.

Our meta-analysis has several limitations. Firstly, the sample size was relatively small and all incorporated items were conducted in China influenced the generalizability of the findings. To resolve this problem, we further verified our results by using public database to improve the credibility of our conclusions. Secondly, the HR values and 95% CIs for certain studies were obtained through KM curves extraction, which may have introduced some bias due to inaccurate calculation. Additionally, the cut-off of LINC00662 expression varied from study to study, which may have led to heterogeneity among studies.

Conclusion

In summary, our study indicated that elevated LINC00662 expression is significantly correlated with shorter survival (including OS and RFS) and worse clinicopathological features (including tumor stage, tumor size, LNM, and DM). Therefore, LINC00662 could be a promising prognostic biomarker and therapeutic target in various cancers. Nevertheless, our conclusions require further confirmation through additional multicenter, high-quality, large-sample studies.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

GZ conceived the study; LF, JW, and YZ performed the literature search; MY, BW, and HM extracted the required data; SM, BL, and XH performed the statistical analyses; GZ and BW wrote a draft; HC reviewed the paper.

Funding

This study was supported by grants from the 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1); Gansu Key Laboratory of molecular diagnosis and precision treatment of surgical tumors (18JR2RA033); Key talent project of Gansu Province of the Organization Department of Gansu provincial Party committee (2020RCXM076); Key Laboratory of gastrointestinal cancer diagnosis and treatment of National Health Commission (2019PT320005); Lanzhou talent innovation and Entrepreneurship Project (2016-RC-56); Gansu University of Chinese Medicine Postgraduate “Innovation Fund” project (2022CX52); Gansu Province Excellent Doctor Fund Project (22JR5RA649).

Acknowledgments

We would like to thank the researchers and study participants for their contributions.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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