Long non-coding RNA LINC-PINT is associated with favorable prognosis in cancer patients: a systematic review and meta-analysis
Highlight box
Key findings
• Long iatrogenic non-protein-coding RNA p53-induced transcript (LINC-PINT) expression was associated with survival in cancer patients.
What is known and what is new?
• LINC-PINT expression was associated with prognosis in cancer patients.
• LINC-PINT expression was associated with favorable survival in cancer patients.
What is the implication, and what should change now?
• LINC-PINT expression may serve as a valuable prognostic marker in cancer patients.
Introduction
Cancer has emerged as a major health problem worldwide. Despite several developments in cancer diagnosis and treatment, the survival rate of cancer patients remains low (1). Therefore, it is imperative to develop biomarkers that can help in early diagnosis and prognostic stratification, and serve as therapeutic targets for cancer patients (2).
Long non-coding RNAs (lncRNAs) are defined as non-coding RNAs longer than 200 nucleotides (3). LncRNAs regulate local protein-coding gene expression at the level of chromatin remodeling, transcriptional control, and post-transcriptional processing (4). There is increasing evidence for the involvement of lncRNAs in various human diseases due to aberrant lncRNA function in differentiation and developmental processes (3,4).
Recently, some lncRNAs have been identified as cancer-related molecules (5). The lncRNA long iatrogenic non-protein-coding RNA p53-induced transcript (LINC-PINT) is abnormally expressed in various cancer (6). Moreover, lncRNA LINC-PINT is identified tumor suppressor with down-regulated expression in many types of cancer cells (7). For example, LINC-PINT acts as a tumor suppressor by sponging microRNA in lung cancer (6). Furthermore, current studies have demonstrated that LINC-PINT is associated with prognosis in cancer patients, but its exact prognostic role has not been quantitatively investigated (6-16). Hence, we integrated eligible studies to explore the relationship between lncRNA LINC-PINT expression and the prognosis of cancer patients. We present this article in accordance with the PRISMA reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-627/rc)
Methods
Literature search
We searched eligible studies through the PubMed, Embase, and Cochrane library searches until February 1, 2024 using the following terms: (LncRNA LINC-PINT or Long non-coding RNA LINC-PINT) and (cancer or tumor or carcinoma or neoplasm or malignancy) and (prognostic or predictive or prognosis or survival or outcome). We also performed a manual search.
Inclusion and exclusion criteria
We enrolled studies that coincide with the following qualifications: (I) studies evaluating the relationship between LINC-PINT expression and survival, and (II) LINC-PINT expression evaluating in human cancer tissue. Reviews, case reports, letters, conference abstracts, non-English articles, and duplicate articles were excluded.
Data extraction
Both authors individually collected the following data from the enrolled studies: first author, publication year, country, cancer type, case number, cancer stage, detection method and cut-off value of LINC-PINT expression, follow-up period, and survival outcome. Hazard ratio (HR) and 95% confidence interval (CI) were calculated from Kaplan-Meier plots. Differences in the data were agreed by reaching a consensus through a discussion.
Quality assessment
Both authors individually evaluated the quality of the enrolled studies by the Newcastle-Ottawa Scale (NOS). Differences in the quality evaluation were agreed by reaching a consensus through a discussion.
Statistical analysis
The relationship between LINC-PINT and survival outcome was assessed by calculating HR with 95% CI, and the heterogeneity of the enrolled studies was evaluated using I2 statistics. The subgroup analysis was also evaluated. The funnel plot with Egger’s test was performed to check for publication, and the sensitivity analysis was carried out to reveal the consistency of the pooled results. StataSE17 (Stata, College Station, TX, USA) was used for all analyses. The P value <0.05 was considered statistically significant.
Results
Study characteristics
We reviewed a total of 86 articles and selected 11 eligible studies (Figure 1). The basic data of the enrolled studies are shown in Table 1. All studies were published in China, and the publication years ranged from 2016 to 2021. Enrolled cases included gastric cancer (n=2), laryngeal squamous cell carcinoma (n=1), lung cancer (n=1), glioblastoma (n=1), breast cancer (n=1), ovarian cancer (n=1), renal cancer (n=1), melanoma (n=1), esophageal cancer (n=1), and pancreatic cancer (n=1). These studies enrolled a total of 2,876 cancer patients. The NOS scores of the included studies suggested relatively good quality, ranging from 7 to 8.
Table 1
| Study | Country | Cancer type | Case number (high/low) | Stage (case number) | Detection method | Cut-off value | Follow-up (months) | Survival outcome | Survival analysis | NOS |
|---|---|---|---|---|---|---|---|---|---|---|
| Yang et al. [2021] (14) | China | Laryngeal squamous cell carcinoma | 15/15 | I–II/III–IV (12/18) | RT-PCR | Median | 40 | OS | KM | 7 |
| Zhang et al. [2021] (6) | China | NSCLC | 58/64 | I–II/III–IV (56/66) | RT-PCR | NR | 60 | OS | KM, MVA | 8 |
| Zhu et al. [2021] (16) | China | Glioblastoma | 338/338 | NR | GEPIA database | NR | 200 | OS, DFS | KM | 7 |
| Chen et al. [2020] (8) | China | Breast cancer | 535/535 | NR | GEPIA database | NR | 300 | OS, DFS | KM | 7 |
| Hao et al. [2020] (10) | China | Ovarian cancer | 20/52 | I–II/III–IV (39/33) | RT-PCR | NR | 120 | OS | KM | 7 |
| Duan et al. [2019] (9) | China | CCRCC | 41/41 | I–II/III–IV (69/13) | RT-PCR | Median | 60 | OS, DFS | KM | 7 |
| Feng et al. [2019] (7) | China | Gastric cancer | 33/39 | I–II/III–IV (19/53) | RT-PCR | Using OriginLab software | 60 | OS | KM | 7 |
| Hong et al. [2019] (11) | China | Gastric cancer | 38/40 | NR | RT-PCR | Youden’s index | 60 | OS | KM | 7 |
| Xu et al. [2019] (13) | China | Melanoma | 138/138 | NR | RT-PCR | NR | 400 | OS, DFS | KM | 7 |
| Zhang et al. [2019] (15) | China | Esophageal cancer | 67/270 | T1–T2/T3 (257/80) | RT-PCR | NR | 40 | OS | KM | 7 |
| Li et al. [2016] (12) | China | Pancreatic cancer | NR | I–II/III–IV (35/26) | RT-PCR | NR | 60 | OS | KM, MVA | 8 |
High: high LINC-PINT expression; low: low LINC-PINT expression. CCRCC, clear cell renal cell carcinoma; DFS, disease-free survival; GEPIA, Gene Expression Profiling Interactive Analysis; KM, Kaplan-Meier; MVA, multivariate analysis; NR, no report; NOS, Newcastle-Ottawa Scale; NSCLC, non-small cell lung cancer; OS, overall survival; RT-PCR, reverse transcription polymerase chain reaction.
Association between LINC-PINT expression and overall survival (OS)
Eleven studies with a total of 2,876 cancer patients assessed a relationship between LINC-PINT expression and OS. The heterogeneity (I2=44.86%, P=0.05) between the studies was moderate that the pooled HR was evaluated by the fixed effects model. The pooled HR was 0.72 (95% CI: 0.64–0.80, P<0.001), suggesting that LINC-PINT expression was associated to favorable OS (Figure 2). In the subgroup analysis of cancer type and case number, the groups with non-digestive system cancer (HR =0.74, 95% CI: 0.66–0.83, P<0.001) and digestive system cancer (HR =0.61, 95% CI: 0.46–0.81, P=0.001), and the groups with case number <100 (HR =0.56, 95% CI: 0.40–0.79, P=0.001) and >100 (HR =0.74, 95% CI: 0.66–0.83, P<0.001) were statistically significant (Table 2, Figure 3).
Table 2
| Subgroup | Number of studies | Number of patients | Pooled HR (95% CI) | P value | Heterogeneity | |
|---|---|---|---|---|---|---|
| I2 (%) | P value | |||||
| Cancer type | ||||||
| Non-digestive system cancer | 7 | 2,328 | 0.74 (0.66–0.83) | <0.001 | 49.30 | 0.07 |
| Digestive system cancer | 4 | 548 | 0.61 (0.46–0.81) | 0.001 | 38.07 | 0.18 |
| Case number | ||||||
| Less than 100 | 6 | 395 | 0.56 (0.40–0.79) | 0.001 | 24.90 | 0.25 |
| More than 100 | 5 | 2,481 | 0.74 (0.66–0.83) | <0.001 | 56.60 | 0.06 |
CI, confidence interval; HR, hazard ratio; LINC-PINT, long iatrogenic non-protein-coding RNA p53-induced transcript.
Association between LINC-PINT expression and disease-free survival (DFS)
Four studies with a total of 2,104 cancer patients evaluated a relationship between LINC-PINT expression and DFS. The heterogeneity (I2=14.52%, P=0.32) between the studies was low that the pooled HR was assessed by the fixed effects model. The pooled HR was 0.70 (95% CI: 0.60–0.82, P<0.001), implying that LINC-PINT expression was associated to favorable DFS (Figure 4).
Publication bias
Funnel plot with Egger’s test was performed to know for publication bias. For OS, funnel plot showed slightly asymmetric appearance, but the Egger’s test revealed that it was not statistically significant (P=0.14) (Figure 5A). For DFS, funnel test with Egger’s test was not significant (P=0.34) (Figure 5B). The trim and fill methods were also evaluated. The pooled results were still significant for OS (HR =0.75, 95% CI: 0.67–0.83) and for DFS (HR =0.69, 95% CI: 0.59–0.81), showing that our initial pooled results were consistent (Figure 6).
Sensitivity analysis
The sensitivity analysis was performed that the enrolled studies were omitted one by one to assess the effect of the studies. The results showed that the pooled HR was not significantly affected by any single study for OS (HR =0.72, 95% CI: 0.64–0.80, P<0.001) and for DFS (HR =0.70, 95% CI: 0.60–0.82, P<0.001) (Figure 7).
Discussion
LncRNAs, a subset of non-coding RNAs, are defined as transcripts >200 nucleotides in length, with no protein translating potential (17). Although they are not translated, lncRNAs have important functions in various biological processes, such as gene regulation and expression, chromatin dynamics, and cellular growth and differentiation (17). Recently, the aberrant function of lncRNAs was linked to many cancers and diseases (18).
LINC-PINT, a novel lncRNA, has been identified to be expressed in multiple cancers, and is believed to be related to the prognosis of cancer patients (6). For example, the expression of LINC-PINT was demonstrated to suppress the malignant progression of cancer cells in non-small cell cancer (6), triple negative breast cancer (8), gastric cancer (7,11), ovarian cancer (10), pancreatic cancer (12), melanoma (13) and laryngeal squamous cell carcinoma (14) as well as esophageal cancer (15) and glioblastoma (16). LINC-PINT expression has also been associated with prognosis in lung, gastric, breast, ovarian, pancreatic, esophageal, laryngeal, renal, brain cancer, and melanoma (6-16).
In this study, we collected 11 related studies and conducted a meta-analysis. We reported the prognostic significance of LINC-PINT expression in cancer patients. We proved that LINC-PINT expression was significantly related to OS and DFS. Regarding the cancer type and case number, the results were statistically significant.
Most of the studies we collected showed that LINC-PINT expression was associated with favorable survival. Only one study (9) reported that high expression of LINC-PINT was significantly correlated with poor clinical outcomes in patients with clear cell renal cell carcinoma. They advocated that overexpression of LINC-PINT promoted cancer cell proliferation, induced cell cycle progression, and inhibited apoptosis (9). Therefore, we hope that future research will clarify the effects of LINC-PINT on cancer.
The study had some limitations. First, all studies were published in China. Therefore, these results may not be necessarily applicable to other regions. Second, cancer type and case number were small, which led to the inaccuracy of our results. Third, HRs with CIs were calculated by processing survival curves, thus the prognostic significance of LINC-PINT expression might be exaggerated.
Conclusions
In conclusion, this study is the first to demonstrate the prognostic significance of LINC-PINT expression in cancer patients. High expression of LINC-PINT is associated with favorable OS and DFS, and it may serve as a valuable prognostic marker in cancer patients.
Acknowledgments
Funding: This work was supported by a research grant from
Footnote
Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-627/rc
Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-627/prf
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-627/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Yu H, Li S, Wu SX, et al. The prognostic value of long non-coding RNA H19 in various cancers: A meta-analysis based on 15 studies with 1584 patients and the Cancer Genome Atlas data. Medicine (Baltimore) 2020;99:e18533. [Crossref] [PubMed]
- Dong B, Chen X, Zhang Y, et al. The prognostic value of lncRNA SNHG1 in cancer patients: a meta-analysis. BMC Cancer 2019;19:780. [Crossref] [PubMed]
- Marchese FP, Raimondi I, Huarte M. The multidimensional mechanisms of long noncoding RNA function. Genome Biol 2017;18:206. [Crossref] [PubMed]
- Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet 2009;10:155-9. [Crossref] [PubMed]
- Qiu MT, Hu JW, Yin R, et al. Long noncoding RNA: an emerging paradigm of cancer research. Tumour Biol 2013;34:613-20. [Crossref] [PubMed]
- Zhang C, Gong C, Li J, et al. Downregulation of long non-coding RNA LINC-PINT serves as a diagnostic and prognostic biomarker in patients with non-small cell lung cancer. Oncol Lett 2021;21:210. [Crossref] [PubMed]
- Feng H, Zhang J, Shi Y, et al. Long noncoding RNA LINC-PINT is inhibited in gastric cancer and predicts poor survival. J Cell Biochem 2019;120:9594-600. [Crossref] [PubMed]
- Chen J, Zhu M, Zou L, et al. Long non-coding RNA LINC-PINT attenuates paclitaxel resistance in triple-negative breast cancer cells via targeting the RNA-binding protein NONO. Acta Biochim Biophys Sin (Shanghai) 2020;52:801-9. [Crossref] [PubMed]
- Duan J, Ma X, Shi J, et al. Long noncoding RNA LINC-PINT promotes proliferation through EZH2 and predicts poor prognosis in clear cell renal cell carcinoma. Onco Targets Ther 2019;12:4729-40. [Crossref] [PubMed]
- Hao T, Huang S, Han F. LINC-PINT suppresses tumour cell proliferation, migration and invasion through targeting miR-374a-5p in ovarian cancer. Cell Biochem Funct 2020;38:1089-99. [Crossref] [PubMed]
- Hong L, Wang H, Wang J, et al. LncRNA PTCSC3 Inhibits Tumor Growth and Cancer Cell Stemness in Gastric Cancer by Interacting with lncRNA Linc-pint. Cancer Manag Res 2019;11:10393-9. [Crossref] [PubMed]
- Li L, Zhang GQ, Chen H, et al. Plasma and tumor levels of Linc-pint are diagnostic and prognostic biomarkers for pancreatic cancer. Oncotarget 2016;7:71773-81. [Crossref] [PubMed]
- Xu Y, Wang H, Li F, et al. Long Non-coding RNA LINC-PINT Suppresses Cell Proliferation and Migration of Melanoma via Recruiting EZH2. Front Cell Dev Biol 2019;7:350. [Crossref] [PubMed]
- Yang X, Miao S, Mao X, et al. LncRNA LINC-PINT Inhibits Malignant Behaviors of Laryngeal Squamous Cell Carcinoma Cells via Inhibiting ZEB1. Pathol Oncol Res 2021;27:584466. [Crossref] [PubMed]
- Zhang L, Chen J, Wang L, et al. Linc-PINT acted as a tumor suppressor by sponging miR-543 and miR-576-5p in esophageal cancer. J Cell Biochem 2019;120:19345-57. [Crossref] [PubMed]
- Zhu H, Chen Z, Shen L, et al. Long Noncoding RNA LINC-PINT Suppresses Cell Proliferation, Invasion, and EMT by Blocking Wnt/β-Catenin Signaling in Glioblastoma. Front Pharmacol 2021;11:586653. [Crossref] [PubMed]
- Bhan A, Soleimani M, Mandal SS. Long Noncoding RNA and Cancer: A New Paradigm. Cancer Res 2017;77:3965-81. [Crossref] [PubMed]
- Schmitt AM, Chang HY. Long Noncoding RNAs: At the Intersection of Cancer and Chromatin Biology. Cold Spring Harb Perspect Med 2017;7:a026492. [Crossref] [PubMed]
