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Elevated nuclear YBX1 expression and the clinicopathological characteristics of patients with solid tumors: a meta-analysis

Authors Zhang C, Yin T , Tao R, Xiao B, Chen J, Li Z, Miao X , Peng Q , Sun L , Zhang W, Ren J, Zhang Z, Zhang Y, Li X , Zhang W

Received 19 November 2018

Accepted for publication 24 February 2019

Published 14 May 2019 Volume 2019:11 Pages 4391—4402

DOI https://doi.org/10.2147/CMAR.S195243

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo



Chunze Zhang,1,2,* Tingting Yin,3,* Ran Tao,4,* Bo Xiao,5,* Jing Chen,4 Zixuan Li,5 Xueyuan Miao,3 Qing Peng,3 Liu Sun,3 Weihua Zhang,1 Junxu Ren,4 Zhao Zhang,1 Ying Zhang,1 Xichuan Li,6 Wei Zhang5


1Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, People’s Republic of China; 2State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, People’s Republic of China; 3Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 4Department of Histology and Embryology, School of Basic Medical Sciences, Hebei North University, Zhangjiakou, Hebei, People’s Republic of China; 5School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People’s Republic of China; 6Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University, Tianjin, People’s Republic of China

 

*These authors contributed equally to this work 



Purpose: Y-box binding protein 1 (YBX1) is a multifunctional protein linked to tumor progression and its elevated expression is an indicator of poor prognosis in various cancers. This meta-analysis aimed to investigate the prognostic value and clinical significance of YBX1 in malignant cancer.
Methods: Relevant articles published through September 12, 2018 were identified from a comprehensive electronic and manual search in PubMed, Web of Science and Embase databases. The combined odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to estimate the relationship among clinicopathological characteristics, overall survival and disease-free-survival of patients with solid tumor and YBX1 expression.
Results: The study included 27 studies and 5,996 patients. Our analysis revealed significant association between increased YBX1 expression and tumor differentiation status, tumor size and lymph node metastasis; moreover, the pooled HR values demonstrated that high nuclear YBX1 expression was significantly associated with worse overall survival (HR=2.14; 95% CI: 1.72–2.67, P<0.001).
Conclusion: The evidence supports YBX1 as a tumor biomarker to guide clinical management and indicate prognosis.

Keywords: solid tumors, YBX1, prognosis, meta-analysis

Introduction

Y-box binding protein 1 (YBX1) is a multifunctional protein of the cold-shock superfamily which plays different roles in both nucleus and cytoplasm. As a transcription regulator within the nucleus, YBX1 regulates the expression of several genes by binding to the Y-box sequence located in the promoter which contributes to transcription regulation. In the cytoplasm, it binds to mRNA to regulate the translation process.1 Hence, YBX1 plays prominent prooncogenic roles in DNA repair,2 RNA splicing,3,4 cell proliferation,5,6 drug resistance,6,7 tumor invasion1,6,8 and metastasis,8 and is an indicator of poor prognosis1 in various cancers, including nasopharyngeal carcinoma,1bladder cancer,7 breast cancer,8 urothelial cancer,6 and melanoma.5 Recently, increasing researches has shown that nuclear expression of YBX1 correlates with poor prognosis in synovial sarcoma and colorectal cancer.4,9,10 Simultaneously, it has been suggested that the value of cytoplasmic YBX1 can act as a prognostic marker for breast cancer.11 This meta-analysis aimed to investigate the prognostic value and clinical significance of YBX1 in malignant solid cancer.

Materials and methods

Literature search strategy and study selection

The literature related to YBX1 prior to September 12, 2018, was retrieved from PubMed, Web of Science and Embase databases. Web searches were performed using the terms: (YBX1 OR YB-1 OR Y-box binding protein 1) AND (cancer OR tumor OR carcinoma OR neoplasm) AND (survival OR prognosis OR prognostic OR outcome). The language was limited to English. The Cochrane Library was also reviewed for related papers.

Criteria for inclusion

The following inclusion criteria were used: (1) randomized controlled trial; (2) patients with pathological diagnosis of malignant solid tumor; (3) connections of YBX1 expression with overall survival (OS) and/or disease-free survival (DFS) were described; (4) the full text of YBX1 expression of original research was published in the aforementioned three databases; (5) the expression of YBX1 was assessed by immunohistochemistry (IHC); (6) hazard ratios (HRs) and confidence intervals (CIs) were available; (7) studies were related to the full protein of YBX1; and (8) the studies of reviews or insufficient data were not included.

Data extraction and quality assessment

Two investigators (Tingting Yin, Bo Xiao and Jing Chen) executed the data extraction and the quality assessment. The following data of the eligible studies included the name of first author; publication year; study region; pathological type of tumors; and number of patients,detection methods, cut-off values, and prognostic outcomes (overall survival [OS], disease-free survival [DFS]). We will use the Engauge Digitizer V4.1 (downloaded from the website at: https://engauge-digitizer.updatestar.com/en) to extract the data of survival when the studies did not have HRs but presented Kaplan-Meier curves.

The authors (Xueyuan Miao) assessed the qualities of the records by using the Newcastle-Ottawa Scale (NOS) independently.12 Moreover, we assessed the score of each selected study based on the patient selection, comparability of the studied group and outcome according to the NOS. The final score of each selected research was scored when there were no conflicts.

Statistical analysis

Stata12.0 (Stata Corporation, College Station, TX, USA) software was used for meta-analysis and publication bias testing. The dichotomous data of hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the relevance between YBX1 expression and OS and DFS, whereas pooled estimates of ORs with 95% CIs were used to assess the relevance between YBX1 expression and clinical characteristics. The I2 statistical test was used for revealing heterogeneity among these studies, and the fixed-effects model and random-effects model were used for meta-analyses with low heterogeneity (I2<30%) and high heterogeneity (I2>30%) conditions. HRs>1 suggestedpoor prognosis of cancer patients with decreased YBX1 expression. Finally, we conducted a simple assessment by sensitivity analysis and evaluation of publication bias (P≤0.05 was considered statistically significant), and the credibility of our research was confirmed.

Results

The characteristics of the included studies

The detailed selection process is described in Figure 1. A total of 27 studies9,11,13-37 published from 2001 to 2016, with 5,996 patients were selected to evaluate the relationship of YBX1 expression and tumor prognosis. All studies shown in Table 1 were published prior to September 12, 2018. The participants in the studies covered a wide variety of countries and cancer types including: gastric cancer, colorectal cancer, lung cancer, breast cancer, hepatocellular carcinoma, prostate cancer, sarcoma, renal cell carcinomas, lymphoma, uterine cervical cancer, pleural mesothelioma, non-Hodgkin’s lymphomas, nasopharyngeal cancer, synovial sarcoma and bladder cancer. The NOS scores of the included 27 studies ranged from 5 to 8 and; therefore, they wewe high-quality.

Table 1 Main characteristics of studies exploring the relationship between YBX1 expression and tumor prognosis

Figure 1 Flow diagram of the selection of eligible studies.

Correlation of YBX1 expression with overall survival (OS)

OS was investigated in 25 studies including 5,768 patients. Two articles explored both nuclear YBX1 and cytoplasmic YBX1, so we regarded them as separate data. The pooled HR values revealed that high YBX1 expression was significantly associated with worse OS (HR=1.90; 95% CI: 1.69–2.14, P=0.005, Figure 2). In addition, because of heterogeneity (I2=46.0%), a random-effects model was used to pool HRs and 95% CIs. A subgroup analysis was conducted to detect the origin of heterogeneity depending on the type of YBX1(Figure 3). Increased nuclear expression of YBX1 (HR=2.14; 95% CI: 1.72–2.67, P<0.001) was significantly associated with worse OS in solid tumors but not with cytoplasmic expression of YBX1 (HR=1.79; 95% CI: 0.88–3.65, P=0.063) or elevated not reported YBX1 expression (HR=1.83; 95% CI: 1.61–2.09, P=0.734). These results indicate that increased nuclear expression of YBX1 is a prognostic factor for various solid tumors.

Figure 2 Forest plot describing the association between YBX1 expression and overall survival (random-effects analysis).Abbreviation: ES, effect size.

Figure 3 Subgroup analysis of overall survival and YBX1 protein type (random-effects analysis).Abbreviation: ES, effect size.

Correlations of YBX1 expression with disease-free survival (DFS)

DFS was investigated in 15 studies including 4,788 patients. One of the studies was treated as the two data in both nucleus and cytoplasm. The pooled HR values revealed that there was a clear correlation between a high expression of YBX1 and a worse DFS (HR=1.84; 95% CI: 1.60–2.12, P<0.001, Figure 4) with obvious heterogeneity ((I2=70.0%), so we adopted a random-effect model for the analysis. The effects of YBX1 expression on DFS in different types of YBX1 protein are shown in Figure 5. Increased nuclear YBX1 expression (HR=3.44; 95% CI: 2.42–4.89, P<0.001) was significantly associated with worse DFS, whereas elevated cytoplasmic expression of YBX1 (HR=1.49; 95% CI: 0.97–2.27, P=0.520) and high expression of YBX1 not reported (HR=1.64; 95% CI: 1.40–1.93, P=0.120) with poor DFS were not significantly associated.

Figure 4 Forest plot describing the association between YBX1 expression anddisease-free survival (random-effects analysis).Abbreviation: ES, effect size.

Figure 5 Subgroup analysis of disease-free survival and YBX1 protein type (random-effects analysis).Abbreviation: ES, effect size.

Correlations of YBX1 expression with clinicopathological parameters

Seventeen eligible articles were used to collect the clinical and pathological parameters. The clinical features of the selected studies are listed in Table S1. Meanwhile, the association of YBX1 expression with clinicopathological parameters is illustrated in Table 2. Elevated expression of YBX1 was related to tumor differentiation status (OR=2.85, 95% CI: 2.10–3.88), tumor size (OR=2.16, 95% CI: 1.61–2.73) and lymph node metastasis (OR=1.74, 95% CI: 1.38–2.19) which were independent of gender (OR=1.06, 95% CI: 0.85–1.33), distant metastasis (OR=1.27, 95% CI: 0.88–1.84) and clinical stages (OR=1.41, 95% CI: 0.94–2.11).

Table 2 Meta-analystic results of the associations of increased YBX1 expression with clinicopathological parameters

Assessment of heterogeneity and sensitivity analysis

Publications about OS, DFS and clinical pathological parameter analyses adopted the random-effect models because there was significant heterogeneity (I2>30%). Moreover, a sensitivity analysis was used to determine whether modifications of the included criteria affected the results (Figure 6). The results indicated that the pooled estimates of the effect of high-expressed YBX1 on OS and DFS in solid tumors did not vary significantly with the exclusion of any individual studies.

Figure 6 Sensitivity analysis of the overall survival (OS) and disease-free survival (DFS) in the meta-analysis. (A) DFS; (B) OS.

Publication bias

The publication bias of these applicable studies was constructed using Begg’s funnel plot with pseudo–95% confidence limits and Egger’s test to assess. The shapes of the funnel plots for OS, DFS and clinicopathological parameters showed no evidence of obvious asymmetry, and Egger’s test indicated the absence of publication bias (P>0.05). The preceding results revealed that this meta-analysis was statistically reliable. Furthermore, these findings provided other strong evidence to verify that high-level of YBX1 was a prognostic indicator for cancer patients (Figure 7).

Figure 7 Funnel plot for the assessment of potential publication bias regarding overall survival (OS), disease-free survival (DFS) and clinicopathological parameters in the meta-analysis. (A) DFS; (B) OS; (C) lymph node metastasis; (D) tumor differentiation status; (E) tumor size.

Discussion

YBX1 (Y-box-binding protein 1) is encoded by the YBX1 gene expression in the nucleus and the cytoplasm and plays pleiotropic roles in DNA repair,2 RNA splicing,3,4 drug resistance, cancer progression, invasion, and metastasis.68 Previous massive studies proved that high level expressions of YBX1, whether in nucleus or cytoplasm were significantly correlated with the clinicopathological features as poor prognostic factors in various cancers.7,911

Here, we reviewed almost all available published articles and conducted the present meta-analysis to investigate the prognostic value and clinical significance of YBX1 in solid malignant cancers. The meta-analysis of 27 studies based on the random-effects model is to discuss all the reported research exploring the hypothesis that a high-level nuclear expression of YBX1 was a promising prognostic factor for worse DFS and OS in patients with various solid tumors. Moreover, phosphorylated YBX1 enters into the nuclear compartment and binds to the promoter region of targeted genes,38 one of the 27 studies explored the relationship between phosphorylated YBX1 and overall survival in patients with high-grade serous ovarian cancer (HR=2.41, 95% CI: 1.34–4.33). This result coincides with our conclusion. However, in our study, although the high expression of YBX1 in cytoplasm was not statistically significant due to the number of cases or to the other reason, the HR value proved that YBX1 was associated with OS and DFS. Therefore, we could not deny directly that increased cytoplasmic YBX1 expression was not associated with OS or DFS. Elevated expression of YBX1 has degenerative feedback regulation with tumor differentiation status, tumor size and lymph node metastasis. Sensitivity analysis showed that no individual studies affected the overall results, indicating the stability of the aggregated results. Furthermore, no publication bias was observed. Thus, we conclude that the expression of YBX1 may be a biomarker of poor clinically pathologic prognostic factors in cancers.

When explaining the results of our meta-analysis, we should consider some restrictions. One of the major restrictions is a lack of stratified analysis for different tumor subtypes, different clinical stages or others. For instance, we previously mentioned that nuclear YBX1 expression predicts poor clinical outcome in stage III colorectal cancer,10 but fewer studies were focused on the other clinical stages of colorectal cancer. Additional studies with larger samples and standard testing methods are required to reach a consensus. Next, different threshold values of high-level YBX1 expression in each study may have led to an increase in the heterogeneity. A common cutoff value should be defined. The third restriction is that all incorporated studies are retrospective studies with positive results, which was considered to be more easily published. Thus, our assessment of the relationship betweene elevated YBX1 expression and outcome carries the possibility of overestimation. Finally, the literature was restricted to English-written papers, which may have introduced language bias. Many included studies that did not report clinicopathological features, which may lead to bias. Given all theselimitations, our results should be considered cautiously.

Conclusion

The present meta-analysis, according to published articles, demonstrated that elevated nuclear YBX1 expression was closely correlated with poorer survival of patients with various solid cancers, such as prostate cancer, sarcoma, renal cell carcinomas, lymphoma, uterine cervical cancer, and pleural mesothelioma. In addition, there are remarkably negative relevant relationships between highly -expressed YBX1 and tumor differentiation status, tumor size and lymph node metastasis. Last, our results should be interpreted carefully for the aforementioned heterogeneity and limitations. The results of this meta-analysis warrant performance of additional clinical studies of YBX1 in human solid tumors.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant 81872236 to Xichuan Li), the Natural Science Foundation of Tianjin (grant 18JCYBJC28100 to Xichuan Li), the Tianjin Health and Family Planning Commission Grant (2014KZ053 to Weihua Zhang, 2017058 to Ying Zhang and 2017057 to Chunze Zhang), and the Open Research Foundation of State Key Laboratory of Medicinal Chemical Biology (2018094 to Chunze Zhang, and 2016YJ029 to Zhao Zhang).

Disclosure

The authors declare no potential conflicts of interest in this work.

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Supplementary material

Table S1 Summarized data of clinical and pathological parameters from the eligible studies

References

1. Liu Q, Tao T, Liu F, Ni R, Lu C, Shen A. Hyper-O-GlcNAcylation of YB-1 affects Ser102 phosphorylation and promotes cell proliferation in hepatocellular carcinoma.. Exp Cell Res. 2016;349(2):230–238.

2. Shiraiwa S, Kinugasa T, Kawahara A, et al. Nuclear Y-box-binding protein-1 expression predicts poor clinical outcome in stage III colorectal cancer. Anticancer Res. 2016;36:3781–3788.

3. Zhao S, Guo W, Li J, et al. High expression of Y-box-binding protein 1 correlates with poor prognosis and early recurrence in patients with small invasive lung adenocarcinoma. Onco Targets Ther. 2016;9:2683–2692.

4. Abd El-Maqsoud NM, Osman NA, Abd El-Hamid AM, Fath El-Bab TK, Galal EM. Golgi Phosphoprotein-3 and Y-Box-Binding Protein-1 Are Novel Markers Correlating With Poor Prognosis in Prostate Cancer. Clin Genitourin Cancer. 2016;14(2):e143–152.

5. Lee A, Woo J, Park H, et al. The value of cytoplasmic Y-box-binding protein 1 as a prognostic marker for breast cancer in Korean. Breast Cancer. 2016;23(5):685–691.

6. Wang Y, Chen Y, Geng H, Qi C, Liu Y, Yue D. Overexpression of YB1 and EZH2 are associated with cancer metastasis and poor prognosis in renal cell carcinomas. Tumour Biol. 2015;36(9):7159–7166.

7. Yan X, Yan L, Zhou J, et al. High expression of Y-box-binding protein 1 is associated with local recurrence and predicts poor outcome in patients with colorectal cancer. Int J Clin Exp Pathol. 2014;7(12):8715–8723.

8. Zhao Z, Liao Y, Li J, et al. Association between higher expression of YB-1 and poor prognosis in early-stage extranodal nasal-type natural killer/T-cell lymphoma.. Biomarkers Med. 2014;8(4):581–588.

9. Nishio S, Ushijima K, Yamaguchi T, et al. Nuclear Y-box-binding protein-1 is a poor prognostic marker and related to epidermal growth factor receptor in uterine cervical cancer. Gynecol Oncol. 2014;132(3):703–708.

10. Song Y, Shiota M, Yokomizo A, et al. Twist1 and Y-box-binding protein-1 are potential prognostic factors in bladder cancer. Urol Oncol. 2014;32(1):31 e31–37.

11. Hyogotani A, Ito K, Yoshida K, Izumi H, Kohno K, Amano J. Association of nuclear YB-1 localization with lung resistance-related protein and epidermal growth factor receptor expression in lung cancer. Clin Lung Cancer. 2012;13(5):375–384.

12. Wu Y, Yamada S, Izumi H, et al. Strong YB-1 expression is associated with liver metastasis progression and predicts shorter disease-free survival in advanced gastric cancer. J Surg Oncol. 2012;105(7):724–730.

13. Szczuraszek K, Halon A, Materna V, et al. Elevated YB-1 expression is a new unfavorable prognostic factor in Non-Hodgkin’s lymphomas. Anticancer Res. 2011;31:2963–2970.

14. Dahl E, En-Nia A, Wiesmann F, et al. Nuclear detection of Y-box protein-1 (YB-1) closely associates with progesterone receptor negativity and is a strong adverse survival factor in human breast cancer. BMC Cancer. 2009;9:410.

15. Gluz O, Mengele K, Schmitt M, et al. Y-box-binding protein YB-1 identifies high-risk patients with primary breast cancer benefiting from rapidly cycled tandem high-dose adjuvant chemotherapy. J Clin Oncol. 2009;27(36):6144–6151.

16. Tay WL, Yip GW, Tan PH, et al. Y-Box-binding protein-1 is a promising predictive marker of radioresistance and chemoradioresistance in nasopharyngeal cancer. Mod Pathol. 2009;22(2):282–290.

17. Shibahara K, Sugio K, Osaki T, et al. Nuclear expression of the Y-box binding protein, YB-1, as a novel marker of disease progression in non-small cell lung cancer.. Clin Cancer Res. 2001;7:3151–3155.

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