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. 2020 Aug 24;10:14136. doi: 10.1038/s41598-020-71104-9

Prognostic significance of Rab27 expression in solid cancer: a systematic review and meta-analysis

Hyun Min Koh 1, Bo Gun Jang 2,3, Dong Chul Kim 4,5,6,
PMCID: PMC7445175  PMID: 32839520

Abstract

Rab27 is an essential molecule of vesicle fusion and trafficking in exosome secretion process, which plays important roles in cancer progression and metastasis. Recent studies reported that Rab27 expression is also associated with cancer prognosis. Therefore, we performed a meta-analysis to reveal the prognostic significance of Rab27 expression in solid cancer. Data were extracted by searching on PubMed, Embase and Cochrane library until February 15 2020. Pooled hazard ratio (HR) with confidence interval (CI) was calculated to evaluate the association between Rab27 expression and survival in solid cancer. Ten studies with 1434 cancer patients were including for this meta-analysis. High expression of Rab27 was associated with poor survival (HR 2.67, 95% CI 1.52–4.69, p = 0.001). High expression of Rab27A was significantly associated with lymph node metastasis (HR 1.53, 95% CI 1.00–2.34, p = 0.048). High expression of Rab27B was significantly correlated with lymph node and distant metastasis (HR 2.15, 95% CI 1.56–2.95, p < 0.001; HR 6.80, 95% CI 3.12–14.85, p < 0.001), and higher TNM stage (HR 2.55, 95% CI 1.78–3.65, p < 0.001). This meta-analysis revealed that Rab27 expression could be a potential prognostic marker in solid cancer.

Subject terms: Tumour biomarkers, Prognostic markers

Introduction

Cancer is a common cause of morbidity and mortality throughout the world1. In 2018, more than 18 million new cancer patients were occurred and 9.5 million died2. In spite of desperate development of new remedies in recent years, the prognosis of cancer remains bleak3. Therefore, recognition of new biomarkers related to the progression of cancer is essential for improving clinical outcomes4.

Rab proteins are small GTPases consisting more than 70 members in human and work as regulators of proteins trafficking, membrane focusing and fusion, and vesicles transportation, which is one of the processes to control the functioning of cells, including cell proliferation, signal communication and protein transportation5,6.

Rab27 is one of the Rab proteins and is made of two components, Rab27A and Rab27B in vertebrates6. Rab27A and Rab27B are expressed in many kinds of secretory epithelial cells and are the essential substances of vesicle trafficking and fusion in the process of exosome secretion, which is known to play significant roles in the progression and metastasis of cancer by controlling the microenvironment of cancer719. Moreover, recent studies reported that Rab27A and Rab27B expression are related with the prognosis of cancer8,2028.

However, the prognostic significance of Rab27 expression is not yet understand systematically in cancer. Therefore, we performed a comprehensive meta-analysis to estimate the prognostic significance of Rab27 expression in solid cancer.

Results

Study characteristics

The literature selection flow of the included studies was presented in Fig. 1. Ten studies including 1434 patients were chosen for our meta-analysis. The basic characteristics of included studies were summarized in Table 1. All studies were published between 2012 and 2019 and were processed in Asia. The included studies were consisted of seven types of cancers, including renal cell carcinoma (n = 1), lung cancer (n = 2), ovarian cancer (n = 1), pancreatic cancer (n = 2), colorectal cancer (n = 2), breast cancer (n = 1), and hepatocellular carcinoma (n = 1). All studies performed immunohistochemistry to evaluate Rab27A or Rab27B expression in the human cancer tissue, and the majority of the cut-off value were scoring system using staining intensity and proportion. The Newcastle-Ottawa Scale (NOS) score is 7 to 8, which is considered to be high quality studies.

Figure 1.

Figure 1

Flow diagram of study selection.

Table 1.

Basic characteristics of the included studies.

Study Country Cancer type Sample size Gender (M/F) Mean age (years) Study period Follow-up (months) Survival outcome Rab27 detection Rab27 associated with prognosis Cut-off value of Rab27 expression Survival analysis NOS
An et al.23 South Korea Clear cell renal cell carcinoma 152 109/43

59.9

(32–83)

2000–2009 Mean 51.96 DSS IHC Rab27A Moderate and strong intensity (> 1 +) MVA 8
Koh et al.26 South Korea Non-small cell lung cancer 133 111/22

Median 66

(31–77)

2002–2009 NA DSS IHC Rab27B  > 30%, stronger than internal control MVA 7
Zhang et al.28 China Lung adenocarcinoma 80 44/36 NA NA NA OS IHC Rab27B High expression (≥ 3) MVA 7
Ren et al.20 China Ovarian cancer 103 0/103 NA 2004–2013 NA OS IHC Rab27B Staining scores with intensity and proportion (≥ 4.5) MVA 7
Zhao et al.8 China Pancreatic cancer 186 99/70 NA 2000–2010 NA OS IHC Rab27B Staining scores with intensity and proportion (≥ 91) MVA 7
Shi et al.22 China Colorectal carcinoma 112 73/39 65.14 2003–2008 NA OS IHC Rab27A Staining scores with intensity and proportion (≥ 4) MVA 7
Wang et al.26 China Pancreatic cancer 186 110/76 NA 2003–2010 NA OS IHC Rab27A Staining scores with intensity and proportion (≥ 91) MVA 7
Bao et al.24 China Colorectal cancer 113 73/40 65.2 2006–2008 NA OS IHC Rab27B Staining scores with intensity and proportion (≥ 4) MVA 7
Zhang et al.27 China Breast cancer 221 0/221 47 2000–2002 Median 79 (60–112) DSS IHC Rab27B Staining scores with intensity and proportion (> 3) MVA 8
Dong et al.21 China Hepatocellular carcinoma 148 108/35 51.6 (29–72) 2005–2009 NA OS IHC Rab27B Positive expression MVA 7

DSS disease-specific survival, IHC immunohistochemistry, MVA multivariate analysis, NA not available, NOS Newcastle–Ottawa Scale, OS overall survival.

Association between Rab27 expression and survival

Ten studies including 1434 cancer patients reported the association between Rab27 expression with survival. The pooled HR was evaluated using random-effects model. High expression of Rab27 was associated with poor survival (Hazard Ratio [HR] 2.67, 95% confidence interval [CI] 1.52–4.69, p = 0.001) although with heterogeneity (I2 = 77.1%, p < 0.001) (Fig. 2).

Figure 2.

Figure 2

Forest plot of the association between Rab27 expression and survival.

Subgroup analysis was performed to investigate the potential source of heterogeneity and revealed that cancer type, sample size, survival outcomes, and protein type could be the main sources of heterogeneity (Table 2). According to the stratification by cancer type, the result of poor survival in patients with high expression of Rab27 was consistently identified in lung cancer (HR 2.17, 95% CI 1.36–3.47, p = 0.001) and pancreatic cancer (HR 2.77, 95% CI 1.50–5.11, p = 0.001) except colorectal cancer (HR 0.90, 95% CI 0.15–5.44, p = 0.911) (Fig. 3A). Based on the sample size, poor survival was correlated to Rab27 expression in both groups (sample size more than 100, HR 3.07, 95% CI 1.42–6.65, p = 0.004; sample size fewer than 100, HR 2.17, 95% CI 1.36–3.47, p = 0.001) (Fig. 3B). On the analysis of survival outcomes, there was significant relationship between Rab27 expression and poor survival in both groups (disease-specific survival, HR 3.57, 95% CI 1.28–9.99, p = 0.015; overall survival, HR 2.33, 95% CI 1.18–4.60, p = 0.015) (Fig. 3C). When it comes to the protein type, there was a significant result in Rab27B (HR 3.27, 95% CI 2.04–5.24, p < 0.001), but not in Rab27A (HR 1.73, 95% CI 0.30–9.89, p = 0.538) (Fig. 3D).

Table 2.

Subgroup analysis of the association between Rab27 expression and survival.

Subgroup Number of studies Number of patients Pooled HR (95% CI) p value Heterogeneity
I2 (%) p value
Cancer type
Colorectal cancer 2 225 0.90 (0.15–5.44) 0.911 90.3 0.001
Lung cancer 2 213 2.17 (1.36–3.47) 0.001 0.0 0.369
Pancreatic cancer 2 372 2.77 (1.50–5.11) 0.001 0.0 0.850
Others 4 624 6.67 (4.11–10.80)  < 0.001 0.0 0.398
Sample size
Fewer than 100 2 213 2.17 (1.36–3.47) 0.001 0.0 0.369
More than 100 8 1221 3.07 (1.42–6.65) 0.004 82.8  < 0.001
Survival outcome
DSS 3 506 3.57 (1.28–9.99) 0.015 68.7 0.022
OS 7 928 2.33 (1.18–4.60) 0.015 80.0  < 0.001
Protein type
Rab27A 3 450 1.73 (0.30–9.89) 0.538 87.7  < 0.001
Rab27B 7 984 3.27 (2.04–5.24)  < 0.001 58.3 0.019

CI confidence interval, DSS disease-specific survival, HR hazard ratio, OS overall survival.

Figure 3.

Figure 3

Figure 3

Forest plot for survival stratified by cancer type (A), sample size (B) survival outcome (C), and protein type (D).

Association between Rab27 expression and clinicopathological characteristics

Analysis of the association between Rab27 expression and clinicopathological characteristics of cancer patients was summarized in Table 3. The results suggested that high expression of Rab27A was significantly associated with lymph node metastasis (HR 1.53, 95% CI 1.00–2.34, p = 0.048) (Fig. 4A). However, there was no significant relationship between Rab27A expression with age, gender, tumor grade and stage, distant metastasis, and TNM stage (Fig. 4B–G).

Table 3.

Association between Rab27 expression and clinicopathological characteristics.

Characteristic Number of studies Number of patients Pooled OR (95% CI) p value Heterogeneity
I2 (%) p value Model
Age (old vs young)
Rab27A 4 579 1.23 (0.86–1.77) 0.255 0.0 0.820 Fixed
Rab27B 7 984 1.11 (0.84–1.48) 0.450 32.4 0.181 Fixed
Gender (male vs female)
Rab27A 4 579 0.69 (0.47–1.01) 0.057 33.9 0.209 Fixed
Rab27B 5 660 0.88 (0.43–1.82) 0.729 74.2 0.004 Random
Tumor size (large vs small)
Rab27B 3 414 1.17 (0.77–1.79) 0.454 0.0 0.386 Fixed
Tumor grade (high vs low)
Rab27A 3 446 1.20 (0.29–5.03) 0.800 82.8 0.003 Random
Rab27B 6 851 1.33 (0.75–2.35) 0.333 55.8 0.046 Random
Tumor stage (high vs low)
Rab27A 3 431 1.02 (0.37–2.78) 0.974 81.3 0.005 Random
Rab27B 5 723 1.43 (1.80–2.57) 0.229 61.3 0.036 Random
Lymph node metastasis (present vs absent)
Rab27A 3 431 1.53 (1.00–2.34) 0.048 49.6 0.137 Fixed
Rab27B 6 836 2.15 (1.56–2.95)  < 0.001 27.9 0.225 Fixed
Distant metastasis (present vs absent)
Rab27A 2 298 2.13 (0.10–44.08) 0.624 78.5 0.031 Random
Rab27B 3 422 6.80 (3.12–14.85)  < 0.001 0.0 0.982 Fixed
TNM stage (high vs low)
Rab27A 4 579 1.78 (0.79–4.02) 0.167 72.9 0.011 Random
Rab27B 6 881 2.55 (1.78–3.65)  < 0.001 30.9 0.204 Fixed

CI confidential interval, OR odds ratio, TNM tumor-node-metastasis.

Figure 4.

Figure 4

Figure 4

Figure 4

Forest plot of the association between Rab27A expression and clinicopathological characteristics. (A) lymph node metastasis, (B) age, (C) gender, (D) tumor grade, (E) tumor stage, (F) distant metastasis, (G) TNM stage.

High expression of Rab27B was significantly correlated with lymph node and distant metastasis (HR 2.15, 95% CI 1.56–2.95, p < 0.001; HR 6.80, 95% CI 3.12–14.85, p < 0.001) (Fig. 5A,B), and higher TNM stage (HR 2.55, 95% CI 1.78–3.65, p < 0.001) (Fig. 5C). But, there was no significant association between Rab27B expression with age, gender, tumor size, grade and stage (Fig. 5D–H).

Figure 5.

Figure 5

Figure 5

Figure 5

Forest plot of the association between Rab27B expression and clinicopathological characteristics. (A) lymph node metastasis, (B) distant metastasis, (C) TNM stage, (D) age, (E) gender, (F) tumor size, (G) tumor grade, (H) tumor stage.

Publication bias and sensitivity analysis

Visual inspection of the Funnel plot revealed asymmetry (Fig. 6A). This suggests the possibility of a visual bias in publishing, however the Egger’s test was not statistically significant (p = 0.849). Thus, the trim and fill method was applied. The results showed the significant association between Rab27 expression with survival (HR 1.85, 95% CI 1.02–3.36, p = 0.042) (Fig. 6B).

Figure 6.

Figure 6

Funnel plot (A) and trim and fill method (B) of the association between Rab27 expression and survival.

The sensitivity analysis was conducted to verify the reliability of our results. The pooled HR for survival was not influenced after one by one, excluding each study, indicating our results are consistent and credible (HR 2.62, 95% CI 2.02–3.40) (Fig. 7).

Figure 7.

Figure 7

Sensitivity analysis of the association between Rab27 expression and survival.

Discussion

The Rab family members are key regulators that involve in the replacement of substances in the various stages of vesicular trafficking17. Rab27 is a valuable member in Rab family and contains Rab27A and Rab27B, which share 70% sequence identity of the amino acid level17,22. Rab27 is located on the membrane-bound compartments and takes part in the docking multivesicular endosomes, which is known to control exosome secretion17,29,30. Recent studies have demonstrated that Rab27 regulates exosome secretion in the many kinds of cells, including dendritic cell, cervical cancer cells, breast cancer cells, melanoma cells, bladder cancer cells, and lung cancer cells6. Moreover, Rab27 has been revealed to function a critical role in the proliferation and invasion of cancer cells by the controlling of exosome secretion, which modulates the tumor microenvironment and the function of cancer cell6. Guo et al. showed that Rab27A affects melanoma cell proliferation and motility, and promotes melanoma invasion and metastasis by mediating exosomes1316. Akavia et al. also reported that Rab27A contributes to proliferation in melanoma by the regulation of vesicular trafficking11. Liu et al. and Li et al. revealed that Rab27 plays significant roles in cell proliferation and invasion in bladder cancer and pancreatic cancer cells, respectively17,18. Bobrie et al. and Peinado et al. demonstrated that Rab27A can enhance tumor progression and metastasis by the modification of exosome secretion and tumor microenvironment12,19. Furthermore, some studies have reported that Rab27 expression is associated with the prognosis of cancer8,2028. Thus, we evaluated that the association between Rab27A expression and survival.

This meta-analysis of 10 studies including 1434 patients assessing the prognostic significance of Rab27 expression in solid cancer revealed that high expression of Rab27 was a potential prognostic marker for poor survival in cancer patients.

In the subgroup analysis of cancer type, poor survival was related to Rab27 expression in lung cancer and pancreatic cancer without heterogeneity. On the other hand, survival was not significantly correlated with Rab27 expression in colorectal cancer. This seems to be due to the conflicting results of the two studies in this group. Thus, additional research is needed in colorectal cancer. Regarding the subgroup of sample size and survival outcomes, poor survival was correlated to Rab27 expression in both groups, respectively. As showed in Fig. 3D, poor survival was significantly associated with high expression of Rab27B, but not with Rab27A. This seems to be due to the study of Shi et al. that reported high expression of Rab27A indicates favorable prognosis showing contrary results with other studies.

With regard to the clinicopathological characteristics, our analysis revealed that high expression of Rab27 was significantly correlated with lymph node metastasis. Moreover, Rab27B was also significantly associated with distant metastasis and TNM stage. This results strongly suggests that high expression of Rab27 is related to the prognosis of cancer patients.

This meta-analysis has the following limitations. First, all included studies originated from Asia, which may lead to our results not reflecting western countries. Second, cancer type and sample size were small, undermining the credibility of our results. Third, the discrepancy of cut-off value determining Rab27A and Rab27B expression may affect our results. However, we demonstrated a comprehensive analysis of the association between Rab27A and Rab27B expression with survival in solid cancer. To the best of our knowledge, this meta-analysis is the first report to systematically evaluate the association between Rab27 expression with survival in solid cancer.

In conclusion, this systematic review and meta-analysis revealed that Rab27 expression could be a prognostic marker in solid cancer.

Methods

Search strategy and selection criteria

We searched the PubMed, Embase and Cochrane library until February 15 2020 using the following terms: (Rab27A or Rab27B) and (cancer or tumor or carcinoma or neoplasm or malignancy) and (prognostic or predict or prognosis or survival or outcome). We reviewed all significant publications in the references of the articles.

The inclusion criteria were: (1) Rab27A or Rab27B was detected in the human cancer tissue, which diagnosed by pathologic examination; (2) the association between Rab27A or Rab27B and survival outcomes was reported; (3) the HR and 95% CI for survival outcomes were provided.

The exclusion criteria were: (1) duplicate studies; (2) conference abstracts, case reports, reviews, letters, and non-English articles; (3) preclinical studies, such as laboratorial or in vitro studies.

Data extraction

Two authors independently collected the following data from the included studies: first author, year of publication, country, cancer type, sample size, clinicopathological characteristics, study period, follow-up period, survival outcomes, Rab27 associated with prognosis, cut-off value of Rab27 expression, and survival data. When there was a disagreement, we reached an agreement through discussion.

Quality assessment

Two authors independently evaluated the quality of included studies by the NOS. The NOS scores ranged from 0 to 9. The studies with NOS scores of greater than 6 were regarded as a high quality.

Statistical analysis

Meta-analysis was performed using StataSE12 (Stata, College Station, TX, USA). Cochran’s Q and I2 statistics were used to assess the heterogeneity among the included studies. An I2 > 50% or a p value < 0.1 was considered as statistically significant in a random-effects model. Pooled HR and 95% CI were calculated for evaluating the prognostic significance of Rab27 expression. Subgroup analysis was performed to assess the source of heterogeneity. Funnel plot and Egger’s test were also performed to evaluate the publication bias. And the sensitivity analysis was applied to assess the reliability of the pooled results. A p value < 0.05 was regarded as statistically significant.

Acknowledgements

The authors received no funding for the research, authorship, and/or publication of this article.

Author contributions

H.M.K and D.C.K designed this review; H.M.K and B.G.J searched the databases and inspected all candidate articles; H.M.K and D.C.K extracted data and analyzed the data; H.M.K and B.G.J assessed the quality of included studies by the NOS; H.M.K wrote the manuscript, and all authors reviewed the manuscript.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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