Prognostic significance of the expression of nuclear eukaryotic translation initiation factor 5A2 in human melanoma
- Authors:
- Published online on: August 29, 2016 https://doi.org/10.3892/ol.2016.5057
- Pages: 3089-3100
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Copyright: © Khosravi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Melanoma is the most lethal form of skin cancer that arises from melanocytes, and although it constitutes only ~4% of all skin cancers it is responsible for >80% of mortalities in patients with skin cancer (1). Since the 1950s, the incidence of melanoma has been rapidly increasing in non-Hispanic white populations worldwide (2). Although surgery may cure the majority of patients in early stages of melanoma, patients with distant metastasis have a poor prognosis with a median survival time of only 6–8 months, and <15% of patients with distant metastatic melanoma survive for 5 years (3). Since melanoma has an extremely high metastatic potential, it is crucial to discover factors that are involved in the progression and metastasis of melanoma in an attempt to identify an effective treatment regimen for this devastating disease.
Eukaryotic translation initiation factor (EIF) 5A is best known for its cytoplasmic role in translation regulation as a eukaryotic translation initiation factor (4,5). In mammals, it is encoded by two highly-associated genes EIF5A1 and EIF5A2. However, a number of studies have suggested that EIF5A1 may also be active in the nucleus, particularly in mammals (6–8). EIF5A1 has been revealed to take part in the nucleocytoplasmic transport of incompletely spliced and unspliced human immunodeficiency virus-1 mRNAs (6) that are translocated across the nuclear envelope via chromosomal maintenance 1 (CRM1), which is a member of the importin β family of transport receptors. The main role of CRM1 is to facilitate the translocation of rRNA, U snRNA and ribosomal subunits across the nuclear envelope (9). EIF5A1 has also been revealed to be capable of interacting and colocalizing with transport receptor exportin 4, which is another member of the importin β family (8). In addition, it has been suggested that EIF5A1 may recognize nitric oxide synthase 2 mRNA in the nucleus and facilitate its transport to the cytoplasm in a CRM1 dependent-manner (10). Furthermore in Saccharomyces cerevisiae, EIF5A1 appears to be involved in mRNA degradation/turnover, which is a process highly associated with nucleocytoplasmic transport of mRNA (11,12). In summary, these data demonstrate a nuclear activity for EIF5A1 that is possibly associated with cellular mRNA metabolism.
EIF5A2, a phylogenetically conserved vertebrate variant of EIF5A1, was first reported to be highly expressed in testis and colorectal adenocarcinoma, and at moderate levels in the brain (13). EIF5A2 shares 83% amino acid identity with EIF5A1 (14) and has been associated with various oncogenic roles, including invasion and metastasis, and a poor prognosis in a variety of cancers, such as ovarian cancer (15), gastric adenocarcinoma (16), colorectal cancer (17,18), hepatocellular carcinoma (HCC) (19), ovarian cancer (20), non-small cell lung cancer (21) and bladder cancer (22,23). However, no studies have investigated the nuclear expression or activity of EIF5A2 in cancer, with the exception of Zender et al (24), who addressed the importance of nuclear EIF5A2 in HCC.
Previously, the present authors reported an increase in the cytoplasmic expression of EIF5A2 in melanoma and its role in melanoma progression and patient survival (25). The present study investigates, using immunohistochemistry and tissue microarray (TMA), the status of nuclear EIF5A2 expression in melanoma. The results revealed that nuclear EIF5A2 is an independent prognostic marker in melanoma, and its expression is significantly increased during melanoma progression. In addition, upregulation of nuclear EIF5A2 was determined to be associated with a significantly poorer 5-year survival rate for all and primary melanoma patients. Furthermore, simultaneous nuclear and cytoplasmic EIF5A2 expression, as well as concurrent nuclear EIF5A2 and matrix metalloproteinase-2 (MMP-2) expression, were associated with a poorer 5-year patient survival rate.
Materials and methods
Patient specimens
In total, 459 formalin-fixed, paraffin-embedded human tissues, consisting of 28 common acquired nevi, 49 dysplastic nevi, 242 primary melanomas and 140 metastatic melanomas, were used in the present study. The human skin tissues and the patients' data were acquired from the 1990–1998 archives of the Department of Pathology, Vancouver General Hospital (Vancouver, Canada), and their use was approved by the Clinical Research Ethics Board of the University of British Columbia (Vancouver, Canada; certificate number H09-01321), in accordance with the Declaration of Helsinki guidelines (26). Patient consent was not required under the Canadian law, since the present report is a retrospective study using anonymized data and several patients had already succumbed to the disease.
TMA construction and immunohistochemistry
TMA construction and immunohistochemical staining were performed as previously described (27,28). Briefly for immunohistochemical staining, the TMA slides were dewaxed by heating at 55°C for 30 min followed by three 5 min washes with xylene. Subsequently, the samples were rehydrated by washing in 100, 95 and 80% ethanol, and distilled water for 5 min each. For antigen retrieval, the samples were heated for 30 min at 95°C in 10 mmol/l sodium citrate (pH 6.0). The samples were incubated with 3% hydrogen peroxide in order to block endogenous peroxidase activity, and were next incubated for 30 min with universal blocking serum (Dako Canada ULC, Mississauga, ON, Canada) and then incubated with a primary rabbit anti-EIF5A2 antibody (dilution, 1:100; catalog no. E9781; Sigma-Aldrich, St. Louis, MO, USA) overnight at 4°C. Subsequently, the slides were incubated for 30 min with a non-diluted biotin-labelled secondary antibody raised in swine (catalog no. K0690; Dako Canada ULC), and then incubated with streptavidin-peroxidase (Dako Canada ULC). Subsequently, the samples were developed with 3,3-diaminobenzidine [Vector Laboratories (Canada), Inc., Burlington, ON, Canada] and counterstained with hematoxylin. Dehydration of the sections was performed using a standard procedure and the slides were sealed with coverslips. For blocking experiments, the anti-EIF5A2 antibody was incubated with a 10 times concentration of its synthetic immunogenic peptide (dilution, 1:10; Biomatik Corporation, Cambridge, ON, Canada) at 4°C the night prior to immunohistochemical staining.
Evaluation of immunostaining
Three independent observers, including one dermatopathologist, from the Departments of Dermatology and Skin Science or Pathology of the University of British Columbia, simultaneously evaluated and scored the nuclear EIF5A2 staining of the TMA, one core at a time, and a consensus score was reached. The intensity of nuclear EIF5A2 staining was scored as 0, 1+, 2+ and 3+ based on visual estimation. The percentage of nuclear EIF5A2-positive cells was scored as follows: 1, 0–25% cells stained; 2, 26–50% cells stained; 3, 51–75% cells stained; and 4, 76–100% cells stained. An immunoreactive score was used to determine the level of nuclear EIF5A2 staining by multiplying the scores of staining intensity and the percentage of positive cells. On the basis of the immunoreactive score, the nuclear EIF5A2 staining pattern was defined as 0, negative; and 1–12, positive (29,30).
Statistical analysis
Differences in demographics and clinicopathological characteristics and nuclear EIF5A2 expression between patients was evaluated by the χ2 test. Survival time was calculated between the date of melanoma diagnosis and the date the patient succumbed to the disease or last follow-up. Kaplan-Meier analysis and log-rank test were used to assess the association between nuclear EIF5A2 expression and patient survival times. The Cox proportional hazards regression model was performed for univariate and multivariate survival analysis. P<0.05 was considered to indicate a statistically significant difference, and all tests were two-sided. SPSS version 16.0 software (SPSS, Inc., Chicago, IL, USA) was used for all analysis.
Results
Association between nuclear EIF5A2 expression and clinicopathologic characteristics of melanoma patients
A total of 713 melanoma patients were enrolled for TMA construction. Due to loss of biopsy cores, insufficient tumour cells present in the cores or loss to follow-up, 382 melanoma (primary melanoma, 242 cases; metastatic melanoma, 140 cases) and 77 cases of nevi (common acquired nevi, 28 cases; dysplastic nevi, 49 cases) were evaluated for nuclear EIF5A2 staining. A synthetic immunogenic peptide against anti-EIF5A2 antibody was used in order to validate the specificity of the antibody used for staining, and the results revealed that this peptide considerably blocked nuclear and cytoplasmic EIF5A2 staining (Fig. 1) (25). The clinical features of the melanoma patients are listed in Table I.
Thickness is one feature that is an extremely important prognostic marker for primary melanoma patients (31). The present analysis demonstrated that in primary melanoma patients, positive nuclear EIF5A2 expression was exhibited by 58% of melanoma patients with a tumour thickness of >2 mm, compared with 45% of melanoma patients with a tumour thickness of ≤2 mm (P=0.036; Table I; Fig. 2A). This suggests that in primary melanoma, nuclear EIF5A2 expression may be induced during the transition between thin and thick melanoma. In all melanoma patients, the expression of nuclear EIF5A2 was detected in 85% of advanced stage melanomas [American Joint Committee on Cancer (AJCC) stages III and IV] compared with 51% of early stage melanomas (AJCC stages I and II) (P<0.001; Table I; Fig. 2B) (32). The association between positive nuclear EIF5A2 expression and melanoma thickness and AJCC stages may be an indication of the involvement of nuclear EIF5A2 expression in melanoma cell invasion.
Nuclear EIF5A2 expression increases with melanoma progression
To study the alterations in the expression of nuclear EIF5A2 with melanoma progression, immunohistochemical staining was performed on TMA slides and samples were categorized into negative and positive EIF5A2 staining groups (Fig. 2C and D). Positive nuclear EIF5A2 staining was observed in 29% of common acquired nevi, 31% of dysplastic nevi, 51% of primary melanomas and 85% of metastatic melanomas. Consequently, nuclear EIF5A2 expression was observed to be significantly higher in primary melanomas compared with dysplastic nevi and common acquired nevi (P=0.010 and P=0.026, respectively; Fig. 2E) and in metastatic melanomas compared with primary melanomas, dysplastic nevi and common acquired nevi (P<0.001; Fig. 2E). This suggests the role of nuclear EIF5A2 in the transformation between nevus and malignant tumors and the development of melanoma metastasis. No difference in nuclear EIF5A2 expression was observed between common acquired nevi and dysplastic nevi (P=0.852; Fig. 2E).
Nuclear EIF5A2 expression is positively associated with poor patient survival
The present study evaluated the association between nuclear EIF5A2 expression and the 5-year survival rate of primary and metastatic melanoma patients by constructing Kaplan-Meier survival curves. Overall and disease-specific 5-year survival rates were poorer for all (P<0.001; Fig. 3A and B) and primary (P=0.014 and P=0.015, respectively; Fig. 3C and D) melanoma patients with positive staining for nuclear EIF5A2 compared with patients with negative staining. The results from the Kaplan-Meier survival analysis were further supported by univariate Cox proportional hazard regression analysis, which indicated that nuclear EIF5A2 expression was a significant prognostic factor for the overall and disease-specific 5-year survival rates of all melanoma patients [hazards ratio (HR), 2.26 and 2.27; 95% confidence interval (CI), 1.57–3.27 and 1.56–3.31; P<0.001; Table II] and primary melanoma patients (HR, 1.95 and 2.00; 95% CI, 1.14–3.36 and 1.13–3.53; P=0.015 and P=0.017; Table II).
 | Table II.Univariate Cox regression analysis on 5-year overall and disease-specific survival rates of 382 total melanoma and 242 primary melanoma patients. |
Nuclear EIF5A2 is an independent prognostic marker for melanoma patients
Results from multivariate Cox regression analysis revealed that nuclear EIF5A2 was an adverse independent prognostic marker for overall and disease-specific 5-year survival rates of all melanoma patients (HR, 1.78 and 1.77; 95% CI, 1.22–2.60 and 1.20–2.62; P=0.003 and P=0.004; Table III) and primary melanoma patients (HR, 1.78 and 1.90; 95% CI, 1.02–3.12 and 1.06–3.43; P=0.043 and P=0.032; Table III). For the analysis, gender, age, AJCC and EIF5A2 expression were included for all melanoma patients, and gender, age, tumor thickness, ulceration status, tumor site, histological subtype and EIF5A2 expression were included for primary melanoma patients.
| Table III.Multivariate Cox regression analysis indicating that nuclear EIF5A2 expression is an adverse independent prognostic marker for 5-year survival rates of melanoma patients. |
Concurrent cytoplasmic and nuclear EIF5A2 expression is correlated with a poorer 5-year survival rate for all and primary melanoma patients
Previously, the present authors investigated the expression of cytoplasmic EIF5A2 in melanoma using TMA and revealed that cytoplasmic EIF5A2 expression is a prognostic marker for melanoma patients (25). The present study analyzed the association between cytoplasmic and nuclear expression of EIF5A2 using the 382 melanoma cases, and the results revealed that there was a direct association between the positive staining of cytoplasmic and nuclear EIF5A2 (P<0.001; Fig. 4A). To further examine this association and its effect on patient survival, the melanoma samples were classified into three groups according to their staining as follows: Category 1, negative cytoplasmic and nuclear EIF5A2 staining; category 2, negative cytoplasmic and positive nuclear EIF5A2 or positive cytoplasmic and negative nuclear EIF5A2 staining; category 3, positive cytoplasmic and nuclear EIF5A2 staining. Based on the results from Kaplan-Meier survival analysis, overall and disease-specific 5-year survival rates for all (P<0.001; Fig. 4B and C) and primary (P=0.002; Fig. 4D and E) melanoma patients were poorest for category 3 patients, best for category 1 patients and intermediate for category 2 patients. Furthermore, multivariate Cox regression analysis demonstrated that the simultaneous positive expression of cytoplasmic and nuclear EIF5A2 (category 3) was an independent prognostic factor for overall and disease-specific 5-year survival for all (HR, 1.87 and 1.87; 95% CI, 1.31–2.68 and 1.28–2.67; P=0.001 and P=0.001; Table IV) and primary (HR, 2.01 and 2.11; 95% CI, 1.15–3.51 and 1.17–3.78; P=0.014 and P=0.013; Table IV) melanoma patients.
| Table IV.Multivariate Cox regression analysis indicating that the simultaneous expression of cytoplasmic and nuclear EIF5A2 is an adverse independent prognostic marker for 5-year survival rates of melanoma patients. |
Simultaneous expression of nuclear EIF5A2 and MMP-2 is associated with poorer 5-year survival rates for all and primary melanoma patients
Results from the TMA study suggested the involvement of nuclear EIF5A2 for developing melanoma invasion, metastasis and poor patient survival. Since cell invasion is one of the hallmarks of cancer that may lead to increased metastasis and poor patient survival, the association between the expression of nuclear EIF5A2 and MMP-2, which is an important factor in the promotion of cancer cell invasion, was evaluated (33). A previous TMA study by the same group indicated that MMP-2 expression was a prognostic marker for melanoma (34). As a result, the present study examined the association between the expression of nuclear EIF5A2 and MMP-2 using the same 369 melanoma cases that had been previously analyzed in the aforementioned TMA study (34). The result revealed that positive staining of nuclear EIF5A2 was directly associated with strong MMP-2 expression (P=0.015; Fig. 5A). To more extensively study the association between MMP-2 and nuclear EIF5A2 expression and their effects on patient survival, the samples were classified into three groups based on their staining as follows: Category 1, negative nuclear EIF5A2 expression and negative-moderate MMP-2 expression; category 2, negative nuclear EIF5A2 expression and strong MMP-2 expression or positive nuclear EIF5A2 expression and negative-moderate MMP-2 expression; category 3, positive EIF5A2 expression and strong MMP-2 expression. Kaplan-Meier survival analyses revealed that overall and disease-specific 5-year survival outcomes for all (P<0.001; Fig. 5B and C) and primary melanoma (P<0.001 and P=0.001, respectively; Fig. 5D and E) patients were most favorable for category 1, least favorable for category 3 and moderate for patients in category 2.
Discussion
Recently, the present authors demonstrated that there was an increase in cytoplasmic EIF5A2 expression with melanoma progression (25); therefore, additional investigation of the nuclear expression of EIF5A2 using TMA data consisting of 459 melanocytic lesions was undertaken. The present study revealed that an increase in nuclear EIF5A2 expression was significantly associated with melanoma progression, thickness and AJCC stage. Nuclear EIF5A2 expression was significantly associated with poorer overall and disease-specific 5-year survival rates of all and primary melanoma patients. This may be a result of the direct association identified by the present study between nuclear EIF5A2 expression and melanoma thickness and AJCC stage, which is also consistent with the hypothesis that EIF5A2 is an oncogene in various cancers (35). Notably, nuclear expression of EIF5A2 and a combination of nuclear and cytoplasmic expression of EIF5A2 were identified as independent prognostic markers for overall and disease specific 5-year survival of all and primary melanoma patients.
Furthermore, the present study observed a direct association between nuclear EIF5A2 expression and a strong expression of MMP-2, which may demonstrate why nuclear EIF5A2 expression is directly correlated with melanoma thickness and a poorer 5-year survival rate for melanoma patients. In addition, simultaneous negative-moderate MMP-2 expression and loss of nuclear EIF5A2 expression (category 3) was demonstrated to be associated with an improved 5-year survival rate compared with either strong MMP-2 expression and loss of nuclear EIF5A2 expression or positive expression of nuclear EIF5A2 and negative-moderate expression of MMP-2 (category 2). This may possibly be a rational for dual therapeutic targeting of nuclear EIF5A2 and MMP-2 in melanoma patients; however, this requires additional study. The importance of MMP-2 in melanoma has also been demonstrated by other studies. MT1-MMP was demonstrated to increase melanoma cell invasion and motility by activating its target MMP-2 (36). Another study identified that expression of activated MMP-2 in a melanoma xenograft model is associated with increased malignancy, highlighting the role of MMP-2 in melanoma invasion and metastasis (37).
The present study also compared the nuclear and cytoplasmic EIF5A2 expression in the same cases of melanocytic lesions and revealed a significant association between positive staining of nuclear and cytoplasmic EIF5A2. However, this association is not perfect, which may indicate the differential regulation of nuclear and cytoplasmic EIF5A2 expression in melanoma. Notably, the present results revealed that simultaneous expression of nuclear and cytoplasmic EIF5A2 (category 3) was associated with a poorer survival outcome compared with the expression of only one form of EIF5A2 (category 2), which was associated with an intermediate survival outcome. This suggests that oncogenic properties of nuclear and cytoplasmic EIF5A2 may at least partly differ from each other in melanoma. Therefore, concurrent expression of the two forms (category 3) may have synergistic or additive effects on melanoma progression, metastasis and patient survival. Previous in vitro results by the present authors, indicated that EIF5A2 promotes melanoma cell invasion partly via increasing the activity of MMP-2 (25). However, further investigation is required to determine which form of EIF5A2 functions this way, and to what extent it is responsible for this role.
To the best of our knowledge, the present study is the first to report the nuclear expression of EIF5A2 and its importance in melanoma. However, the presence of EIF5A2 in the nuclei of HCC cells has been previously demonstrated (24). Exportin 4 (Xpo4) is a tumour suppressor that belongs to the importin-β family of nuclear transporters, and EIF5A is known to be a substrate of Xpo4 (8,38). Knockdown of Xpo4 in murine hepatoma cells leads to nuclear accumulation of EIF5A1 and EIF5A2, which significantly increases the in vitro proliferation of murine liver progenitor cells (24). In a human HCC cell line, XPO4 inactivation was revealed to contribute to tumour maintenance. In the same study, EIF5A2 was required for efficient proliferation of cells lacking XPO4, suggesting the importance of nuclear accumulation of EIF5A2 in mediating the oncogenic effects associated with XPO4 loss (24). A similar phenomenon is observed when an increase or decrease in the nuclear accumulation of β-catenin and FOXO affects tumorigenesis as a result of deregulation of the WNT and AKT signalling pathways, respectively (39). In addition, nuclear expression of EIF5A2 has also been observed in the human bladder carcinoma 5637 cell line (23).
In conclusion, the present study examined the expression profile of nuclear EIF5A2 and revealed that nuclear EIF5A2 expression is increased during melanoma progression and is associated with a poor 5-year survival rate in all melanoma and primary melanoma patients. In addition, the present study identified that nuclear EIF5A2 was an independent prognostic factor for the 5-year survival of all and primary melanoma patients, suggesting that nuclear EIF5A2 may be a potential target candidate for melanoma therapy. Simultaneous expression of cytoplasmic and nuclear EIF5A2 was associated with a poor survival outcome as well. Similar to HCC, the presence of nuclear and cytoplasmic EIF5A2 may be a reason for the existence of a shuttling mechanism between the cytoplasm and nucleus in melanoma. Additional investigation is required to further determine the mechanisms behind the subcellular localization of EIF5A2, the biological functions of nuclear EIF5A2 and its role in the tumorigenesis of melanoma.
Acknowledgements
The authors would like to thank Dr Ladan Fazli from the Vancouver Prostate Centre (Vancouver, Canada) for her advice in pathology and Dr Anand Rotte from the Department of Dermatology and Skin Science of the University of British Columbia (Vancouver, Canada) for providing the MMP-2 database used in the present study for the correlation analysis between the expression of nuclear EIF5A2 and MMP-2. The present study was funded by grants from the Canadian Institutes of Health Research (Ottawa, Canada; grant nos. MOP-93810, MOP-110974 and CCI-117958), the Canadian Dermatology Foundation (Ottawa, Canada; grant no. CDFYZ1315) and the Canadian Cancer Society Research Institute (Toronto, Canada; grant no. CCS-2-11-7007). Mr. Shahram Khosravi received a scholarship from the Natural Sciences and Engineering Research Council of Canada (Ottawa, Canada; grant no. NSERC IPS 9415).
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