Clinicopathological and functional implications of the inhibitor of apoptosis proteins survivin and XIAP in esophageal cancer
- Authors:
- Published online on: January 9, 2018 https://doi.org/10.3892/ol.2018.7755
- Pages: 3779-3789
Abstract
Introduction
Esophageal cancer is the eighth most common type of cancer worldwide and the sixth leading cause of cancer-related mortality (1). Squamous-cell carcinoma is the predominant histological type, however in the USA, and Western European countries the incidence of esophageal adenocarcinoma (EAC) is steadily rising and exceeds that of esophageal squamous-cell carcinoma (ESCC) (2–6). State-of-the-art treatment algorithms for esophageal cancer consist of multidisciplinary approaches, including surgical resection, combinatory chemo- and radiotherapy, as well as endoscopic procedures (7,8). However, despite aggressive and multimodal treatment concepts the prognosis of patients with esophageal cancer remains disappointing, with overall 5-year survival rates of approximately 20% (9). Poor outcome in esophageal cancer patients is particularly related to late diagnosis at advanced stages of the disease and high rates of cancer recurrence even after an adequate initial therapy with curative intend (9–11). Unfortunately, the efficacy of current chemo- and radiotherapy regimens has been largely exhausted and further intensification is predominantly associated with an increase in undesirable systemic toxicity. To overcome the difficulty of adverse effects, novel therapeutic concepts focus on the development of targeted anticancer therapies that specifically inhibit aberrant molecular pathways triggered by genomic and proteomic alterations in cancer cells.
In this context, during the last decades the Inhibitor of apoptosis protein (IAP) family attracted considerable attention. Considering their overexpression as well as their association with tumor progression, treatment resistance and poor prognosis in various human cancers, IAPs represent promising targets for cancer therapy. Initially, these proteins were found to function as endogenous inhibitors of caspases, however today it has become increasingly clear that IAPs affect additional cellular functions such as proliferation, migration, invasion and metastasis (12–14). The two most extensively studied members of the IAP family are survivin/BIRC5 and X-linked inhibitor of apoptosis protein (XIAP)/BIRC4 (12,14–19). Interestingly, survivin and XIAP have been demonstrated to be important partners accomplishing their antiapoptotic and pro-metastatic functions by direct interaction (13,20).
Aim of this study was to analyze the expression of survivin and XIAP in a large number of tissue specimens from esophageal cancer patients, including primary tumors and tumor adjacent non-malignant mucosa. Expression levels of both IAPs were correlated with clinicopathological variables and overall survival according to the REporting recommendations for tumor MARKer prognostic studies (REMARK) (21). In addition, we analyzed the antitumor activity of small molecule survivin inhibitor YM155 and XIAP inhibitors Birinapant and GDC-0152 in esophageal cancer cell lines originating from both, ESCC as well as EAC.
Materials and methods
Patient selection and clinicopathological data
Previously constructed tissue microarrays (TMA) containing tissue samples retrieved from human EAC and ESCC were used to assess survivin and XIAP expression (22). All formalin-fixed and paraffin-embedded (FFPE) tissue specimens originated from the Institutes of Pathology of the University Hospitals in Duesseldorf and Cologne. The patients who had undergone radical en bloc esophagectomy and lymphadenectomy with curative intent irrespective of tumor stage and microscopic resection margin at the University Hospital of Duesseldorf and Cologne between 1986 and 2005 were included in this study. Exclusion criteria were preoperative neoadjuvant therapy, macroscopic incomplete resection (R2), esophageal tumors other than squamous cell carcinoma or adenocarcinoma and samples with insufficient tumor material. In addition, 73 tissue samples of tumor adjacent, non-malignant esophageal mucosa were analyzed for survivin and XIAP expression. Information on TNM staging (depth of invasion, lymph node and distant metastasis) as well as grading were retrospectively obtained from the original pathological reports. Data regarding overall survival as well as age at the time of surgery and gender were reviewed. The study was carried out in accordance to Good Clinical Practice, the Declaration of Helsinki and an Institutional Review Board (IRB)-approval of the Medical Faculty, Heinrich Heine University Duesseldorf (IRB-no. 3821) was retrieved.
Immunohistochemistry
Two µm thick sections were cut from each TMA block and mounted on superfrost microscope slides. Immunohistochemical staining was performed as recently described (23,24). Two independent investigators (LD and LMJ) blinded to clinicopathological information evaluated the expression of survivin and XIAP using the immunoreactivity score (IRS) according to Remmele (25). This score is calculated by multiplying the intensity of staining (0, no staining; 1, weak staining; 2, strong staining; 3, very strong staining) with the percentage of positive cells (0, no positive cells; 1, <10% positive cells; 2, 11–50% positive cells; 3, 51–80% positive cells; 4, 81–100% positive cells). In case of differing results the samples in question were re-examined by both observers simultaneously and a consensus decision was made. For survivin, nuclear and cytoplasmic protein expression were separately determined. A tissue slide of pretested human colon and renal cell carcinoma, known to express survivin or XIAP intensively, served as a positive control. Sections incubated with isotype control antibodies were used as negative controls.
Cell lines
ESCC cell lines KYSE30, KYSE270, KYSE410 and KYSE520, established by Shimada et al (26), were obtained from the German collective of microorganisms and cell cultures (DSMZ, Braunschweig, Germany). EAC cell lines OE19 and OE33 were acquired from the European collection of cell cultures (ECACC, Salisbury, UK). All cell lines were maintained in RPMI medium supplemented with 10% heat inactivated FCS, penicillin and streptomycin at 37°C in an atmosphere with 5% CO2. DNA fingerprinting, conducted as previously described, confirmed that no cross contamination had occurred (27).
Functional in vitro assays
Cell viability and proliferation were assessed in 96-well culture plates with 2×103 cells per well. After 24 h cells were incubated with YM155, Birinapant, GDC-0152 or dimethyl sulfoxid (DMSO) vehicle control for 48 h. The CellTiter 96® AQueous Non-Radioactive Cell Proliferation Assay (Promega Corporation,, Madison, WI, USA) was used to measure cell viability. Changes in cell proliferation were quantified based on BrdU-incorporation using a Cell Proliferation ELISA BrdU assay (Roche Applied Science, Mannheim, Germany). Both assays were conducted according to the manufacturer's protocols. Absorbance was measured using the Infinite® 200 microplate reader (Tecan Group Ltd., Crailsheim, Germany). The absorbance values of treated cells are presented as a percentage of the absorbance of DMSO treated control cells.
Western blot analysis
1×105 cells were seeded in 25 cm2 cell culture flasks, grown overnight and treated with YM155 or DMSO vehicle control for 24 h. Subsequently, cells were lysed in RIPA buffer (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) and supplemented with protease inhibitor mix (cOmplete; Roche Diagnostics, Indianapolis, IN, USA). Lysates (20 µg) were separated on SDS-PAGE gels and transferred to nitrocellulose membranes. Membranes were blocked with TBS-T buffer containing 5% nonfat dry milk and incubated with primary antibodies overnight at 4°C. Blots were washed and incubated with secondary antibodies. Immune-Star™ Western C™ Kit (Bio-Rad Laboratories, Inc., Hercules, CA, USA) and the Versa Doc Imaging System (Bio-Rad Laboratories GmbH, Munich, Germany) were used for signal detection. The experiments were repeated three times and one representative western blot (WB) was chosen for presentation.
Reagents
Sepantronium Bromide (YM155), Birinapant and GDC-0152 were purchased from Selleckchem (Houston, TX, USA). Antibodies used for immunohistochemistry (IHC) or WB analysis were raised against survivin (NB500-201; 1:750 dilution for IHC and 1:1,000 dilution for WB; Novus, Littleton, CO, USA), XIAP (clone 48, 1:35 dilution for IHC or Clone 28, 1:1,000 dilution for WB; both BD Biosciences, San Jose, CA, USA), PARP (9542; 1:1,000 dilution; Cell Signaling, Denver, MA, USA), α-tubulin (Clone DM1A; 1:5,000 dilution; Sigma-Aldrich; Merck KGaA) and GAPDH (Clone 6C5; 1:5,000 dilution; Abcam, Cambridge, UK). Isotype control was performed using mouse IgG1k (MOPC-21; 1:70 dilution; Abcam) and rabbit immunoglobulin fraction (Code X0903; 1:15,000 dilution; Dako, Glostrup, Denmark).
Statistical analysis
Differences of IAP expression levels in esophageal cancer specimens and adjacent non-neoplastic mucosa were analyzed using the Mann-Whitney U test. For numerical data, a correlation between clinicopathological variables and expression levels of survivin or XIAP was examined using the Mann-Whitney U test. The chi-square test was implemented for categorical data. Spearman's correlation coefficient was used to test a relationship between survivin and XIAP expression levels. For some analyses immunoreactivity scores were categorized into high (IRS>2) or low (IRS≤2) expression of survivin and XIAP, respectively. The cut-off value for this categorization was set according to the median IRS for survivin and XIAP expression in all investigated EC tissue samples. Outcome measures included overall survival, defined as the period from the date of surgery until the date of last follow up or until death of any cause. Patients with incomplete tumor resection or who died within 30 days after operation were excluded from the survival analysis. Kaplan-Meier curves were generated and assessed using the log-rank (Mantel Cox) test and hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. For multivariate survival analysis all variables were included into a logistic regression analysis. Analyses were performed using GraphPad Prism for Windows (version 5; GraphPad Software, Inc., La Jolla, CA, USA) and SPSS statistics for Windows (version 17.0; SPSS, Inc., Chicago, IL, USA). P<0.05 was considered to indicate a statistically significant difference.
Results
Patients and outcome
Using our selection criteria, a total number of 90 EAC and 120 ESCC patients who underwent radical en bloc esophagectomy between 1986 and 2005 could be enrolled into our study. Unfortunately, 10 EAC patients and 6 ESCC patients had to be excluded from our analysis because of insufficient evaluable tumor material after immunohistochemical staining procedure. Clinicopathological characteristics of these remaining 80 EAC and 114 ESCC patients are summarized in Table I. The median age of EAC patients at the time of surgery was 66 years (range, 36–82) and 58 years in the group of ESCC patients (range, 37–83). A total of 67 EAC and 108 ESCC patients met all predefined inclusion criteria for our survival analysis. EAC and ESCC patients had a mean follow-up time of 38.0 month (range, 1–120) and 22.8 month (range, 1–120 month), respectively. A total of 47 EAC patients and 89 ESCC patients died during the follow up period. Mean overall survival of EAC patients was 49.3 month (range, 1–120 month; 95% CI: 38.4–60.2 month) and 28.3 month for ESCC patients (range, 1–120 month; 95% CI: 21.8–34.8).
Survivin and XIAP expression in esophageal cancer
As expected, immunohistochemical staining of TMAs showed a cytoplasmic and nuclear expression for survivin, whereas XIAP was exclusively localized in the cytoplasm (Fig. 1A). Both IAPs were aberrantly expressed in esophageal cancer tissue, when compared to adjacent non-neoplastic tumor mucosa, with significantly increased expression levels in both ESCC and EAC (Fig. 1B). Interestingly, XIAP and nuclear survivin expression levels were significantly higher in EAC when compared to ESCC (Fig. 1B). Of note, cytoplasmic survivin expression correlated positively with XIAP expression in EAC (rs=0.442; P<0.001) (Fig. 1D). In contrast, we did not detect a correlation between survivin and XIAP expression in ESCC samples.
To further elucidate a correlation between survivin or XIAP expression levels and clinicopathological variables, two statistical approaches were used. First we compared the IRS across groups for each clinicopathological parameter. This approach revealed that high XIAP expression strongly correlated with female gender and advanced tumor stages in ESCC patients. Furthermore, high nuclear survivin expression levels were associated with poorly differentiated (G3) ESCC (Fig. 1C). In contrast, no significant correlation between survivin or XIAP expression and clinicopathological variables became evident in EAC patients. Next, by categorizing IAP expression into high (IRS>2) or low (IRS≤2) we could confirm the correlation of high XIAP expression and female gender as well as high nuclear survivin expression and poorly differentiated (G3) ESCC (Tables II and III).
 | Table II.Associations between SVV and XIAP expression, and clinicopathological variables in esophageal adenocarcinoma. |
| Table III.Associations between SVV expression, and clinicopathological variables in esophageal squamous-cell carcinoma. |
XIAP is an independent negative prognostic marker in ESCC
Univariate survival analysis of EAC patients, using Kaplan-Meier curves and log-rank test revealed that the presence of lymph node and distant metastases were significantly associated with poor overall survival. However, neither survivin, nor XIAP expression levels correlated with poor prognosis in EAC patients (Table IV). Moreover, multivariate logistic regression analysis confirmed the presence of distant metastasis as independent negative prognostic factor in EAC patients (Table V).
In contrast to these findings, univariate analysis in the group of ESCC patients revealed that high levels of XIAP expression were significantly associated with a poor prognosis (Fig. 1E; Table IV). Importantly, multivariate logistic regression analysis confirmed high XIAP expression levels as an independent negative prognostic factor in our cohort of ESCC patients (Table V).
In vitro effects of survivin and XIAP directed therapy in esophageal cancer cells
A compilation of cell lines originating from human esophageal cancer comprising four ESCC (KYSE30, KYSE270, KYSE410 and KYSE520) and two EAC (OE19 and OE33) cell lines were analyzed for survivin and XIAP expression using Western blot analysis. As shown in Fig. 2A survivin and XIAP expression were detectable in all esophageal cancer cell lines independent of their histological subtype. To explore the effect of a small molecule mediated inhibition of survivin and XIAP on esophageal cancer cell viability, we incubated ESCC as well as EAC cell lines with increasing concentrations of the survivin antagonist YM155 and the XIAP antagonists Birinapant and GDC-0152. YM155 decreased the cell viability dose dependently in all investigated cell lines, with IC50 values ranging between 4.6 and 23.6 nM (Fig. 2B). In contrast, XIAP inhibitors Birinapant and GDC-0152 exhibited no measurable effect on cancer cell viability (Fig. 2B). As only YM155 demonstrated in vitro cell growth inhibitory effects, we focused our further analysis on this small molecule survivin inhibitor. Comparable to the effect observed on cell viability, YM155 treatment significantly reduced cell proliferation of ESCC and EAC cells as measured by BrdU incorporation (Fig. 2C). Since YM155 has been demonstrated to execute its anti-tumor effects through inhibition of survivin mRNA transcription, we analyzed survivin protein expression in YM155 treated cells using Western blot analysis. As expected, YM155 treatment decreased survivin protein levels in all esophageal cancer cell lines accompanied by a PARP cleavage, indicating apoptotic cell death (Fig. 3). Of note, YM155 also induced a decrease in XIAP expression levels in KYSE270 and KYSE 520 cell lines (Fig. 3).
Discussion
Given their importance in therapy-resistance and tumor progression, IAP family members survivin and XIAP display promising biomarkers and novel druggable targets for innovative anti-cancer therapies (14,28). Notably, both IAPs act synergistically in many respects, as they stabilize each other and realize their antiapoptotic and pro-metastatic functions by direct interaction (13,20). Published data on survivin and XIAP expression in esophageal cancer are in part controversial or even incomplete and none of the studies reported so far has analyzed survivin and XIAP expression in the same cohort of esophageal cancer patients. In ESCC survivin expression could be correlated with clinicopathological parameters and was linked to poor survival in the majority of published studies (29–36). In contrast, the prognostic impact of XIAP expression and its association to pathological variables in ESCC patients has not yet been adequately investigated. To date only one published study exists, demonstrating a correlation of high XIAP expression and poor survival in a collective of ESCC patients treated with adjuvant radiotherapy after radical esophagectomy (37). Moreover, the value of survivin and XIAP expression in EAC patients is even less clear and available data more limited. To the best of our knowledge, studies investigating XIAP expression in EAC patients have not been published yet and only two studies analyzing survivin expression exist. However, the results of these two studies are contradictory. Whereas, Malhotra et al (38) demonstrated an association between high survivin expression and an increased risk of death, Rosato et al (29) detected no prognostic relevance for survivin expression in their collective of 56 EAC patients. Furthermore, both studies did not comprehensively analyze correlations between survivin expression and clinicopathological parameters.
Consistent with, previous reports we could show that cytoplasmic and nuclear survivin, as well as XIAP expression are significantly increased in EAC and ESCC tissue specimens, when compared to non-malignant tumor adjacent mucosa (32,38–40). This cancer specific expression pattern represents an important basis for the use of both proteins in targeted therapies. Another interesting finding of our analysis was the observation that expression levels of cytoplasmic survivin and XIAP were significantly correlated in EAC specimens, indicating the important role of their intermolecular cooperation. Interestingly, Dohi et al (20,41) could demonstrate that survivin and XIAP interaction predominantly takes place inside the mitochondria and cytoplasm. Particularly non-phosphorylated, mitochondrial survivin stabilizes XIAP and protects it from polyubiquitination and subsequent proteosomal degradation (20,41).
Whereas in EAC patients a correlation between survivin or XIAP expression levels and clinicopathological parameters became not evident, in ESCC high XIAP expression was associated with female gender and advanced tumor stages. In addition, nuclear survivin was linked to poorly differentiated (G3) ESCC. Consistent with our findings, Zhou et al (37) detected high XIAP expression levels in advanced ESCC and Takeno et al (30) revealed that increased survivin expression levels were associated with poorly differentiated esophageal cancer. Thus, suggesting a potential role of both IAPs in ESCC progression.
Although a prognostic value of survivin expression in esophageal cancer has been reported by several studies (29–33,36,38), there exist some conflicting data (29,42,43). In this context, our analysis revealed no significant correlation between survivin expression and overall survival in ESCC or EAC patients. In contrast to survivin, much less effort has been spent in investigating the prognostic value of XIAP expression in esophageal cancer. To date, only Zhou et al (37) reported that high levels of XIAP expression were associated with poor outcome in ESCC patients. Of note, our analysis verified the prognostic relevance of XIAP in ESCC patients. However, for EAC patients a prognostic relevance of XIAP became not evident.
To elucidate the potential of an IAP directed therapy in esophageal cancer we made use of the most advanced small-molecule survivin inhibitor YM155, known to repress survivin promoter activity by disrupting proteins like SP1 and interleukin enhancer-binding factor-3 (44,45). In this context, Qin et al (46) and Zhao et al (47) published promising results concerning the antitumor effects of YM155 treatment in ESCC cell lines. However, to the best of our knowledge, for the first time we report also effects of YM155 in EAC. We could show that the small molecule survivin inhibitor effectively reduces survivin expression, cell viability and proliferation in esophageal cancer cell lines, irrespective of their histologic subtype. In addition, we detected considerable PARP cleavage in all investigated EAC and ESCC cell lines after YM155 treatment, indicating apoptotic cell death (48). Consistent with our results, Qin et al (46) demonstrated decreased cell viability and survivin expression as well as a significant PARP cleavage in YM155 treated ESCC cells. Moreover, they reported that the small-molecule survivin inhibitor enhanced radiosensitization by the abrogation of G2 checkpoint and the inhibition of homologous recombination repair (46). In contrast to our findings, Zhao et al (47) observed that YM155 did not trigger apoptosis, but induced parthanatos, a cell death depending on PARP-1 hyper-activation in ESCC cell lines KYSE410 and KYSE150 (47). However, the key message of both published studies investigating the effects of YM155 treatment in esophageal cancer so far is that YM155 kills esophageal cancer cells and represents a promising tool for novel therapeutic approaches in esophageal cancer patients.
In addition, we tested the effects of the small molecule XIAP antagonists Birinapant and GDC-0152. Both compounds mimic the effects of the second mitochondrial-derived activator of caspases (Smac), which acts as an endogenous antagonist of XIAP, cIAP1 and cIAP2 (49–51). In contrast to YM155, both small molecule IAP antagonists failed to achieve cytotoxic effects on esophageal cancer cells in vitro. Although smac mimetics have been shown to promote cell death by competing with caspases for binding to the BIR domains of XIAP, cIAP1 or cIAP2 (52–54), these IAP-antagonizing compounds turned out to exhibit single agent activity only in a small subset of tumor cells (54,55). This observation might be explained by different mechanisms contributing to Smac mimetic resistance in malignant cells including a tumor necrosis factor α (TNFα) mediated up-regulation of cIAP2, the inability to form a ripoptosome complex or a defective PI3K signaling pathway (56,57).
In conclusion, our analysis of survivin and XIAP protein expression in esophageal cancer tissue specimens revealed that only XIAP may be regarded as a prognostic marker in ESCC but not in EAC. In addition, small-molecule survivin inhibitor YM155 induced impressive cytotoxic effects on esophageal cancer cells in vitro even at nanomolar concentrations. Unfortunately small molecule XIAP antagonists did not exhibit single agent activity in our experiments. However, as they might be effective in combination therapies with other chemotherapeutics or radiation, we suggest that future studies should investigate the efficacy of Smac mimetic-based combination therapies in esophageal cancer.
Despite the limitations of the study including its retrospective design and the lack of in vivo experiments, our findings underline the potential role of survivin and XIAP in the oncogenesis of esophageal cancer and provide a rationale for future clinical studies investigating the therapeutic efficacy of IAP directed therapies in esophageal cancer patients.
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