Poor prognosis in cholangiocarcinoma patients with low FBXW7 expression is improved by chemotherapy
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- Published online on: March 29, 2017 https://doi.org/10.3892/ol.2017.5946
- Pages: 3653-3661
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Copyright: © Ishii et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
The incidence of cholangiocarcinoma (CC), which is a major cause of cancer-associated mortality in Asia, is rising worldwide (1). Despite recent advances in cancer therapy, it is difficult to completely cure CC as radical surgical resection is the only effective curative treatment (2). Additionally, chemotherapy regimens for patients with CC with recurrent and metastatic lesions have been insufficient. However, small populations of patients with CC have obtained significant benefits from conventional chemotherapy (3,4). Therefore, to improve patient prognoses and risk assessments, additional studies are required to identify novel markers and therapeutic targets.
F-box and WD repeat domain-containing 7 (FBXW7), which is an F-box protein consisting of 1 of the 4 subunits of the Skp Cullin F-box containing ubiquitin ligase complex, induces the degradation of oncoproteins including c-Myc, CyclinE, mammalian target of rapamycin (mTOR), Notch and myeloid cell leukemia 1 (MCL1) via ubiquitin-mediated degradation pathways (5,6). The degradation of c-Myc by FBXW7 leads to cell cycle dormancy or the G0 state, therefore, FBXW7 alteration serves an important role in, and is a major cause of, carcinogenesis (7). Takeishi et al (8) revealed that ablation of the FBXW7 gene in mouse leukemia-initiating cells of chronic myeloid leukemia induced cell cycle re-entry via accumulation of c-Myc, and subsequently increased the sensitivity of the cells to chemotherapy. Concomitantly, it is known that loss of FBXW7 function is associated with resistance to anti-tubulin agents via the accumulation of the anti-apoptotic protein MCL1, a member of the B-cell lymphoma 2 family (9). Therefore, the role of FBXW7 in chemosensitivity is controversial.
In a previous study of clinical samples, low FBXW7 expression levels were associated with poor prognosis and cancer progression in a number of human malignancies including breast cancer (10), hepatocellular (11) and esophageal carcinoma (12,13). In intrahepatic and perihilar CC, it was demonstrated that low FBXW7 expression levels are associated with cancer progression and the increase of migration and invasion rates due to the accumulation of mTOR, an FBXW7 degradation target, as demonstrated in vivo and in vitro (14). Furthermore, Enkhbold et al (15) revealed that low FBXW7 expression levels in clinical samples of intrahepatic CC were associated with significantly poor prognosis, although their number of cases was small. However, few studies have addressed the role of FBXW7 in the prognosis and chemosensitivity of patients with CC, whether intrahepatic or extrahepatic disease.
The purpose of the present study was to determine the clinical significance of FBXW7 expression in CC. The expression levels of FBXW7 were investigated in CC tissue samples using immunohistochemistry to evaluate whether this protein qualifies as a marker of poor prognosis and chemosensitivity for patients with this disease.
Materials and methods
Patients and samples
A total of 100 patients with CC who underwent surgical resection at the Gunma University Hospital (Maebashi, Japan) and the Gunma Prefecture Saiseikai-Maebashi Hospital (Maebashi, Japan) between January 1996 and December 2011 were included in the present study. There were 69 males and 31 females. The mean age of patients was 68.1 years, range, 36–94 years. Intra- and extrahepatic CC were diagnosed in 14 and 86 patients, respectively. Operative procedures were as follows: Among patients diagnosed with intrahepatic CC, 11 underwent right or left hepatectomy and 3 underwent sectionectomy, and among those diagnosed with extrahepatic CC, 14 underwent hepatectomy with bile duct resection, 63 underwent pancreatoduodenectomy, 3 underwent hepato-pancreatoduodenectomy and 6 underwent bile duct resection alone. For all cases, lymph node dissection was performed according to the location of the tumor. The median follow-up period for survivors was 30.4 months, range, 2.2–115.2 months. The pathological stage of CC was determined according to the 7th edition of tumor-node-metastasis (TNM) classification of Union for International Cancer Center (16). A total of 80 patients were staged as R0, no local residual tumor, and 20 patients were staged as R1, microscopic residual tumor. Recurrence occurred in 56 patients, while 64 patients received chemotherapy. Chemotherapy was recommended for all patients, however, those with dysfunction of the vital organs and those who chose not to receive chemotherapy were excluded. The details of chemotherapy are as follows: 30 patients received tegafur/gimeracil/oteracil (S-1), 24 received gemcitabine, 17 received tegafur-uracil, 7 received gemcitabine + S-1, and 2 received gemcitabine + cisplatin, including overlap. None of the patients had received neoadjuvant chemotherapy and irradiation prior to surgical resection. Patient backgrounds are summarized in Table I. Written informed consent was obtained from all patients included in the present study, which was approved by the institutional review board at Gunma University Hospital.
Immunohistochemical staining
A paraffin-embedded block of CC specimens was cut into 2-µm thick sections and mounted on glass slides. Each section was deparaffinized by xylene and dehydrated in alcohol. Endogenous peroxidase was inhibited using 0.3% H2O2/methanol for 30 min at room temperature. The sections were soaked in heated water with 0.5% Immunosaver (Nisshin EM Co. Ltd., Tokyo, Japan) at 98°C for 45 min. Non-specific antigens were blocked by Protein Block, Serum-Free (Dako; Agilent Technologies, Inc., Santa Clara, CA, USA) at room temperature for 30 min. The sections were then incubated with rabbit polyclonal primary antibody against FBXW7 (cat. no., ab109617; dilution, 1:300; Abcam, Cambridge, MA, USA) for 24 h at 4°C. Subsequent to washing in PBS, the Histofine Simple Stain MAX-PO (MULTI) kit (Nichirei Biosciences, Inc., Tokyo, Japan) was applied for visualizing primary antibody and incubated at room temperature for 45 min. The chromogen 3,3′-diaminobenzidine tetrahydrochloride (DAB) was applied as a 0.02% solution containing 0.005% H2O2 in 50 mM ammonium acetate-citrate acid buffer (pH 6.0). Finally, counterstaining of the nucleus was performed using Mayer's hematoxylin solution. A negative control was included by replacing the primary antibody with PBS in 0.1% bovine serum albumin, and confirmed no detectable staining in this case.
Additionally, 3 sequential sections of each sample were treated with primary antibodies against c-Myc (cat. no., ab32072; dilution, 1:50; Abcam) and the cell proliferation marker Ki-67 (cat. no., M7240; dilution, 1:150; Dako; Agilent Technologies, Inc.), according to the aforementioned protocol, to evaluate the correlations between FBXW7, c-Myc and cell proliferation.
Assessment of FBXW7 and c-Myc expression
Nuclear staining of FBXW7 in cancerous tissue was evaluated in 5 randomly selected fields, and the intensity scored. The intensity score ranged from 1 to 3, with 1, weak; 2, moderate; and 3, strong, and was evaluated in each sample.
The expression level of c-Myc was evaluated in the nucleus of the cancerous tissue. The proportion of positively staining tumor cells was evaluated, regardless of the staining intensity. A percentage of positive tumor cells ≥10% was defined as ‘positive’ expression and <10% was defined as ‘negative’ expression (17).
Statistical analysis
Data for the continuous variables were expressed as the mean ± standard deviation, or median and range. The association between FBXW7 expression and clinicopathological characteristics was analyzed using the χ2 test and the Wilcoxon signed-rank test. Survival curves were described using the Kaplan-Meier method, and differences in survival between groups were compared using the log-rank test. Univariate and multivariate analysis by the Cox proportional hazards model was used to identify prognostic factors. P<0.05 was considered to indicate a statistically significant difference. All statistical analyses were performed using the JMP software package (version 10.0.0; SAS Institute Inc., Cary, NC, USA).
Results
Analysis of FBXW7 expression in CC tissues by immunohistochemistry
FBXW7 expressed in the nucleus was measured by immunohistochemistry. Therefore, nuclear FBXW7 expression was evaluated in 100 CC samples. FBXW7 expression was observed in normal bile duct epithelium (Fig. 1A); however, the expression was lower in cancerous areas (Fig. 1B and C). Similarly, FBXW7 expression was reduced at the site of lymph node metastases (Fig. 1E and F). These CC samples were divided into 2 groups according to the intensity of nuclear FBXW7 staining in the cancerous areas. A score of 1 in cancerous tissue samples was considered a low expression level of FBXW7 (Fig. 1B and C); scores of 2 or 3 were considered as high expression (Fig. 1D). A total of 54 samples exhibited high FBXW7 expression, whilst 46 exhibited low FBXW7 expression. Additionally, the correlation among FBXW7, c-Myc and marker of proliferation Ki67 (Ki-67) expression was investigated using immunohistochemistry in 3 sequential sections (Fig. 2). Low FBXW7 expression samples demonstrated enhanced expression of c-Myc and Ki-67 (Fig. 2A), while high FBXW7 expression samples exhibited lower expression of c-Myc and Ki-67 (Fig. 2B). Low FBXW7 expression was significantly associated with nuclear c-Myc accumulation (P<0.001).
Association between FBXW7 expression and clinicopathological characteristics of CC
The clinicopathological characteristics of patients listed according to FBXW7 expression are summarized in Table II. Low FBXW7 expression levels were significantly associated with progressive tumor size (P=0.049). Furthermore, the median recurrence-free survival time of the low FBXW7 expression group was significantly shorter compared with that of the high FBXW7 expression group (P=0.044). However, there were no significant differences with respect to age, sex, histology, tumor stage, lymph node metastasis, recurrence and chemotherapy.
 | Table II.Clinicopathological characteristics according to FBXW7 expression in 100 patients with cholangiocarcinoma. |
Prognostic value of FBXW7 expression in CC
Patients with low FBXW7 expression exhibited significantly poorer prognoses compared with those with high FBXW7 expression in terms of overall and cancer-specific survival (P=0.016 and P=0.007, respectively; Fig. 3A and B). Notably, even in cases of negative lymph node metastasis, the low FBXW7 expression group also exhibited significantly poorer prognosis compared with the high FBXW7 expression group for overall survival (P=0.032; Fig. 3C). The association between FBXW7 expression and survival subsequent to chemotherapy was also examined. In the high FBXW7 expression group, cancer-specific survival times were not significantly different among patients with or without chemotherapy (Fig. 3D). In the low FBXW7 expression group, however, cancer-specific survival times in patients who received chemotherapy were significantly longer compared with that of patients who did not (P=0.001; Fig. 3D). Due to various chemotherapy regimens in the cohort of the present study, a sub-analysis was performed according to chemotherapy regimen, such as S-1, gemcitabine, and tegafur-uracil. However, each regimen demonstrated similar results, and there were no significant differences between the regimens (data not shown). Additionally, the present study considered whether differences in patient characteristics, including exhibiting a more aggressive-stage tumor, may explain the difference in survival outcomes between patients with low FBXW7-expression who underwent chemotherapy compared with those who did not. However, no such differences were observed (Table III). These data therefore suggest that patients with low FBXW7 expression are sensitive to chemotherapy compared with patients with high FBXW7 expression.
| Table III.Association between clinicopathological characteristics and chemotherapy in patients with low FBXW7 expression. |
Univariate and multivariate analyses of overall survival are summarized in Table IV. Low FBXW7 expression was a prognostic factor on univariate analysis, including with histology, tumor stage, lymph node metastasis and recurrence. However, on multivariate analysis, only low FBXW7 expression in CC was an independent poor prognostic factor, thus outweighing the existing clinicopathological factors for overall survival in the cohort of the present study (P=0.043).
| Table IV.Univariate and Multivariate analysis for overall survival using the Cox proportional hazards model. |
Discussion
In the present study, it was demonstrated that low FBXW7 expression levels in the nucleus are associated with tumor size and poor prognosis in patients with CC, and is associated with enhanced c-Myc and Ki-67 expression. Furthermore, the efficacy of chemotherapy differed according to FBXW7 expression levels, as the low FBXW7 expression group was more sensitive to chemotherapy compared with the high FBXW7 expression group.
c-Myc is a target protein of FBXW7, and is regulated and degraded via ubiquitin-proteasome pathways. Therefore, the loss of FBXW7 function results in the accumulation of c-Myc (18,19). Additionally, as c-Myc serves an important role in cell cycle regulation, particularly in G0-G1 phase transition (20), the overexpression of c-Myc in tumors is associated with aggressive proliferation (21,22). It has been demonstrated that hematopoietic stem cells from conditional FBXW7 gene knockout mice exhibited c-Myc accumulation, and were therefore difficult to maintain in a quiescent state, leading to excessive acceleration of their cell cycle, exhaustion and even leukemogenesis (23). Additionally, the suppression of FBXW7 by small interference RNA in human colorectal cancer cell lines resulted in enhanced c-Myc expression and increased proliferation (24). In a previous study of clinical samples, low FBXW7 expression correlated with greater tumor size in gastric cancer and intrahepatic CC (14,25). The present study was consistent with previous findings, as cancer tissue samples with low FBXW7 expression exhibited enhanced nuclear c-Myc and Ki-67 staining. Thus, the data of the present study suggest that the greater tumor sizes observed in the low FBXW7 expression group were caused by an acceleration of the cell cycle, and subsequently of proliferation, due to c-Myc accumulation.
Low levels of FBXW7 protein and/or messenger RNA were revealed to be associated with poor prognoses in breast (10,26), gastric (25), non-small cell lung (27) and esophageal cancer (12,13). The present study demonstrated that low FBXW7 expression in CC was an independent poor prognostic factor that outweighed existing clinicopathological factors, including TNM stage. Thus, the evaluation of FBXW7 expression is a potentially a useful marker for predicting prognosis in patients with CC.
Previously, molecular pathways that regulate FBXW7 stability and cellular functions have been investigated extensively. Gene mutation, copy number variations and transcriptional- and post-transcriptional controls are hypothesized to suppress FBXW7 function in cancer (28). FBXW7 gene alterations are often detected in human malignancies, with the rate identified to be ~6% (29). As for mechanisms for the modification of FBXW7 activity other than gene alteration, previous studies have revealed that FBXW7 is regulated by p53 (30,31), microRNA (miR-223 and miR-27) (32,33) and self-ubiquitination in a phosphorylation-dependent manner (34,35). The mutation rate of FBXW7 in CC is ~15–35%, which is as high as in patients with T-cell acute lymphoblastic leukemia (36,37). These data suggest that FBXW7 mutations serve an important role in CC development, and are one of the important suppression mechanisms of FBXW7 in CC. However, the association between FBXW7 mutations and FBXW7 protein expression, as evaluated by immunohistochemistry in the present study, remains unclear and requires additional investigation.
Previous studies have examined the association between FBXW7 and chemosensitivity. It was demonstrated that low FBXW7 expression produced resistance to anti-tubulin agents such as paclitaxel due to MCL1 accumulation (9,27). Additionally, another report revealed that low FBXW7 expression is associated with resistance to doxorubicin in hepatocellular carcinoma (38). However, FBXW7 depletion in leukemia-initiating cells of chronic myeloid leukemia promotes cell cycle re-entry through c-Myc accumulation, and leads to the high sensitivity to imatinib in leukemia-initiating cells and thus enhanced eradication (8). Thus, FBXW7 has a dichotomous role with respect to chemosensitivity (39). In the present study, the cancer-specific survival in patients with CC with low FBXW7 expression levels who underwent chemotherapy exhibited improved prognosis compared with patients who did not, despite there being no difference in outcomes according to chemotherapy administration in patients with CC with high FBXW7 levels (Fig. 3D). c-Myc accumulation and increased Ki-67 positive cells were also confirmed in the low FBXW7 expression group. Notably, it was demonstrated that the overexpression of c-Myc sensitized pancreatic cancer cell lines to cisplatin (40), and that pediatric medulloblastoma cells are sensitive to chemo- and radiation therapy because of their high c-Myc expression (41). Based on these observations, it appears that c-Myc accumulation as regulated by FBXW7 induces chemosensitivity in patients with clinical CC. The evaluation of FBXW7 expression in CC clinical samples may contribute to predicting the efficacy of chemotherapy and selecting those patients who are expected to benefit from it.
The present study had several limitations, including the retrospective design, single-center cohort and disease heterogeneity, such as intra- and extrahepatic disease, and heterogeneous treatment groups. In particular, as aforementioned, a sample bias of patients according to receipt of chemotherapy was an important issue in the present study, as patients who did not wish to undergo chemotherapy were excluded from the adaptation criteria of chemotherapy. Accordingly, additional studies in larger series, preferably prospective multi-center cohorts, are required to confirm these data.
In conclusion, low expression levels of the cell cycle regulator and tumor suppressor FBXW7 contributed to shorter survival and greater tumor size in patients with CC. The evaluation of FBXW7 expression levels may therefore be a useful predictor of poor prognosis and cancer progression in CC, particularly extrahepatic CC, considering the cohort of the present study. Conversely, low FBXW7 expression was associated with prolonged survival times in patients with CC treated by chemotherapy; this suggests that FBXW7 may be a surrogate marker for predicting the efficacy of chemotherapy in CC.
Acknowledgements
The present study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS; grant numbers 26461969, 15K10129 and 15K10085). The present study was also supported in part by Uehara Zaidan, the Medical Research Encouragement Prize of The Japan Medical Association, the Promotion Plan for the Platform of Human Resource Development for Cancer and New Paradigms - Establishing Centers for Fostering Medical Researchers of the Future programs by the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Gunma University Initiative for Advanced Research (GIAR).
Glossary
Abbreviations
Abbreviations:
|
CC |
cholangiocarcinoma |
|
FBXW7 |
F-box and WD repeat domain-containing 7 |
|
TNM |
tumor-node-metastasis |
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