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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 4  |  Page : 1076-1081

Comparison of clinicopathological parameters with FoxM1 expression in renal cell carcinoma


1 Department of Pathology, Faculty of Medicine, Harran University, Sanliurfa, Turkey
2 Department of Pathology, Sanliurfa Balikligol State Hospital, Sanliurfa, Turkey
3 Department of Urology, Faculty of Medicine, Harran University, Turkey
4 Department of Pathology, Faculty of Medicine, Kocatepe University, Afyonkarahisar, Turkey

Date of Web Publication9-Jan-2015

Correspondence Address:
Sezen Kocarslan
Department of Pathology, Faculty of Medicine, Harran University, Yenisehir campus, Sanliurfa
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.137988

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 > Abstract 

Aim: To investigate the relationships between expression of forkhead box M1 (FoxM1) and clinicopathologic parameters and Ki-67 expression in patients with renal cell carcinoma (RCC).
Materials and Methods: A total of 67 cases of RCC including 47 cases of clear cell RCC (ccRCC), five cases of papillary RCC (pRCC), eight cases of chromophobe RCC (chRCC), four cases of unclassified (with sarcomatoid pattern) RCC (sRCC), and three cases of multilocular RCC (mRCC) were included to this study. The expression of FoxM1 protein was assessed in 67 samples of RCC using immunohistochemical methods and the relationship between the expression levels of FoxM1 with clinicopathological characteristics and Ki-67 expression of RCC patients. For statistical analysis, the cases were grouped into the ccRCC and non-ccRCC group.
Results: Immunohistochemistry analyses showed that FoxM1 protein expression in 47 ccRCC samples was significantly correlated with tumor size, stage, nuclear grade, capsule invasion, perinephric fat invasion, and Ki-67 expression (P < 0.05 for all); whereas, no correlations were found in patients' age, gender, and lymph node metastasis (P > 0.05 for all). In 20 non-ccRCC; overexpression of FoxM1 was strongly associated with tumor size (P < 0.05). There was no relationship between FoxM1 expression with other clinicopathological parameters and Ki-67 expression in non-ccRCC (P > 0.05 for all).
Conclusion: This study showed that FoxM1 have a progressive oncogenic role in ccRRC. Our results suggested that higher expression of FoxM1 in tumor tissues predicts a locally aggressive behavior and poor outcome of patients with ccRCC, but not in patient with non-ccRCC.

 > Abstract in Chinese 

肾细胞癌的临床病理参数与FOXM1表达的比较

摘要

目的:探讨肾细胞癌(RCC)患者FOXM1表达、临床病理参数和Ki-67的表达之间的关系。

材料和方法:共67例肾细胞癌(RCC),包括透明细胞癌(ccRCC)47例,乳头状癌(pRCC)5例,嫌色细胞癌(chRCC)8例,未分类的4例(伴肉瘤样型)(sRCC),和多房性肾癌(mRCC)3例。采用免疫组化方法测定FOXM1蛋白在67例RCC的表达,评价FOXM1表达与临床病理参数、Ki -67表达水平之间的关系。为了统计分析,病例分为透明细胞癌组和非透明细胞癌组。

结果:免疫组化分析表明47例ccRCC样本FOXM1蛋白表达与肾透明细胞癌肿瘤大小,阶段,核级,包膜浸润,肾周脂肪浸润,及Ki -67的表达显著相关(P<0.05);发现与患者年龄、性别和淋巴结转移没有相关(P > 0.05)。在20例非透明细胞癌中, FOXM1过度表达与肿瘤大小密切相关(P<0.05),而与其他临床病理参数及Ki- 67的表达没有相关性(P>0.05)。

结论:本研究表明FOXM1在ccRRC中有渐进的致癌作用。我们的研究结果表明,透明细胞癌患者肿瘤组织中FOXM1的高表达预示局部侵袭性行为,预后差,但在非透明细胞癌病人中不是这样。

关键词:临床病理参数,FOXM1,Ki-67,免疫组织化学,肾细胞癌


Keywords: Clinicopathological parameter, FoxM1, Ki-67, immunohistochemistry, renal cell carcinoma


How to cite this article:
Kocarslan S, Guldur ME, Ekinci T, Ciftci H, Ozardali HI. Comparison of clinicopathological parameters with FoxM1 expression in renal cell carcinoma. J Can Res Ther 2014;10:1076-81

How to cite this URL:
Kocarslan S, Guldur ME, Ekinci T, Ciftci H, Ozardali HI. Comparison of clinicopathological parameters with FoxM1 expression in renal cell carcinoma. J Can Res Ther [serial online] 2014 [cited 2019 Nov 17];10:1076-81. Available from: http://www.cancerjournal.net/text.asp?2014/10/4/1076/137988


 > Introduction Top


Renal cell carcinoma (RCC) arises from the epithelium of the renal tubule and is the most common neoplasm of kidney in the adult. They account for nearly 90% of renal tumors and 3% of adult malignancies. It is the 12 th most common site in men and 17 th in women. The neoplasms of the kidney are classified by using the World Health Organization (WHO) 2004 system. This system describes tumor subtypes with distinct histopathologic features, clinical behavior, and genetic alterations. The most common histologic type of RCC is clear cell carcinoma (ccRCC; 75-85%). Papillary and chromophobe subtypes (pRCC and chRCC) constitute 10 and 5%, respectively. Multilocular RCCs (mRCCs) make up small groups of RCCs and unclassified RCC amounts to 4-5% of cases. [1] This classification is important for clinical management of renal tumors. RCCs have high potential of metastases and at diagnosis, only 30-40% have localized disease whilst 25-30% will have metastatic cancer. [2] Therefore, it is crucial to anticipate the prognosis of RCC patients for planning and improving treatment methods. The prognosis of RCC patients is usually affected by some clinicopathological parameters such as, tumor size and stage and Fuhrmann nuclear grade. These clinical parameters are useful for prognostication whilst there are helpful methods. There is still lack of specific molecular markers to predict the prognosis of RCC patients. In recent years, it has been proposed that specific prognostic markers for ccRCC including p53, CD-44, CD-95, B7-H4, pAkt, adipose differentiation-related protein, gammaenolase, IMP3, Ki67, and G250/CAIX; though large-scale clinical application is impossible. Despite the consecutive progress in medical technology, the clinical characteristics of RCC remain difficult to predict. [3] Therefore, novel prognostic markers of RCC could be beneficial.

Forkhead box M1 (FoxM1) is a proliferation-associated transcription factor. [4] It has different functions in tumorigenesis and its elevated levels are generally associated with cancer progression. Some studies have showed that FoxM1 is one of the most common overexpressed genes in human solid tumors. [5] Several studies have recorded that FoxM1 expression is significantly correlated with primary tumor stage and aggressive phenotype of ccRCC. These studies evaluated FoxM1 levels in only ccRCC patients, not in the other types of RCC. [6],[7] Beyond these studies, the present study was aimed to investigate the relationship between expression of FoxM1 and clinicopathologic parameters of patients with ccRCC and non-ccRCC including patients' age, gender, tumor nuclear grade, tumor size, stage, lymph node metastasis, and tumor subtypes. Moreover, we aimed to evaluate the association between the FoxM1 and Ki-67, a well-established proliferation and progression marker in RCC, levels.


 > Materials and Methods Top


Patients

A total of 67 cases of RCC including 47 cases of clear cell RCC (ccRCC), five cases of pRCC, eight cases of chRCC, four cases of unclassified (with sarcomatoid pattern) (sRCC), and three cases of mRCC were retrospectively collected by retrieval of the pathology reports of patients who underwent curative surgery for RCC at the hospital of the Harran University between 2002 and 2012. The paraffin blocks and slides of each patient were retrieved from the archive. The clinicopathological parameters of the patients were re-evaluated by a review of the patients' medical records and slides. Patients receiving chemotherapy or radiotherapy before surgery were excluded from this study. The tumors were graded according to Fuhrman's nuclear grading system. The TNM stage was determined according to the seventh edition of the American Joint Committee on Cancer (AJCC) staging system. Additionally, for statistical analysis, the cases were grouped into the ccRCC group, and the non-ccRCC group. The study was approved by institutional review board of the Harran University.

Immunohistochemical staining for FoxM1

All tissue samples were fixed in 10% formaldehyde solution and embedded in paraffin blocks. Paraffin blocks containing representative tumor were selected after review of the corresponding tumor identified. All blocks were cut in 4-μm-thick sections, These slides were deparaffinized with xylene and rehydrated in graded ethanol (100-95-75%), followed by boiling in 10 mmol/L of ethylenediaminetetraacetic acid (EDTA) buffer (pH 8.0) for antigen retrieval. After inhibition of endogenous peroxidase activities for 5 min with 3% H 2 O 2 , and incubation overnight at 4΀C with primary polyclonal rabbit antihuman FoxM1 antibody (Biorbyte Biotechnology Inc, 1:50 dilution). After washing thrice with phosphate-buffered saline (PBS), the slides were incubated with horseradish peroxidase conjugated goat anti-rabbit IgG for 60 min, followed by reaction with diaminobenzidine (DAB) cromogen and counterstaining with Mayer hematoxylin. Samples incubated with PBS instead of primary antibodies were used as negative controls.

Immunohistochemical staining for Ki-67

All blocks were cut in 4-μm-thick sections. These slides were deparaffinized with xylene and rehydrated in graded ethanol (100-95-75%), followed by boiling in 10 mmol/L of citrate buffer (pH 6.0) for antigen retrieval. After inhibition of endogenous peroxidase activities for 5 min with 3% H 2 O 2 , the tissue sections were incubated with primary monoclonal mouse antibodies against Ki67 (Biogenex Biotechnology). After washing thrice with PBS, the slides were incubated with horseradish peroxidase conjugated goat anti-rabbit IgG for 60 min, followed by reaction with DAB cromogen and counterstaining with Mayer hematoxylin. Samples incubated with PBS instead of primary antibodies were used as negative controls.

Evaluation of immunohistochemical staining

FoxM1 staining

FoxM1 antigen staining was localized to the cytoplasm. Each section was evaluated and scored by two pathologists in a blinded fashion without any learning of the clinical event or other clinicopathological details. The predetermined scoring system by Xue et al., was used. [6] Immunohistochemical staining of FoxM1 was evaluated using a semiquantitative scoring system for both staining intensity and the percentage of positive cells. A score was calculated by multiplying the intensity (negatively scored as 0, mildly scored as 1, moderately scored as 2, and strongly scored as 3) by percentage of stained cells (0, <5%; 1, 5-25%; 2, 26-50%; 3, 51-75%; and 4, 76-100%; respectively). Scores of multiplication were graded as follows: -, 0; +, 1-3; ++, 4-8; and +++, 9-12. Additionally, for statistical analysis, the - and 1+ cases were pooled into the low-expression group, and the 2+ and 3+ cases were pooled into the high-expression group.

Ki-67 Staining

Ki-67 antigen staining was localized to the nucleus. After scanning the slides at low magnification to determine the most evenly stained tissue areas, a minimum of 1,000 tumor cells were counted at high power, and the number of labeled cells was calculated as a percentage of the total cell count. 0 - no nuclear staining is observed in tumor cells; 1 - nuclear staining is detected in 1-10% of the tumor cells; 2-11-20%; 3->20%. Additionally, for statistical analysis, the 0 and 1 proliferation levels were pooled into the low-expression group, and the 2 and 3 proliferation levels were pooled into the high-expression group.

Statistical analysis

Statistical data were analyzed using Statistical Package for Social Sciences (SPSS Inc, Chicago, IL, USA, version 11.5) software. The association between the FoxM1 expression and clinicopathological parameters was explored with Pearson Chi-square and Fisher's exact test. P values less than 0.05 were regarded as statistically significant and two-sided tests were used for all analyses.


 > Results Top


The clinical and pathological characteristics of the RCC patients

The patients included 31 (46.3%) men and 36 (53.7%) women. The mean age was 58.5 years (range, 23-85 years) and the mean tumor size was 8.31 cm (range, 2-21 cm). According to Fuhrman's nuclear grading system; of the RCC cases, five (7.5%) showed Fuhrman nuclear grade 1, 29 (43.3%) showed Fuhrman nuclear grade 2, 26 (38.8%) showed Fuhrman nuclear grade 3, and the remaining seven (10.4%) were Fuhrman nuclear grade 4. According to the seventh edition of the AJCC staging system; 19 (28.4%) cases were classified as pT1, 27 (40.3%) cases were classified as pT2, and 21 (31.3%) cases were classified as pT3. Lymph node dissection was performed in 51 (76.1%) of the 67 cases. Of the 67 cases, 40 (59.7%) were classified as pN0, 11 (16.4%) were classified as pN1, and 16 (23.9%) were classified as pNx.

Immunohistochemical expression of FoxM1 and its relationship with clinicopathological parameters

In the FoxM1 staining; the cell cytoplasm staining were observed in RCC cells in all RCC tissue samples, positive staining signals of FoxM1 were detected in 28 (41.8%) with low immunoreactivity and in 39 (58.2%) with high immunoreactivity. In ccRCC tissue samples, positive staining signals of FoxM1 were detected in 17 (36.2%) with low immunoreactivity and in 30 (63.8%) with high immunoreactivity [Figure 1]a and b. In non-ccRCC tissue samples, positive staining signals of FoxM1 were detected in 11 (55.0%) with low immunoreactivity and in nine (45.0%) with high immunoreactivity, respectively [Figure 2]a and b. In five pRCC tissue samples, positive staining signals of FoxM1 were detected in three (60.0%) with low immunoreactivity and in two (40.0%) with high immunoreactivity. In chRCC tissue samples, positive staining signals of FoxM1 were detected in one (12.5%) with low immunoreactivity and in seven (87.5%) with high immunoreactivity. In four sRCC tissue samples, positive staining signals of FoxM1 were detected in four (100%) with low immunoreactivity. In three mRCC tissue samples, positive staining signals of FoxM1 were detected in three (100%) with low immunoreactivity. ccRCC and non-ccRCC cases were comparable with regard to FoxM1 expression (P = 0.154). The association between clinicopathological characteristics and tumor cell FoxM1 expression (low vs high) has been summarized in [Table 1] and [Table 2]. In ccRCC; the relationship between FoxM1 expression and tumor size, tumor stage, nuclear grade, capsule invasion, and perinephric fat invasion was statistically significant as shown in [Figure 3]a-c (P = 0.001, P = 0.026, P = 0.016, P = 0.001, and P = 0.028, respectively). There was no significant correlation of the FoxM1 expression with patients' age, gender, and lymph node metastasis (P = 0.753, P = 0.679, P = 0.249; respectively). In non-ccRCC, the relationship between FoxM1 expression and tumor size was statistically significant (P = 0.022). There was no significant correlation of the FoxM1 expression with other clinicopathological parameters of patients (P > 0.05).
Figure 1: Immunohistochemical staining of forkhead box M1 (FoxM1) in clear cell renal cell carcinoma (ccRCC). (a) FoxM1 staining was considered as high expression in this ccRCC sample (original magnification, ×400), (b) FoxM1 staining was considered as low expression in this ccRCC sample (original magnification, ×400)

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Figure 2: Immunohistochemical staining of FoxM1 in non-ccRCC. (a) FoxM1 staining was considered as high expression in this papillary RCC sample (original magnification, ×400). (b) FoxM1 staining was considered as low expression in this papillary RCC sample (original magnification, ×400)

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Figure 3: In ccRCC the relationship between FoxM1 expression and pathological parameters, (a) In ccRCC the relationship between FoxM1 expression and primary tumor size. (b) In ccRCC the relationship between FoxM1 expression and primary tumor stage. (c) In ccRCC the relationship between FoxM1 expression and Fuhrman nuclear grade

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Table 1: FoxM1 protein expression in 47 ccRCC tissues determined by immunohistochemistry


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Table 2: FoxM1 protein expression in 20 non-ccRCC tissues determined by immunohistochemistry


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Immunohistochemical expression of Ki-67 and its relationship with FoxM1 expression

In all RCC tissue samples, positive staining signals of Ki-67 were detected in 36 (53.7%) with low immunoreactivity and in 31 (46.3%) with high immunoreactivity. In ccRCC tissue samples, positive staining signals of Ki-67 were detected in 22 (46.8%) with low immunoreactivity and in 25 (53.2%) with high immunoreactivity [Figure 4]a and b. In non-ccRCC tissue samples, positive staining signals of Ki-67 were detected in 14 (70%) with low immunoreactivity and in six (30%) with high immunoreactivity. Positive significant correlation was found between the FoxM1 and Ki-67 levels in ccRCC (P < 0.001); whereas, no significant correlation was found between the FoxM1 and Ki-67 levels in non-ccRCC (P = 0.336).
Figure 4: (a) Ki-67 staining was considered as low expression in this ccRCC sample (original magnification, ×400), (b) Ki-67 staining was considered as high expression in this ccRCC sample (original magnification, ×400)

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 > Discussion Top


To the best of our knowledge, this is the first report investigating FoxM1 levels both in ccRCC and non ccRCC patients, and is the first comparing FoxM1 with Ki-67 expressions in RCC. The main findings of the present study were that: (i) FoxM1 expression was associated with advanced tumor stage, nuclear grade, and tumor size in ccRCC, (ii) FoxM1 expression was correlated with Ki-67 expression in patients with ccRCC.

FoxM1 was first identified as a mitotic phase phosphoprotein (MMP2). It is a member of winged helix transcription factor family. [8],[9] Previous studies have showed that FoxM1 have an oncogenic role in preponderance of human cancers since it is upregulated in various cancer types. Teh et al., have shown that FoxM1 was upregulated in basal cell carcinomas. [10] Li et al., have indicated that FoxM1b directly regulated vascular endothelial growth factor (VEGF) gene transcription, which is at least partially responsible for FoxM1b-mediated promotion of human gastric cancer angiogenesis, growth, and metastasis. [11] Gemenetzidis et al., have revealed that FoxM1 was upregulated early during oral cancer progression. [12] Nakamura et al., have shown that FoxM1 was aberrantly expressed in acute myelogenous leukemia (AML) cells and has an important role in their proliferation. They have elucidated that inhibition of FoxM1 represented an attractive target for leukemia therapy. [13] Chu et al., have proposed that FoxM1 overexpression is a molecular marker predicting increased invasive/metastatic potential of colorectal carcinoma and a poorer prognosis. [14] It is clear that FoxM1 plays a crucial role in tumorigenesis. FoxM1 expression level has been shown in numerous types of human cancer to be dose-dependently correlated with tumor progression starting from cancer predisposition and initiation of early premalignancy and progression to metastatic invasion. [13],[15] Therefore, the inhibition of FoxM1 expression would block steps of all the tumorigenesis.

Unfortunately there were few reports about relationship between expression of FoxM1 and clinicopathological characteristics of patients with RCC. [6],[7] Wu et al., have evaluated the expression of FoxM1 and have investigated its clinical and prognostic significance in 87 patients with ccRCC. They have reported that FoxM1 was overexpressed in ccRCC, and its expression level was strongly associated with ccRCC tumor stage and tumor recurrence. FoxM1 protein expression was not associated with age, tumor grade, and tumor size. [7] Xue et al., have evaluated the expression of FoxM1 by using real-time quantitative polymerase chain reaction (PCR), Western blot, and immunohistochemistry, and have investigated its clinical and prognostic significance in 83 patients with ccRCC. They have demonstrated that the FoxM1 expression was upregulated in the majority of the ccRCC tissue specimens at both mRNA and protein levels. They have determined that overexpression of FoxM1 was positively correlated with the aggressive phenotype of ccRCC and predicted poor survival of patients. It has been presented that downregulation of FoxM1 in ccRCC resulted in the inhibition of migration, invasion, and angiogenesis. [6] In the current study, we investigated whether immunohistochemical FoxM1 expression might be associated with the progression of RCC in 67 patients and our findings depicted that overexpression of FoxM1 was strongly associated with advanced tumor stage, nuclear grade, and tumor size in ccRCC. There was no relationship between FoxM1 expression with patients' age, gender, and lymph node metastasis. The present study mainly supports findings of Xue et al., and Wu et al., as all three studies have revealed increased FoxM1 expression in various circumstances of RCC. Wu et al., have revealed in case of advanced tumor stage and recurrence despite no association of FoxM1 expression with tumor grade and size; whereas, Xue et al., have revealed association of FoxM1 expression with advanced tumor grade, stage, lymph node, and distant metastasis. Our study mainly differs from these two studies regarding the evaluation of non ccRCC patients, and analyzing and comparing the Ki-67 with FoxM1 levels.

It is well-established and proved that Ki-67 is a proliferation marker that is present in all proliferating cells, and value of the Ki-67 index has become reliable method of obtaining information on the proliferative capacity of tumors. Published series confirm that Ki-67 has important role of cell proliferation in RCC progression. [16],[17],[18] In our study, we also reveal a positive correlation between expression levels of Ki-67 and FoxM1 in ccRCC. Although not definitively, this would demonstrate that FoxM1 as a proliferation marker of ccRCC and predicts its progression.

Certain limitations of the present study should be considered. First, this is a retrospective study and sample size was relatively small. Second, more detailed information would be gained by assessing the FoxM1 expressions, along with disease-free survival the investigation would perhaps provide deeper insight into increased expression of FoxM1 in patients with RCC and might add to the value of our manuscript.


 > Conclusion Top


In summary, all of these studies have showed that FoxM1 have a progressive oncogenic role in ccRRC. The results of our study suggested that higher expression of FoxM1 in tumor tissues predicts a locally aggressive behavior and poor outcome of patients with ccRCC, but not in patient with non-ccRCC. Regarding the various features of FoxM1, further large-scale researches are needed to confirm/exclude the potential role of FoxM1 as a marker for advanced ccRCC and as a novel target for anticancer therapy in ccRCC. We think that this study should be supported by further studies.

 
 > References Top

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Wu XR, Chen YH, Liu DM, Sha JJ, Xuan HQ, Bo JJ, et al. Increased expression of forkhead box M1 protein is associated with poor prognosis in clear cell renal cell carcinoma. Med Oncol 2013;30:346.  Back to cited text no. 7
    
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Teh MT. FOXM1 coming of age: Time for translation into clinical benefits? Front Oncol 2012;2:146.  Back to cited text no. 8
    
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Wang IC, Zhang Y, Snyder J, Sutherland MJ, Burhans MS, Shannon JM, et al. Increased expression of FoxM1 transcription factor in respiratory epithelium inhibits lung sacculation and causes Clara cell hyperplasia. Dev Biol 2010;347:301-14.  Back to cited text no. 9
    
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Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res 2002;62:4773-80.  Back to cited text no. 10
    
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Li Q, Zhang N, Jia Z, Le X, Dai B, Wei D, et al. Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression. Cancer Res 2009;69:3501-9.  Back to cited text no. 11
    
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Gemenetzidis E, Bose A, Riaz AM, Chaplin T, Young BD, Ali M, et al. FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation. PLoS One 2009;4:e4849.  Back to cited text no. 12
    
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Nakamura S, Hirano I, Okinaka K, Takemura T, Yokota D, Ono T, et al. The FOXM1 transcriptional factor promotes the proliferation of leukemia cells through modulation of cell cycle progression in acute myeloid leukemia. Carcinogenesis 2010;31:2012-21.  Back to cited text no. 13
    
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Chu XY, Zhu ZM, Chen LB, Wang JH, Su QS, Yang JR, et al. FOXM1 expression correlates with tumor invasion and a poor prognosis of colorectal cancer. Acta Histochem 2012;114:755-62.  Back to cited text no. 14
    
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Gemenetzidis E, Elena-Costea D, Parkinson EK, Waseem A, Wan H, Teh MT. Induction of human epithelial stem/progenitor expansion by FOXM1. Cancer Res 2010;70:9515-26.  Back to cited text no. 15
    
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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