| Abstract|| |
Context : Exon 3 mutation of β-catenin is associated with the carcinogenesis. Aims: In this study we aimed to detect the expression of exon 3 mutations of β-catenin in colorectal TSA, TA/VTA, and CRC. Materials and Methods : Immunohistochemistry staining for β-catenin was performed for 30 TSA, 20 tubular adenomas (TA)/villous tubular adenomas (VTA), and 21 colorectal carcinoma (CRC) cases. DNA sequencing of the exon 3 of β-catenin gene was performed for 8 TSA cases, 6 TA cases, 5 VTA cases, and 10 CRC cases with positive staining in the nuclei and cytoplasm. Statistical Analysis: A Fisher exact test and chi-square test were used to analyze the differentiations of the expression of β-catenin in TSA, TA/VTA, and CRC. Results : The percentages of β-catenin expression in TSA, TA/VTA, and CRC were 76.6% (23/30), 70.0% (14/20), and 95.2% (20/21), respectively, and were significantly different among these three types of tissue specimens (χ2 = 22.805, P < 0.001). Although β-catenin expression levels in TSA were not related to it in TA/VTA, they were significantly different between TSA/TA/VTA and CRC. The degree of dysplasia was well correlated with β-catenin expression (TSA: P < 0.01; TA/VTA: P < 0.05). But β-catenin exon 3 mutations were not detected in any of these tissue specimens. Conclusions : Aberrant β-catenin expression is associated with the degree of dysplasia in TSA. β-catenin likely plays an important role in the pathogenesis of colorectal TSA and conventional adenomas.
Keywords: β-catenin, colorectal cancer, colorectal serrated adenomas, DNA sequencing, immunohistochemistry
|How to cite this article:|
Dai X, Wang L, Zhang L, Han Y, Yang G, Li L. The expression and mutation of β-catenin in colorectal traditional serrated adenomas. Indian J Pathol Microbiol 2012;55:288-93
|How to cite this URL:|
Dai X, Wang L, Zhang L, Han Y, Yang G, Li L. The expression and mutation of β-catenin in colorectal traditional serrated adenomas. Indian J Pathol Microbiol [serial online] 2012 [cited 2019 Jun 20];55:288-93. Available from: http://www.ijpmonline.org/text.asp?2012/55/3/288/101732
| Introduction|| |
Colorectal serrated lesions, which are characterized by a saw-tooth-like serrated pattern, are a series of lesions in the colorectum. Colorectal serrated lesions can be divided into different subtypes, based on morphology, which include hyperplastic polyps (HP), sessile serrated adenomas (SSA), and traditional serrated adenomas (TSA). HP is usually found in the left side of the colon with a lesion size of less than 5 mm. Histological analysis shows that HP has many features, including crypts with a serrated pattern, narrow of crypts base portion, and the lack of atypical serrated structure. Based on the amount of mucus, HP can be divided into the microvesicular type (MVHP), the goblet cell-rich type (GCHP), and the mucin-poor type (MPHP). SSA is typically located in the right side of colon with a lesion size greater than 10 mm without a pedicle or distinct border. Histological analysis shows that SSA has an obscure border, abnormal structures of the serrated crypt, gland expansion, and branch-shaped inverted T or L-shaped crypt. The expanded crypt base is adjacent to the muscularis mucosa. Cells in the middle and top portion of the crypt are atypical. TSA is found in the entire colon with a predominant location in the left side of the colon or in the rectum. Histological analysis showed a serrated crypt structure and dysplastic epithelia that was not adjacent to the muscularis mucosa, which is called ectopic crypt formation (ECF). Usually HP does not develop into a malignant lesion, whereas SSA and TSA have an increased rate of malignancy. Therefore, SSA and TSA are considered to precursor lesions of colorectal cancers. ,,,,,,,
In addition to the adenoma-carcinoma procedure of the carcinogenesis (APC) pathway, the colorectal serrated lesion has been recently found to be the second predominant pathway for colorectal carcinogenesis. The molecular and genetic alterations of the colorectal serrated lesion are as follows: (1) BRAF gene mutations, (2) the CpG island methylation phenomenon (CIMP), and (3) microsatellite instability (MSI). ,,
β-catenin is a tumor suppressor gene encoded by CTNNB1, which is a critical molecule for proper cell adhesion and the Wnt signaling pathway, expresses at a low level in normal cells.  The β-catenin gene has 16 exons. Importantly, the third exon encodes the NH2 domain, which contains Ser33, Ser37, Ser45, and Thr41. These residues are sites at which β-catenin is phosphorylated by GSK3β. Mutation or deletion of these sites can result in the dissociation of β-catenin and from the GSK3β complex and subsequent cytoplasmic stabilization of β-catenin. Cytoplasmic β-catenin is then translocated into the nucleus, where it binds to TCF and activates downstream signaling pathways that regulate tumor growth.
Recent researches on colorectal serrated lesions have demonstrated that the mutated sequences in the colorectal cancer gene (MCC) is a new pathway, which is associated with β-catenin and inhibits Wnt signaling in colorectal carcinogenesis. Wnt is one of the most critical pathways involved in the carcinogenesis of many adenocarcinomas, including colorectal conventionl adenomas. When activated by Wnt binding, the Wnt pathway inhibits a second complex of proteins that includes axin, GSK-3, and APC protein. The axin/GSK-3/APC complex promotes the proteolytic degradation of the β-catenin intracellular signaling molecule. Thus, cytoplasmic β-catenin is stabilized translocates to the nucleus where it interacts with TCF/LEF family of transcription factors to promote specific gene expression. Although a few studies have been reported, the relationship between the Wnt pathway and colorectal serrated lesions is still unclear. ,,
In this study, we investigated the expression of β-catenin and the presence of exon 3 mutations in 30 cases of TSA, 20 cases of conventional adenomas (CAD), and 21 cases of invasive adenocarcinomas (IAD). We analyzed the relationship between β-catenin expression/mutation and the degree of TSA dysplasia, the differential expression of β-catenin in TSA and CAD, as well as the relationship between β-catenin expression and patinents' survival status. These results probably provide new information for the role of β-catenin in the carcinogenesis of colorectal serrated lesions.
| Materials and Methods|| |
A total of 1685 cases tissue sections were obtained from January 2003 to January 2008 at the 252 Hospital of PLA and Julu County Hospital of Hebei Province, China. These cases were diagnosed as colorectal adenomas or polyps according to hymatoxylin and eosin staining. Tissue sections from 91 cases with the characteristics of colorectal serrated lesions were selected for pathological analysis by three pathologic experts according to WHO standards. ,,, Thirty cases of TSA were selected for microscopy, which revealed that these specimens had serrated structures with dysplastic epithelia and ectopic crypt formation (ECF) after excluding HP, SSA or mixed serrated lesions. A total of 20 cases of tubular adenomas (TA)/villous tubular adenomas (VTA) and 21 cases of colorectal carcinoma (CRC) were randomly selected. These adenomas were categorized as having mild dysplasia, moderate dysplasia, or a high grade of intraepithelial neoplasia (which includes high grade dysplasia, in situ carcinoma, and intramucosal carcinoma). The staging criteria for dysplastic morphology are listed as follows: (1) mild dysplasia characterized by atypical cells with a reduced number of goblet cells in the glandular tubes, crowd-arranged pen-shaped nuclei in basal cells, a multiple layer not exceeding 1/2 of the cells with extended glandular tubes; (2) moderate dysplasia characterized by more cells with atypia, multiple layers of nuclei occupying 2/3 of the epithelial cells; and (3) high grade intraepithelial neoplasia characterized by obvious dysplastic cells, a budding phenotype, intramucosal infiltration, heteromorphous nuclei, bubble-shaped nuclei with heterogeneous sizes, and the lack of muscularis mucosae infiltration. 
Tissue specimens were fixed in 4% formaldehyde and embedded in paraffin. Paraffin-embedded tissue blocks were serially sectioned into 4 μm sections. Immunohistochemical staining was performed using a kit from MaxVision biocompany as described in the manufacturer's instructions. Briefly, the sections were deparaffinized, moisture was removed, and they were treated with 3% H 2 O 2 to eliminate endogenous peroxidase activity. Antigen retrieval was performed by heat-induced epitope retrieval in a pressure cooker at 100°C for 2 minutes. Next, the sections were incubated with mouse antihuman β-catenin monoclonal antibody (Maixin Biotech. Corp. Ltd., Fuzhou, China) for 2 hours at room temperature. Then the sections were washed with 0.01M PBS three times, and the secondary antibody was added and incubated for 30 minutes at room temperature. Staining was visualized with the diaminobenzidine (DAB) chromogen. Slides were then counterstained with hematoxylin and dehydrated through multiple graded ethanol solutions and coverslipped. In negative controls the primary antibody was replaced with PBS.
Analysis of β-Catenin Exon 3 Mutation
DNA was extracted using the QIAamp DNA FFPE kit according to the manufacturer's instructions. The primers were synthesized by Yingjun Maixin Biotech. Corp. Ltd., (Shanghai, China). The primers sequences  were as follows:
The PCR amplicon was 272 bp. PCR was performed using PrimeSTAR™HS (Premix) from Takara Biotech. Corp. Ltd. (Dalian, China). A 50 μl reaction contained the following reagents: 25 μl of Premix, 1 μl of template DNA, 1 μl of primer 1, 1 μl of primer 2, and 22 μl of distilled water. PCR conditions are as follows: an initial denaturing step at 95°C for 5 minutes; 35 cycles of 94°C 1 minutes, 57.6°C 1 minutes, 72°C 1 minutes," and a final extension at 72°C for 7 minutes. PCR reactions were separated on an agarose gel by electrophoresis. The bands at 272 bp were visualized using a gel-imaging machine. Amplicons were sequenced at the Yingjun Maixin Biotech. Corp. Ltd., (Shanghai, China) using BigDye R XTermin TM V3.1 kit and an ABI 3730 DNA analyzer (Carlsbad, CA, USA). The identity of the amplicons was verified by sequence alignment with sequences in GenBank.
Data Records and Analysis
Immunohistochemistry results were determined by the methods described by Maruyama et al.  Briefly, the expression of β-catenin on the cell membrane, in the cytoplasm, and nuclei was recorded. A > 70% expression of β-catenin on the cell membrane was considered normal, whereas a > 10% expression of β-catenin in the cytoplasm and nuclei was considered abnormal. Normal expression was recorded as negative (-), and abnormal expression was recorded as positive (+). Abnormal expression was further divided into the following three types: light yellow staining 1+, yellow staining (2+), and yellow-dark brown staining (3+).
DNA sequencing results were analyzed visually to identify whether there was noise or double peaks. Mutated sequences were aligned against PUBMED nucleotide sequences using BLAST.
We followed up the 21 CRC cases with β-catenin immunohistochemistry staining. There were 15 CRC cases to be alive until now.
Statistical analysis was performed using the SPSS18.0 software. Immunohistochemistry results were analyzed using the Fisher exact test. P < 0.05 was considered statistically significant.
| Results|| |
Morphologic Features of Colorectal Serrated Adenomas
As shown in [Figure 1]a-d, the colorectal serrated lesion samples were categorized into HP, SSA, TSA, mixed serrated polyps/adenomas, and mixed serrated/tubular adenomas according to observed under light microscopy by three different pathologic experts carefully. [Figure 1]E-H showed adenomas with mild dysplasia, moderate dysplasia, or a high grade of intraepithelial neoplasia, which includes high-grade dysplasia, in situ carcinoma, and intramucosal carcinoma.
|Figure 1: (a-d) Morphological features of colorectal serrated lesions. (a) Hyperplastic polyps (HP) (b) Sessile serrated adenomas (SSA). (c) Traditional serrated adenomas (TSA). (d) TSA with fi liform and villus (H&E stain, ×200). (E--H) Serrated adenoma with diff erent types of dysplasia. (e) TSA with mild--moderate dysplasia. (f) TSA with moderate dysplasia. (g) and (h) Different regions in the same sections. (g) Filiform and villi in the gland with moderate dysplasia. (H) High grade intraepithelial neoplasia. (H&E stain, scale bar: 20 μm). (I-L) Immunohistochemistry showing expression of b-catenin in colorectal adenomas and CRC tissues. Positive IHC signals were visualized with DAB (3, 3¢-diamino-benzidine-tetrahydrochloride) (brown reaction product). All sections were counterstained with haematoxylin. (i) Positive staining on the membrane of epithelial cells of normal colorectal mucosa (light brown signals). (j) Positive staining on the cell membrane and with week cytoplasmic staining of TA (light brown signals). (k) Positive staining on the cell membrane and with stronger cytoplasmic and nuclei staining of TSA (dark brown signals). (l) Strongest positive staining in the cytoplasm and nuclei of CRC (dark brown and black signals). (Immunohistochemistry stain, scale bar: 20 μm)|
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Expression of β-Catenin in Various Adenoma Lesions
IHC with antibody to β-catenin demonstrated that the β-catenin positive signals were located on the cell membrane and in the cytoplasm and nucleus of adenoma cells or CRC cells [Figure 1]I-L. The percentages of β-catenin expression in TSA, TA/VTA, and CRC were 76.6% (23/30), 70.0% (14/20), and 95.2% (20/21), respectively. These expression levels were significantly different among the three types of tissue specimens (P < 0.001). When compared TSA with TA/VTA, β-catenin expression levels were not significantly different. However, β-catenin expression levels were significantly different between the TSA/TA/VTA and CRC tissue specimens. The staining intensity gradually increased with the severity of dysplasia. This effect was most noticeable in the 0% 3+ staining in TSA and TA/VTA specimens compared to the 42.8% 3+ staining in CRC specimens. In addition, abnormal nuclei staining was observed in one TSA case and three CRC cases, but was not observed in any TA/ VTA case [Table 1].
|Table 1: Expression of β-catenin in various colorectal adenoma lesions and CRC tissues|
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The Relationship between β-Catenin Expression and the Degree of Dysplasia
The tissue specimens were divided into the following four groups: mild dysplasia, moderate dysplasia, high-grade intraepithelial neoplasia (which included high grade dysplasia, in situ carcinoma, and intramucosal carcinoma), and infiltrating cancer (CRC). The expression of β-catenin in TSA with mild dysplasia, moderate dysplasia, and high-grade dysplasia were 53.8%, 100%, and 80.0%, respectively. By contrast, the expression of β-catenin in TA/VTA with mild dysplasia, moderate dysplasia, and high-grade dysplasia were 50%, 83.3%, 100%, respectively. Among these samples, the four high-grade dysplastic samples were all VTA. The expression of β-catenin was significantly different [Table 2]. The expression of β-catenin in the two groups of adenomas was correlated well with the degree of dysplasia. (TSA: P < 0.01; TA/VTA: P < 0.05).
|Table 2: The relationship between the expression of β-catenin and the severity of dysplasia|
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The Relationship between β-Catenin Expression in CRC and the Patients Survival Status
Twenty-one CRC cases with β-catenin immunohistochemical staining were followed up. There were 15 CRC cases got survival status data but six cases lost. Followed up time from 30 to 40 months after their operation. Among 15 CRC cases, 14 cases were with positive staining of β-catenin, in which 10 cases survived and 4 cases died. One case of CRC patient who showed β-catenin negative is still surviving [Table 3]. We can not make statistical analysis, because the quantition of the cases is very little; from this result, it was difficult to make more correlation between β-catenin expression in CRC and the patients' survival status.
|Table 3: The relationship between β-catenin expression in CRC and the patient's survival status|
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Amplification of the β-Catenin Exon 3 Gene in Different Adenoma Lesions and CRC Tissues
We detected the expression of b-catenin exon 3 mRNA in TSA, TA, VTA, and CRC tissues using RT-PCR, and found that both adenomas and CRC expressed b-catenin, and the amplification product was 272 bp [Figure 2].
|Figure 2: Amplification of β-catenin exon 3 mRNA in colorectal adenomas and CRC tissues. We amplifi cated the β-catenin exon 3 mRNA in colorectal adenomas and CRC tissues using RT-PCR, and the product was 272 bp. (M: marker; S: TSA; T: TV; V: VSA; C: CRC.)|
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Mutation Analysis Results
Based on abnormal β-catenin expression, assessed by immunohistochemical staining, mutation analysis was performed on 8 TSA, 6 TA, 5 VTA, and 10 CRC cases. A mutation in exon 3 of β-catenin was not detected in any of these tissue specimens [Figure 3].
|Figure 3: DNA sequencing of exon 3 gene results for TSA, TA, VTA, and CRC samples. a, b, c, d represented TSA, TA, VTA, and CRC, respectively. The baselines were smooth without noise waves and double peaks|
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| Discussion|| |
In normal, differentiated cells, β-catenin, as a tumor suppressor gene, is associated with E-cadherin and functions in cellular adhesion, whereas free cytoplasmic β-catenin is maintained at low levels by proteasomal degradation.  It has been shown that elevated β-catenin expression in the cytoplasm and nucleus is a biomarker for metastasis and poor patient prognosis. , Furthermore, aberrant expression of β-catenin is associated with differentiation status, Duke's staging, and lymph node metastasis in colorectal cancer.  These observations indicate that β-catenin plays a critical role in the transformation and progression of colorectal cancer. β-catenin is mainly expressed in the membrane of normal cells. In contrast adenocarcinomas and tissues undergoing adenoma malignant changes show a decrease in membrane expression with a concomitant increase in nuclear expression. In addition, the abnormal expression of β-catenin is correlated with the severity of epithelial dysplasia of colon adenomas. ,, These results demonstrate that decreased membrane expression and increased nuclear β-catenin expression are associated with the progression of adenomas to adenocarcinomas. In this study, we found that the expression of β-catenin was increased in areas of advanced dysplasia in TSA, TA/VTA, and CRC specimens. Thus, the aberrant expression and relocalization of β-catenin from the membrane to the cytoplasm could be used as a biomarker for colon adenomas.
The serrated carcinogenesis process may occur through two pathways. One pathway is due to a BRAFE gene mutation, which can inhibit the apoptosis of normal colon epithelial cells and lead to serrated MVHP and SSA/P. The other pathway is not related to the BRAFE gene mutation, but it may be related to a KRAS mutation, which leads to the generation of GCHP and TSA. Although little information is currently known regarding GCHP, TSA is usually considered to be a premalignant lesion. It has been shown that methylation of the MTMG gene can lead to MSI-L cancers. 
There have been few studies on the role of β-catenin in colorectal serrated lesions. Wu et al.  used immunohistochemistry to analyze β-catenin expression in 22 SSA cases and 19 HP cases. They found that β-catenin was mainly expressed in the basal cells of SSA, but it was widely distributed in HP. Shinichi et al.  found that 67% (35/54) of SSA cases, 36% (4/11) of TSA cases, and none of the (0/12) HP cases had abnormal β-catenin expression in the nuclei. This study demonstrated that β-catenin plays a vital role in the carcinogenesis of colorectal serrated lesion and the Wnt signaling pathway is involved in SSA progression.
In this study, we found that expression of β-catenin was correlated with the severity of dysplasia, which was in agreement with previous data. Our results indicate that the Wnt signaling pathway is not only involved in the carcinogenesis of conventional adenomas of colorectal, but it is also involved in the pathogenesis of colorectal serrated lesions and correlates with the severity of dysplasia. From the follow-up data, it was difficult to find the correlation between β-catenin expression in CRC and the patients' survival status, because the case numbers were too less to make statistical analysis.
There have only been a few studies on β-catenin gene mutation in colorectal serrated lesions. Shinichi et al.  did not find any β-catenin gene mutations in SSA, TSA or HP tissues. In another previous study, however, mutations of the β-catenin gene in CRC were shown to be in 10% of samples.  Yet another study demonstrated a 40--50% rate of mutation in β-catenin in CRC.  In our study, we based our selection of samples for mutation analysis on immunohistochemistry expression data. Eight TSA samples, six TA samples, five VTA samples, and 10 CRC samples were selected for sequencing. Interestingly, none of these samples had a mutation in exon 3 of the β-catenin gene, even though three CRC cases and one TSA case had positive β-catenin staining in the nuclei. A similar phenomenon had also been reported by Fukuchi et al.,  who described nuclear staining of β-catenin without mutation. This phenomenon could be due to the following reasons: (1) mutation in other exons, (2) mild alterations in APC, or (3) alterations in other Wnt family proteins. Therefore, further studies are needed to investigate these other potential molecular mechanisms.
| Acknowledgments|| |
We thank Dr. Jian Chen (252 Hospital of PLA, Baoding, China) and Dr. Xinzhong Zhang (Julu County Hospital of Hebei Province, China) for providing tissue specimens.
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Dongsishitiao Street, Dongcheng District, Beijing, People's Republic of China
Source of Support: This work was supported by National Natural Science Foundation of China (30872956) and the Capital Medical Development Foundation of Beijing (2007-3025), Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]