| Abstract|| |
Background: Activation of Notch-1 signaling pathway and loss of membranous beta-catenin have been known to play key roles in the progression of uterine cervix cancer and thus this study focused any alteration in the expression patterns for Notch-1, p53, and cyclin D1 as well as beta-catenin in squamous carcinoma in situ (CIS) and invasive squamous carcinomas to investigate their roles in the progression of CIS to squamous carcinomas. Materials and Methods: Three Notch-1 signaling proteins, such as Notch-1, TP53, and cyclin D1, and a component of cell adhesion complex, beta-catenin, were immunohistochemically stained in 112 uterine cervical tumors including 74 CIS and 38 invasive squamous carcinomas (11 microinvasive and 27 invasive carcinomas). Each immunohistochemical result was compared between CIS and squamous carcinoma groups and the difference was statistically analyzed. Results: Notch-1 protein expression was significantly higher in the microinvasive and invasive carcinomas than in CIS lesions (P = 0.001). Cyclin D1 and p53 immunoreactivities tended to be expressed higher in the invasive group than in CIS (P = 0.056 and 0.060). Membranous beta-catenin expression was significantly reduced in squamous carcinomas compared to CIS (P = 0.000). However, both CIS and squamous carcinoma groups revealed no interrelationship among Notch-1 signaling proteins and beta-catenin. Conclusion: Altered expressions of Notch-1 signaling proteins and beta-catenin in the progression of CIS into squamous carcinoma of uterine cervix suggests that Notch-1 signaling pathway and cell adhesiveness might play key roles in the stromal invasion of CIS cells.
Keywords: Beta-catenin, carcinoma in situ, cyclin D1, Notch-1 protein, squamous carcinoma, TP53 protein, uterine cervix
|How to cite this article:|
Myong NH. Altered expressions of Notch-1 signaling proteins and beta-catenin in progression of carcinoma in situ into squamous carcinoma of uterine cervix. Indian J Pathol Microbiol 2017;60:21-6
|How to cite this URL:|
Myong NH. Altered expressions of Notch-1 signaling proteins and beta-catenin in progression of carcinoma in situ into squamous carcinoma of uterine cervix. Indian J Pathol Microbiol [serial online] 2017 [cited 2017 Jul 23];60:21-6. Available from: http://www.ijpmonline.org/text.asp?2017/60/1/21/200045
| Introduction|| |
The recent studies have demonstrated that Notch signaling plays an important role in the transformation of human cervical epithelial cells and exerts regulations on tumor growth, invasion, metastasis, and angiogenesis in several human carcinomas including the cervix cancer.,, Human Notch proteins are a family of transmembrane receptors that interact with ligands such as Delta-like or Jagged, which leads to liberate the intracytoplasmic domain (ICD) of Notch (Notch-ICD). The released Notch-ICD has been reported to be translocated to the nucleus and regulates target genes such as Hes1 as a transcription factor. Cyclin D1 is an important target molecule that can be expressed commonly for Notch and NF-κB signaling pathways because both pathways have been shown to cross-talk in diverse cellular situations., There is a conclusive evidence of linkage between high-risk human papilloma-viruses (HPVs) and cervical cancer, and the E6 and E7 proteins of HPVs are known to inactivate the major tumor suppressors p53 and Rb, respectively, to maintain the transformed tumor cell type. Notch-1 expression has been reported to be up-regulated in human breast and uterine cervix carcinomas., Its molecular mechanism of increased Notch-1 expression in the tumorigenesis has yet to be determined clearly; however, the activation of Notch-1 signaling in cooperation with HPV E6-associated p53 inactivation was shown to be involved in cellular transformation through a PI3K-Akt-dependent pathway in an immortalized keratinocyte cell line, HaCaT., Loss of membranous beta-catenin has been recently reported to be found early in the preinvasive phases (hyperplasia or dysplasia) of oral squamous neoplasm. It has been rarely reported to have no interrelationship between Notch-1 and beta-catenin expression patterns in a pilot study.
Cervical carcinoma is a malignancy that evolves slowly from cervical intraepithelial neoplasm to invasive squamous carcinomas. Especially, high-grade squamous intraepithelial lesions including carcinoma in situ (CIS) are generally known to progress to invasive carcinoma if untreated in 10%–20% of cases. There has been only an immunohistochemical study to elucidate the role of Notch-1 signaling pathway in the early progression of human uterine cervix cancer. Therefore, we compared the protein expressions for Notch-1 signaling pathway and a cell adhesion complex between CIS and invasive squamous carcinomas of the cervix to focus their roles in the stromal invasion for early progression of CIS lesions to uterine cervix carcinomas.
The purposes of this immunohistochemical study are to evaluate the expressions of Notch-1 signaling proteins and a cell adhesion protein in the early progression of the human uterine cervix cancer and further to delineate its epigenetic mechanism of stromal invasion.
| Meterials and Methods|| |
One hundred twelve patients with cervical carcinoma who had undergone hysterectomy from 1999 to 2009 at Dankook University Hospital were included. Patients' ages ranged from 31 to 88 years. They had a median age of 52 and 56 years at the diagnosis of CIS and invasive squamous carcinoma, respectively. They had not received irradiation and anticancer chemotherapy before surgery. Stages by the FIGO classification system (2008) included 74 cases of 0 (CIS), 17 Ia (microinvasive), and 21 Ib-IIIb (invasive). Clinical follow-up was not done in any CIS case, whereas microinvasive and invasive carcinoma cases were followed up for 1–10 years, with each median period of 5.25 and 2 years, respectively. During the follow-up periods, 13 cases of the invasive carcinoma (62%) were treated with radiation only or concurrent chemoradiation, and one of microinvasive carcinomas (6%) received an additional radiotherapy. Neither recurrence nor distant metastasis was found in microinvasive carcinoma group; however, 5 (24%) out of 21 invasive carcinoma cases showed either recurrent cervix cancer or distant metastasis in lung, liver, kidney, and brain. This study was approved by the Institutional Review Board (IRB) of Dankook University (DKU IRB 2015-04-032).
Tissue sample preparation by tissue microarray technique on 112 uterine cervical tumors
The 112 paraffin blocks of human uterine cervical tumors were obtained from 74 cases of CIS (stage 0), 17 microinvasive (stage Ia), and 21 invasive (stage Ib–IIIb) squamous carcinomas. Among 112 cervical tumors, 59 tumor specimens were paired with their own normal samples for the tissue microarray (TMA) assay. TMA blocks were constructed using the pairs of the most representative tumor and normal tissue cores with a diameter of 2 mm, which were obtained from appropriate areas in formalin-fixed paraffin-embedded tissue blocks. These tissue cores were transferred and embedded into the recipient block that had sixty empty 2 mm-sized holes. Using a microtome, 4 μm thick serial sections were cut from the TMA blocks and were transferred to poly-L-lysine-coated slides.
Immunohistochemical staining procedure and the semiquantitative interpretation of the staining results
The microarray tissue sections were deparaffinized with standard xylene, rehydrated using graded alcohols, and rinsed with water. The sections were microwaved in 10 mM citrated buffer at 90°C for 10 min and then treated with 3% H2O2-phosphate-buffered saline solution to reduce an endogenous peroxidase activity. They were incubated with a normal bovine serum to reduce nonspecific antibody binding and subsequently subjected to primary antibody reactions. Monoclonal or polyclonal antibodies against Notch-1 (D1E11, Cell signaling, MA, USA), cyclin D1 (SP4, Neo Markers, CA, USA), TP53 (Clone SP5, Lab Vision, CA, USA), and beta-catenin (17C2, Novocastra, UK) were reacted with the sections for 1 hour at room temperature using dilution ratios of 1:300, 1:200, 1:100, and 1:150, respectively. A negative control was incubated without the primary antibodies. Detection of the immunoreactive staining was carried out by following the avidin-biotin-peroxidase complex method and using the LSAB kit (DAKO, Glostrup, Denmark). The sections were subjected to a color reaction with 3,3-diaminobenzidine tetrahydrochloride that contained 3% H2O2 in Tris buffer. They were lightly counterstained with Meyer's hematoxylin.
The immunoexpressions for three Notch-1 signaling proteins and beta-catenin were analyzed semiquantitatively as follows: Notch-1 expression was interpreted to be increased to activate the Notch-1 signaling pathway when more than 5% of the tumor cells were immunostained distinctly either as a membranous or as a cytoplasmic pattern. Cyclin D1 was considered overexpressed when the tumor cells were immunoreactive at more than 3% of their nuclei because its immunoreactivity was generally lower than 3% in the normal tissue. TP53-immunostained nuclei were interpreted as having a mutated or inactivated p 53 gene when the immunoreactivity was more than 5% of entire tumor cell nuclei. Beta-catenin expression was considered as being reduced or lost when more than 5% of the tumor cells lost their membranous immunoreactivity because the normal cervical epithelial cell membranes were almost entirely immunoreactive with beta-catenin.
The comparison of each immunoreactivity for Notch-1, p53, cyclin D1, and beta-catenin between two uterine cervix tumor groups of CIS and squamous carcinomas and their inter-relationships were analyzed in each group by a Pearson Chi-square test using SPSS software (SPSS 21.0, Chicago, IL, USA). All tests were two-sided and P < 0.05 was considered statistically significant.
| Results|| |
- Immunohistochemical expression patterns of Notch-1 signaling proteins including Notch-1, cyclin D1, and p53 in the normal and neoplastic cervical epithelia.
Notch-1 protein was immunostained at both cytoplasms and cell membranes of normal epithelial tissues in the exocervical squamous, metaplastic squamous, and endocervical glandular epithelia [Figure 1]. The normal distribution was confined to be the parabasal layers of squamous and the basal portions of metaplastic and endocervical epithelia. The tumor cells showed membranous or cytoplasmic immunostaining in both CIS and squamous carcinomas; however, the staining intensity tended to be more intense in the carcinoma cells than in those of CIS [Figure 2]. Cyclin D1 protein was confined to the parabasal cell nuclei of normal exocervical squamous epithelium, but the immunostained nuclei were diffusely found in the CIS and squamous carcinoma lesions [Figure 3]. p53 immunoreactivity was not found in the normal cervical epithelial cells, whereas the tumor cell nuclei were variably immunoreactive for the mutated p53 protein.
|Figure 1: Exocervical squamous (a), metaplastic squamous (b), and endocervical glandular (c) epithelia showed both cytoplasmic and membranous staining patterns for Notch-1 protein at their basal and parabasal areas (a, ×400; b and c, ×200)|
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|Figure 2: Carcinoma in situ (a) and invasive carcinoma (b) cells were immunostained diffusely for Notch-1 protein at the cell membranes and cytoplasms with moderate and strong intensities, respectively (a and b, ×400)|
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|Figure 3: Cyclin D1 immunostaining revealed the nuclear immunoreactivity mainly at their parabasal layer of the normal cervical epithelium (a), but diffusely scattered immunoreactive nuclei in carcinoma in situ (b) and invasive carcinoma (c) (a-c, ×400)|
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- Expressions of three Notch-1 signaling proteins are increased significantly in the squamous carcinomas compared to the CIS.
Notch-1 protein expression of both cytoplasmic and membranous patterns was found more frequently in 30(78.9%) of 38 carcinomas than in 39(47.3%) of 74 CIS cases. The difference of immunoreactivities between two groups was statistically significant by Pearson Chi-square test (P = 0.001) [Table 1]. Furthermore, Notch-1 immunoexpression of the membranous pattern only was significantly increased in the invasive carcinomas (12/38, 31.6%) compared to CIS cases (5/74, 6.8%) (P = 0.001). Cyclin D1 protein was overexpressed higher in 14 out of 36 carcinomas (38.9%) than in 13 out of 62 CIS cases (21.0%) and the difference was marginally significant by Pearson Chi-square test (P = 0.056) [Table 2]. Mutated p53 protein tended to show the nuclear immunoreactivity more frequently in the carcinoma group (19/35, 54.3%) than in CIS lesions (25/73, 34.2%) (P = 0.060) [Table 3].
|Table 1: Comparison of Notch-1 immunoexpression between carcinoma in situ and invasive squamous carcinoma groups of uterine cervix|
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|Table 2: Cyclin D1 overexpression in carcinoma in situ and invasive squamous carcinoma groups of uterine cervix|
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|Table 3: Comparison of p53 immunoreactivities between carcinoma in situ and invasive squamous carcinoma groups of uterine cervix|
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- Interrelationships between the immunoexpressions of the Notch-1 signaling proteins including Notch-1, cyclin D1, andP 53 in the CIS and squamous carcinoma groups (data not shown).
p53 protein expression in CIS group was significantly higher in the Notch-1-positive cases than in the Notch-1-negative ones (17/35, 68.0% vs. 8/36, 32.0%) (P = 0.026). It was also positively correlated with cyclin D1 expression (13/62, 34.8% vs. 8/23, 12.8%) and the difference of cyclin D1 immunoreactivities between p53-positive and negative CIS cases was marginally statistically significant (P = 0.055). However, there was neither significant interrelationship between Notch-1 and cyclin D1 expressions in CIS group nor any other interrelationships between Notch-1, cyclin D1, and p53 in the invasive group alone or all 112 cases.
- Immunostaining patterns and comparison of beta-catenin expressions in the normal, CIS, and carcinoma cases.
Normal cervical epithelium revealed relatively distinct membranous immunostaining pattern, whereas CIS and carcinoma cases showed multiple foci of reduced or no membranous staining [Figure 4]. Loss of beta-catenin expression more than 5% of the entire area was found more in squamous carcinomas (77%, 27 of 35 cases) than in CIS cases (31%, 21 of 68 cases). The difference in the reduced beta-catenin expression was statistically significant between CIS and squamous carcinoma groups (P = 0.000) [Table 4].
|Table 4: Loss of membranous beta-catenin expression in the carcinoma in situ and invasive squamous carcinoma groups of uterine cervix|
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|Figure 4: Normal cervical squamous epithelium (a) showed diffusely distinct membranous immunostaining pattern for beta-catenin, whereas the carcinoma in situ (b) and squamous carcinoma (c) had multiple foci with loss of the membranous immunoreactivity (above a dashed line and at the arrows, respectively) (a and b, ×200; c, ×400)|
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- The interrelationship between β-catenin expression and Notch-1 signaling proteins (data not shown).
Overall cases including 74 CIS lesions and 38 squamous carcinomas did not reveal any interrelationship between immunoexpressions for beta-catenin and three Notch-1 signaling proteins.
| Discussion|| |
Notch-1 signaling pathway has been reported to play an essential role in the induction of the cervical carcinogenesis, which is upregulated directly by HPV oncoprotein E6 and E7 expressions. A few immunohistochemical studies on cervical dysplastic and neoplastic lesions showed increased membranous and cytoplasmic Notch-1 protein expression compared to the normal cervical epithelium and stronger Notch-1 overexpression in carcinomas.,, In general, Notch pathway is considered fundamentally to control the fates of undifferentiated, proliferative cell populations. If mutations are accumulated in uncommitted cells until the cells fail to attain the normal differentiation and underlie to develop a neoplasm, the nature of the accumulated mutations determines whether Notch-1 signaling pathway is activated or not. Cyclin D1 is a main target molecule of Notch-1 pathway and has been reported to be overexpressed in several human carcinomas including breast, lung, and colon.,, p53 has been known to regulate Notch-1 expression, but its exact mechanism has not been established yet especially in the tumor cells. Wild-type p53 has been reported to activate Notch-1 expression to suppress normal epithelial cell proliferation, whereas p53 mutated or inactivated by HPV E6 protein has known to induce down-regulation of Notch-1, a tumor-suppressor, to promote the epithelial cell proliferation. However, the contradictory results have been reported, that activated Notch-1 inhibits p53-induced apoptosis and sustains transformation by HPV type 16 E6 and E7 oncogenes. Although the results for the role of Notch-1 in the tumors are still controversial, it has been thought conclusively that Notch-1 activation is necessary to proliferate or transform the neoplastic phenotype of cervical cancers., Loss of membranous β-catenin expression has been thought to occur in the progression of several epithelial cancers., An oral cancer study has demonstrated that losses of membranous β-catenin and membranous E-cadherin are correlated with progression of oral squamous neoplasia and significantly associated with clinical stages including tumor stages and nodal status. Loss of membranous β-catenin expression has also been proposed to promote malignant transformation and progression by triggering cyclin D1 expression in a breast cancer study. In this study, immunohistochemical staining results using TMA blocks revealed that Notch-1 protein expression is increased significantly in 30(78.9%) of 38 invasive tumors compared to 39(47.3%) of 74 CIS cases (P = 0.001). This result might indicate that Notch-1 signaling activation by increased Notch-1 expression plays a role in the progression of the CIS lesions into the squamous carcinomas. Furthermore, cyclin D1 overexpression and mutated p53 protein expression tended to be higher in invasive carcinomas than in the CIS cases, respectively (P = 0.056 and 0.060). These results suggest that these protein components are important in the activation of Notch-1 signaling pathway to play a role in the stromal invasion of CIS cells of the uterine cervix. Rizzo et al. have reported that knockdown of Notch-1 in a breast cancer cell line significantly inhibited extracellular matrix invasion of the tumor cells and they suggested a role of Notch-1 signaling pathway in controlling stromal invasion. The subcellular location of a Notch marker may provide important clues as to the activity status of the Notch pathway that may be more informative than simple staining intensity and/or fraction of positive cells. However, nuclear Notch is very difficult to detect by routine immunohistochemistry on paraffin sections, because nuclear Notch is rapidly degraded and the amount of Notch in the nucleus is a small fraction of cellular Notch. In the present study, the invasive carcinoma group showed no nuclear Notch-1 immunoreactivity but its intense membranous expression. A recent study for breast cancers also suggested that the tumors where the estrogen pathway is active tend to accumulate Notch-1 at the cell membranes., Cyclin D1 is generally known to be essential in cellular adhesion, motility, and stromal invasion. A recent study showed that nontransforming Notch-ICD proteins fail to activate cyclin D1 transcription, which suggested that the mechanism of Notch-ICD to transform cells is related to the induction of cyclin D1 expression. Our result of higher cyclin D1 expression in the invasive carcinoma group than in the CIS lesion suggests that Notch-1 pathway is activated to help the progression by increasing cell proliferation through the induction of cyclin D1. CIS lesions in the present study showed the positive interrelationship between p53 inactivation and Notch-1 or cyclin D1 activation although overall cases or invasive carcinomas did not reveal any interrelationship among Notch-1 signaling proteins including Notch-1, cyclin D1, and p53. The significant correlations of p53 expression with Notch-1 and cyclin D1 in the CIS lesions suggest that p53 inactivation might play as an inducer in the Notch-1 signaling pathway activation. The correlation between the protein expressions for Notch-1 and beta-catenin has not been reported yet in the uterine cervix, except for an oral cancer study that found no significant association between the expression patterns of beta-catenin and Notch-1. In the present study, there was also no significant association between them; however, the accumulated data by further advanced techniques and large-scaled studies seem to be needed to get a conclusion.
In summary, the present study showed that increased expressions of the Notch-1 signaling proteins including Notch-1, p53, and cyclin D1 proteins and also reduced beta-catenin expression were found to be important in the progression of CIS to invasive squamous carcinoma of uterine cervix. However, the role of Notch-1 protein in general tumorigenesis has been still controversial due to its function as tumor suppressor protein that is positively correlated with intact p53 protein. Therefore, more study results on the tumors of several sites including cervix will be needed to confirm our conclusion that the activated Notch-1 signaling pathway through Notch-1, p53, and cyclin D1 protein expressions and loss of a cell adhesion complex molecule, beta-catenin play key roles in the stromal invasion of CIS cells of human uterine cervix.
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Department of Pathology, College of Medicine, Dankook University, 119 Dandae-ro, Anseo-dong, Cheonan-si, Chungnam, 31116
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]