Journal of Pathology and Translational Medicine

Original Articles

MAD2 Expression in Ovarian Carcinoma: Different Expression Patterns and Levels among Various Types of Ovarian Carcinoma and Its Prognostic Significance in High-Grade Serous Carcinoma: Po Eun Park, Ji Yun Jeong, Sun Zoo Kim, Ji Young Park; Korean J Pathol. 2013;47(5):418-425. Published online October 25, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.5.418

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Background

Mitotic arrest deficiency protein 2 (MAD2) is a key component of spindle assembly checkpoint function, which mediates cell apoptosis through microtubule kinetics. Aberrant expression of MAD2 is believed to be associated with the development of chromosome instability. MAD2 also has a signihicant role in cellular drug resistance to taxane chemotherapeutic agents.

Methods

Expression of MAD2 and p53 was investigated using immunohistochemistry in 85 cases of ovarian carcinomas. Clinicopathological data including progression-free survival were analyzed.

Results

A significant (p=.035) association was observed between the grade of serous carcinoma and the expression level of MAD2. While low-grade serous carcinoma showed a low-level expression of MAD2, high-grade serous carcinoma showed a high-level expression of MAD2. We also determined that low-level expression of MAD2 was associated with reduced progression-free survival (PFS) (p=.016) in high-grade serous carcinoma.

Conclusions

MAD2 expression in ovarian carcinoma is related to the grade of serous carcinoma and PFS of high-grade serous carcinoma. Expression level of MAD2 detected by immunohistochemistry may serve as an indicator in predicting the response of microtubule-interfering chemotherapeutic agents.

Citations

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The role of the MAD2-TLR4-MyD88 axis in paclitaxel resistance in ovarian cancer
Mark Bates, Cathy D. Spillane, Michael F. Gallagher, Amanda McCann, Cara Martin, Gordon Blackshields, Helen Keegan, Luke Gubbins, Robert Brooks, Doug Brooks, Stavros Selemidis, Sharon O’Toole, John J. O’Leary, David Wai Chan
PLOS ONE.2020; 15(12): e0243715. CrossRef
Aneuploidy: Cancer strength or vulnerability?
Giorgia Simonetti, Samantha Bruno, Antonella Padella, Elena Tenti, Giovanni Martinelli
International Journal of Cancer.2019; 144(1): 8. CrossRef
The association between MAD2 and prognosis in cancer: a systematic review and meta-analyses
Tara Byrne, Helen G. Coleman, Janine A. Cooper, W. Glenn McCluggage, Amanda McCann, Fiona Furlong
Oncotarget.2017; 8(60): 102223. CrossRef
Identification of transcription factors (TFs) and targets involved in the cholangiocarcinoma (CCA) by integrated analysis
L Yang, S Feng, Y Yang
Cancer Gene Therapy.2016; 23(12): 439. CrossRef
Proteins of the mitotic checkpoint and spindle are related to chromosomal instability and unfavourable prognosis in patients with myelodysplastic syndrome
Kelly Roveran Genga, Francisco Dário Rocha Filho, Francisco Valdeci de Almeida Ferreira, Juliana Cordeiro de Sousa, Fernando Sergio Studart, Silvia Maria Meira Magalhães, Fabíola Fernandes Heredia, Ronald Feitosa Pinheiro
Journal of Clinical Pathology.2015; 68(5): 381. CrossRef

Alteration of G1/S Cell Cycle Regulatory Proteins in Carcinogenesis of Cutaneous Squamous Cell Carcinomas.: Soyoung Im, Changyoung Yoo, Ji Han Jung, Hyun Joo Choi, Jinyoung Yoo, Seok Jin Kang, Kyo Young Lee; Korean J Pathol. 2009;43(6):542-549.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.6.542

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Abstract PDF

BACKGROUND
Aberration of the cell cycle regulatory proteins has been reported to contribute to the development and progression of human malignancy. We studied the expression of G1/S cell cycle regulatory proteins to investigate the carcinogenesis in cutaneous squamous cell lesions. METHODS: We evaluated the expressions of p16, pRb, cyclin D1 and Ki-67 protein by immunonohistochemistry in cases of normal skin (n=15), seborrheic keratosis (SK; n=26), actinic keratosis (AK; n=30), Bowen's disease (BD; n=37), keratoacanthoma (KA; n=23), and squamous cell carcinoma (SCC; n=22). RESULTS: The Ki-67 expression gradually increased from SK, through AK, to BD. The expression of p16 was more increased in BD than that in AK. The decreased expressions of p16 and Rb, and the increased expression of cyclin D1 were observed to a greater degree in SCC than those in BD. The expressions of cyclin D1 and Ki-67 were higher in SCC than those in KA. CONCLUSIONS: The altered expressions of p16, Rb, and cyclin D1 were considered to be related to the carcinogenesis in the cutaneous squamous cell lesions. Therefore, immunohistochemical studies of the cell cycle regulatory proteins and a combined analysis may be helpful as an adjunct to the histomorphology in the diagnosis of cutaneous squamous cell lesions.

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Expression of pRb, p53, p16 and Cyclin D1 and Their Clinical Implications in Urothelial Carcinoma
Kyungji Lee, Eun Sun Jung, Young-Jin Choi, Kyo Young Lee, Ahwon Lee
Journal of Korean Medical Science.2010; 25(10): 1449. CrossRef

The Role of gadd and p53 Genes in Apoptosis and Cell Cycle Delay by Genotoxic Agents.: Jung Young Lee, Jung Duk Lee, Seung Myung Dong, Eun Young Na, Min Sun Shin, Su Young Kim, Sug Hyung Lee, Won Sang Park, Nam Jin Yoo; Korean J Pathol. 1998;32(4):239-247.

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Abstract PDF: The aim of this study was to investigate the relationships between the gadd genes expression and an apoptosis induction in two different growing cell types after treatments with cisplatin and methylmethan sulfonate (MMS). We have examined the kinetics and specificity of gadd45 and gadd153 expression following cisplatin and MMS treatments to HL-60 cells and primary cultured human kidney (HKN) cells. We have also determined an induction time of apoptosis by DNA fragmentation analysis and the presence of the cell cycle arrest by a flow cytometric measurement. The results were as follows. In non-adherent HL-60 cells, a typical ladder pattern was observed within 4 hours after treatments of 20 micrometer of cisplatin and 100 microgram/ml of MMS. At the same time while adherent HKN cells failed to exhibit a ladder pattern at even higher doses of genotoxic agents. Since HL-60 cells do not have p53 gene, these findings suggest the presence of a p53-independent apoptotic pathway. The increasing patterns of the mRNA levels of gadd45 and gadd153 varied with the type of genotoxic agents. In the case of MMS treatment, the induction was rapid and transient, regardless of the cell types. The mRNA level peaked at 4 hours after MMS treatment and markedly decreased after 12 hours. On the other hand, cisplatin-induced transcriptions of gadd45 and gadd153 continued to increase for at least 24 hours and reached a peak level at 48 hours after cisplatin treatment, regardless of the cell types. HL-60 cells revealed G2 arrest following 24 hours after cisplatin and MMS treatments. These findings suggest that the regulation mechanism of apoptosis between adherent and non-adherent cells, might be different and that gadd45 and gadd153 might have an important role in DNA repair rather than apoptosis. Also, the findings suggest that an expression pattern of gadd45 and gadd153 might be different according to the type of genotoxic agents.

Significance of Expression of p16, Cyclin D1, Rb, and p53 Protein and Correlation with Clinicopathologic Prognostic Factors in Invasive Ductal Carcinoma of the Breast.: Mi Ja Lee, Ho Jong Jeon, Kweon Cheon Kim; Korean J Pathol. 2000;34(4):288-299.

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Abstract PDF: The retinoblastoma (Rb)/cyclin D1/p16 pathway is an important constituent of cell cycle regulation. Perturbations in this pathway due to a variety of genetic aberrations have been reported in many human cancers including breast cancer. We examined the significance of immunoexpression of p16 protein, cyclin D1 protein, Rb protein (pRb), and p53 protein in 128 cases of invasive breast carcinoma. The results were correlated with survival rate and clinicopathological variables, including age, histologic grade, lymph node status, tumor size, estrogen receptor (ER), and progesterone receptor (PR) content. Abnormal expressions of p16 and pRb which were defined as negative staining were seen in 21% and 43% of tumors, respectively. There was a significant inverse relationship between p16 and pRb expression. There was no correlation between p16 staining and any other parameters, including survival rate, cyclin D1, p53, and clinicopathologic variables. Surprisingly, there was a trend for tumors which were positive for pRb to be grade III ductal carcinomas. Cyclin D1 positivity was noted in 46% of cases. The expression of cyclin D1 protein was significantly higher in lower histologic grade, higher ER and PR expression. The expression of p53 protein showed a significant correlation with high tumor grade. In a Cox multivariate analysis, neither p16, pRb, cyclin D1 nor p53 was an independent predictor, but tumor size and lymph node status were independent predictors of patient outcome.

Expressions of MAGE-3, PCNA, p21, and p53 Proteins in the Hypopharyngeal Squamous Cell Carcinoma Cell Line (PNUH-12) Analysed by Bivariate Flow Cytometry.: Hee Kyung Chang, Deok Jun Kim, Hwan Jung Roh, Bang Hur, Kang Dae Lee, Spagnoli Spagnoli; Korean J Pathol. 2000;34(11):901-908.

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Abstract PDF: MAGE (melanoma antigen gene) is a tumor specific shared antigen, presented by HLA class I molecules, which is recognized by cytotoxic T lymphocytes. MAGE proteins are expressed in malignant tumor cells, in contrast to no expression in normal or benign tissues except for testis and placenta. MAGE might be a potential target for immunotherapy of malignant tumors. However, its biological aspects associated with cell cycle are not yet described. The flow cytometry is a useful tool for objective and quantitative analyses of heterogenous tumor cell population. To understand the status of MAGE related to cell cycle and its relationship with p53 as the G1 checkpoint regulator, p21, and PCNA as a proliferative index, we investigated expression of MAGE-3 protein, mutant p53, p21, and PCNA by flow cytometry and immunohistochemical stain. In addition, double stains for MAGE-3/p53, p53/PCNA, and p53/p21 were analysed with bivariate flow cytometry. DNA histograms using MAGE-3/PI (DNA) and p53/PI (DNA) were also analysed. The cell line (PNUH- 12) used for this study originated from a hypopharyngeal squamous cell carcinoma, which has point mutation (exon 7, C-->G) of p53. The expression rate of MAGE-3 was 83%, PCNA 85%, and p53 81%. No expression for p21 was identified. MAGE-3 was expressed in cytoplasm, while both PCNA and p53 were expressed in nuclei of tumor cells. With bivariate analyses, coexpression rates of MAGE-3/p53 and p53/PCNA were 0.96 and 0.97, respectively. Both MAGE-3 and p53 showed constantly high level throughout the cell cycle. These results suggest that expression of MAGE-3 and mutant p53 is not dependent on the cell cycle. p21 seems to be inactivated.

Expression of Cyclin D1, Cyclin E, p21Cip1 and p27Kip1 in Chemically Induced Rat Mammary Tumor Treated with Tamoxifen and Transforming Growth Factor-1.: Tae Jung Jang, Jae Hum Park, Mee Yon Cho, Ki Kwon Kim, Jung Ran Kim; Korean J Pathol. 2001;35(2):151-157.

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Abstract PDF: BACKGROUND
Tamoxifen (TAM) inhibits the action of estrogen by binding to estrogen receptors, and also has non-estrogen receptor mediated cytostatic activities. Transforming growth factor-1 (TGF-1) inhibits the proliferation of many other cell types, such as epithelial, hematopoietic and endothelial cells.
METHODS
We investigated the effects of tamoxifen on the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors and the expression of cyclin D1, cyclin E, p21Cip1, and p27Kip1 by performing immunohistochemistry and Western blot analysis, and studied whether TGF-1 injection amplified the effects of TAM. When tumor size reached between 10-15 mm in the largest dimension, the rats were divided into 3 groups: DMBA-control group (n=12), DMBA-TAM group (n=14) and DMBA-TAM plus TGF-1 group (n=5).
RESULTS
The consecutive administration of TAM markedly decreased the tumor development compared with the DMBA-control group. The DMBA-TAM and DMBA-TAM plus TGF-1 groups showed decreased expression of bromodexoyuridine, cyclin D1, cyclin E, and p21Cip1 when compared with those of the DMBA-control group. On the other hand, the labeling index of p27Kip1 was higher in the DMBA-TAM plus TGF-1 group than in the DMBA-control group.
CONCLUSION
TAM suppresses tumor development, which may be associated with down-expression of cyclin D1 and cyclin E, and overexpression of p27Kip1, and addition of TGF-1 does not influence tumor development treated by TAM.

Relationship between Expression of Anaphase-promoting Complex and Prognostic Factors in Invasive Ductal Carcinoma of Breast.: Minseob Eom, Kwang Hwa Park, Kwang Gil Lee, Sang Yeop Yi, Yup Kang, Soon Hee Jung; Korean J Pathol. 2003;37(1):19-25.

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Abstract PDF: BACKGROUND
The role of the anaphase-promoting complex (APC) is to promote the degradation of mitotic cyclins and other substrates involved in sister chromatid adhesions. The APC appears to be responsible for the degradation of cyclin B and may have a potential role in the loss of control concerning cell proliferation in mammalian cells. However, a direct link between the defects in the APC components and oncogenesis has not been estabilished. This study investigates the relationship between APC expression and variable prognostic factors in invasive ductal carcinoma of the breast.
METHODS
We evaluated 108 cases of invasive ductal carcinoma surgically resected from January, 1996 to May, 2000 at Wonju Christian Hospital, Wonju College of Medicine, Yonsei University. Immunohistochemical stains for APC, estrogen receptor, and Ki-67 were done in paraffin sections using the avidin-biotin complex method. The results were compared with clinical and pathologic parameters and flow cytometric DNA analysis factors.
RESULTS
Forty cases (37.0%) showed immunopositive reactions for APC. The APC positivity in histologic grades 1, 2, and 3 were 28 cases (84.4%), 33 cases (60.0%), and 7 cases (35.0%), respectively (p=0.0011). The APC expressions in cases with the number of mitosis of less than 10, 10-19, and more than 20 per 10 high power fields, were noted in 37 cases (75.5%), 26 cases (63.4%), and 5 cases (27.8%), respectively (p=0.0016). The mean value of the Ki-67 labeling index was 221.7 in the APC-positive group and 317.9 in the APC-negative group (p= 0.0091). DNA flow cytometric analysis revealed higher APC expressions in cases with diploid patterns (p=0.0095). The APC expression rate increased significantly with decreasing histologic grade, with decreasing mitotic activity, in cases with a low Ki-67 labeling index, and those in the diploid group (p<0.05). The APC expression was not statistically correlated with clinical stage, tumor size, and estrogen receptor status.
CONCLUSIONS
These findings suggest that positive APC expression may be considered as a good prognostic factor of invasive ductal carcinoma, and loss of APC expression may be related with the progression of breast cancer.

The Expression of G1-S Cell Cycle Inhibitors in Normal Placenta and Gestational Trophoblastic Diseases.: Yan Hua Xuan, Kyung Hee Kim, Yoon La Choi, Geung hwan Ahn, Seoung Wan Chae, Ho chang Lee, Ok Jun Lee, Seok Hyung Kim; Korean J Pathol. 2008;42(2):67-74.

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Abstract PDF: BACKGROUND
The objective of this study is to determine the expression pattern of G1-S inhibitor molecules in normal trophoblasts and gestational trophoblastic diseases, including hydatidiform moles and choriocarcinoma.
METHODS
A total of 157 cases comprising 47 normal placentas and 110 gestational trophoblastic diseases such as choriocarcinoma (19 cases) and hydatidiform moles (91 cases of which 58 were complete, 12 were partial and 21 were invasive mole) were immunohistochemically analyzed on paraffin blocks using anti-p21, antip27, anti-p16, anti-p53, anti-pRb antibodies.
RESULTS
The results revealed that in the normal placenta, all the G1-S cell cycle inhibitors were maximally expressed by the first-trimester trophoblasts and these levels decreased with gestational age. The expression of p21 and p53 was greatly enhanced in the gestational trophoblastic diseases, particularly in invasive mole and choriocarcinoma, whereas the p27 expression was significantly downregulated in choriocarcinoma. Especially, Rb expression was typically enhanced in the invasive mole, but not in choriocarcinoma. The expression level of p16 was low in all the cases, and particularly in choriocarcinoma.
CONCLUSIONS
In conclusion, we demonstrated that the expression of G1/S cell cycle inhibitors correlates well with normal trophoblast differentiation, and these expressions are considerably altered in the gestational trophoblastic diseases, including complete/partial/ invasive hydatidiform mole and choriocarcinoma.

Expression of c-kit and Cell Cycle Regulators in Non-small Cell Lung Carcinoma.: Sun Hee Chang, Mee Joo, Hanseong Kim; Korean J Pathol. 2006;40(6):427-431.

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Abstract PDF: BACKGROUND
The abnormal expression of c-kit is implicated in the pathogenesis of a variety of solid tumors. The Rb pathway and p53 act as cell cycle regulators. The purpose of this study was to assess the expression of c-kit, Rb, p53, p16 and cyclin D1 and their relationship to clinical and pathological parameters in patients with non-small cell lung carcinomas (NSCLC(s)).
METHODS
Tissue microarrays consisting of 2 mm cores from the corresponding blocks were constructed from 54 NSCLC(s). Immunohistochemical staining for c-kit, Rb, p53, p16 and cyclin D1 was performed. C-kit immunostaining was considered positive if > or =10% of tumor cells were immunoreactive along the membrane and/or in cytoplasm. For Rb, p53, p16 and cyclin D1, tumor cells showing a nuclear staining pattern were interpreted as positive.
RESULTS
We found that c-kit was expressed in 13 (24%) cases, Rb was lost in 39 (72%) cases, p53 was expressed in 28 (52%) cases, p16 was lost in 42 (78%) cases and cyclin D1 was expressed in 33 (61%) cases. The c-kit expression was significantly higher in adenocarcinoma (39%) than in squamous cell carcinoma (8%). We did not find any correlation between c-kit, Rb, p53, p16 and cyclin D1 expression and clinicopathological parameters such as: age, tumor size, lymph node involvement, disease stage and distant metastasis. There was a direct correlation between p53 expression and Rb loss.
CONCLUSIONS
These results suggest that c-kit may be a useful therapeutic target for patients with c-kit positive tumors, and that the disruption of Rb and p53 pathways may play an important role in the development and progression of NSCLC(s).

Alteration of G1/S Cell Cycle Regulatory Proteins in Ovarian Epithelial Tumors.: Jee Yeon Kim, Hwal Woong Kim, Kyung Un Choi, Chang Hun Lee, Mee Young Sol, Hyun Jeong Kang, Dong Hoon Shin; Korean J Pathol. 2006;40(4):274-281.

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Abstract PDF: BACKGROUND
Disturbances of the cell cycle regulatory proteins are key events underlying the development and/or progression of human malignancies. The aim of this study was to evaluate the expression of G1/S cell cycle regulatory proteins in ovarian epithelial tumor.
METHODS
We simultaneously evaluated the expression of cyclin D1, cyclin E, CDK4, CDK2, p16, Rb, E2F1, p53 and the Ki67 labelling index (LI) by immunohistochemical methods in 148 cases of ovarian epithelial tumor of the benign (n=47), borderline (n=29), and malignant type (n=72).
RESULTS
The expression of cyclin E, CDK2, p16, Rb, E2F1, p53 and the Ki67 LI gradually increased from the benign type, through the borderline type, to the malignant tumors. Between the borderline and malignant tumors, the increased expression of cyclin E, E2F1, and p53, and the decreased expression of Rb were significantly associated with malignancy. The reduced Rb expression and the increased E2F1 expression were correlated with the FIGO stage and the histologic grade in the malignant ovarian epithelial tumors. CONCLUSIONS: Cyclin E, E2F1, and p53 overexpressions and the loss of Rb are the important components during carcinogenesis of ovarian epithelial tumors. Our results suggest that in- creased expression of E2F1 should be considered as a new parameter for the prognosis of patients with malignant ovarian epithelial tumors.

Expression of Cell Cycle-Regulatory Proteins in Rectal Cancer: Significance of the Tumor Response to Preoperative Radiochemotherapy and for the Prognosis.: Jinyoung Yoo, Jung Ha Shin, Ji Han Jung, Hyun Joo Choi, Seok Jin Kang, Chang Suk Kang, Kyo Young Lee; Korean J Pathol. 2006;40(3):217-224.

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Abstract PDF: BACKGROUND
Preoperative radiochemotherapy (PRCT) improves the outcomes for patients suffering with locally advanced rectal carcinoma, compared with surgery alone. However, there are no reliable factors predicting the survival and therapeutic benefits.
METHODS
The cell-cycle regulatory proteins were investigated in the pretreatment biopsies from 68 patients who were suffering with rectal cancer by performing immunohistochemical studies of p53, p21, cyclin D1, Rb and p16 protein. The tumor response was graded on a three-scale grading system: no response (NR), partial remission (PR) and complete remission (CR).
RESULTS
The tumors were positive for p53, p21 and cyclin D1 in 46 (67.6%), 32 (47.1%) and 14 (20.6%) cases, respectively. Abnormalities in Rb immunostaining were observed in 9 (13.2%) cases, while an abnormal p16 expression was noted in 59 (86.8%) tumors. Forty-two patients (61.8%) responded to PRCT: 18 (26.5%) cases achieved a CR and 24 (35.3%) cases achieved a PR. None of the above molecular markers were significantly associated with tumor response. However, the altered expression of p16 showed a significant correlation with overall survival (p=0.001). The high expression of p21 demonstrated a trend for longer survival (p=0.061).
CONCLUSIONS
Of the cell-cycle regulatory proteins, p16 may be a valuable marker for to predict rectal cancer patients' survival; however, the role of each cell-cycle regulatory protein for the therapeutic benefits of PRCT needs to be further studied.

Expression of Anaphase Promoting Complex in Surgically Resected Squamous Cell Carcinoma and Adenocarcinoma of the Lung.: Ji Sun Song, Soon Hee Jung, Minseob Eom, Sang Yeop Yi, Kwang Hwa Park, Yup Kang, Ho Young Kim; Korean J Pathol. 2006;40(1):52-59.

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Abstract PDF: BACKGROUND
The anaphase promoting complex (APC) promotes the degradation of mitotic cyclins as well as other substrates involved in sister chromatid adhesion. This study was carried out to examine the relationship between the APC expression and the clinicopathological variables, in an attempt to determine the role of the APC in the proliferation of lung cancer and to evaluate the possibility of an aberrant APC function in surgically resected squamous cell carcinomas and adenocarcinomas of the lung.
METHODS
Immunohistochemical staining was performed for APC, Ki-67, cyclin B1, Cdc2, MMP-2 and VEGF in 55 cases of squamous cell carcinoma and 34 cases of adenocarcinoma of the lung, using the avidin-biotin-peroxidase method.
RESULTS
The immunohistochemical stains for APC revealed a positive reaction in 49 cases (55.1%). The APC expression level was higher in the cyclin B1-positive group (p= 0.01), the Cdc2-positive group (p=0.001), the MMP-2-positive group (p=0.03), the group with lymph node metastasis (61.4% vs 48.9%), and the group with stage II/III cancer (60.7%) compared with those with stage I (42.9%).
CONCLUSIONS
The APC may have an aberrant function, such as a change in its role in controlling the cell cycle, and might be associated with the invasiveness and proliferation of tumor cells.

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