Cancer Research and Treatment

Original Articles

Effects and Mechanisms of Metformin on the Proliferation of Esophageal Cancer Cells In Vitro and In Vivo: Jian-Cai Tang, Rui An, Yi-Qing Jiang, Jian Yang; Cancer Res Treat. 2017;49(3):778-789. Published online November 11, 2016; DOI: https://doi.org/10.4143/crt.2015.485

Purpose
The purpose of this study was to observe the effects of metformin on human esophageal cancer cell and to investigate its possible mechanisms.
Materials and Methods
Cell viability was detected by using a Cell Counting Kit-8, while cell cycle and apoptosis were assessed by flow cytometry and western blot was used to measure the expression of the related proteins. RNAi was used to knockout pyruvate kinase muscle isozyme 2 (PKM2). An Eca109 tumor model was established to evaluate the antitumor effect in vivo. Immunohistochemistry was determined based on the expression of PKM2 and Bim in tumor tissues. Tunnel was used to assess tumor cell apoptosis.
Results
Esophageal cancer cells viability was reduced after metformin treatment. The cell cycle was arrested in the G0/G1 phase, apoptosis was induced, caspase 3 was activated, caspase 9 was downregulated, and the pro-apoptotic protein Bim increased. Further study revealed that metformin could suppress the expression of insulin-like growth factor 1 receptor and its downstream proteins, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT/PKB), phosphorylation of AKT (pAKT), mammalian target of rapamycin (mTOR), p70S6K, and PKM2. Insulin-like growth factor 1 partly reversed metfromin-induced apoptosis and attenuated the repression effect of metfomin to PI3K, pAKT, and PKM2. Knockout PKM2 resulted in the activation of caspase 3, down-regulation of caspase 9, and increased expression of Bim. In the Eca109 xenograft model, metformin significantly reduced tumor growth. Furthermore, we found that metformin treatment increased the rate of apoptosis, down-regulation of PKM2, and up-regulation of Bim in tumor tissues.
Conclusion
Metformin restrained esophageal cancer cell proliferation partly by suppressing the PI3K/AKT/mTOR pathway.

Citations

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Metformin in Esophageal Carcinoma: Exploring Molecular Mechanisms and Therapeutic Insights
Stavros P. Papadakos, Alexandra Argyrou, Vasileios Lekakis, Konstantinos Arvanitakis, Polyxeni Kalisperati, Ioanna E. Stergiou, Ippokratis Konstantinidis, Dimitrios Schizas, Theocharis Koufakis, Georgios Germanidis, Stamatios Theocharis
International Journal of Molecular Sciences.2024; 25(5): 2978. CrossRef
Ianus Bifrons: The Two Faces of Metformin
Umberto Goglia, Iderina Hasballa, Claudia Teti, Mara Boschetti, Diego Ferone, Manuela Albertelli
Cancers.2024; 16(7): 1287. CrossRef
Metformin and the PI3K/AKT signaling pathway: implications for cancer, cardiovascular, and central nervous system diseases
Hemin Ashayeri Ahmadabad, Somayeh Mohammadi Panah, Hojat Ghasemnejad‐Berenji, Shabnam Ghojavand, Morteza Ghasemnejad-Berenji, Mohammad Rafi Khezri
Naunyn-Schmiedeberg's Archives of Pharmacology.2024;[Epub] CrossRef
Changes in the expression of cancer- and metastasis-related genes and proteins after metformin treatment under different metabolic conditions in endometrial cancer cells
Carsten Lange, Jana Brüggemann, Theresa Thüner, Julia Jauckus, Thomas Strowitzki, Ariane Germeyer
Heliyon.2023; 9(6): e16678. CrossRef
Metformin Induces a Caspase 3-Unrelated Apoptosis in Human Colorectal Cancer Cell Lines HCT116 and SW620
Bustanur Rosidi, Diana Priyatno, Teguh Pribadi Putra, Irawan Yusuf
Cancer Management and Research.2023; Volume 15: 475. CrossRef
Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models
Mirian Galliote Morale, Rodrigo Esaki Tamura, Ileana Gabriela Sanchez Rubio
Biomolecules.2022; 12(3): 357. CrossRef
Metformin-Induced Heat Shock Protein Family A Member 6 Is a Promising Biomarker of Esophageal Squamous Cell Carcinoma
Nobufumi Sekino, Masayuki Kano, Sohei Kobayashi, Kentaro Murakami, Haruhito Sakata, Takeshi Toyozumi, Satoshi Endo, Yasunori Matsumoto, Hiroshi Suito, Masahiko Takahashi, Ryota Otsuka, Masaya Yokoyama, Tadashi Shiraishi, Koichiro Okada, Toshiki Kamata, Ta
Oncology.2022; 100(5): 267. CrossRef
The Role of PKM2 in the Regulation of Mitochondrial Function: Focus on Mitochondrial Metabolism, Oxidative Stress, Dynamic, and Apoptosis. PKM2 in Mitochondrial Function
Jing Gao, Yuwei Zhao, Tao Li, Xueqi Gan, Haiyang Yu, Daniel Lopez Malo
Oxidative Medicine and Cellular Longevity.2022; 2022: 1. CrossRef
Association of Common Use Pharmaceuticals in Reducing Risk of Esophageal Adenocarcinoma: A SEER–Medicare Analysis
Holli A. Loomans-Kropp, Matthew Chaloux, Ellen Richmond, Asad Umar
Cancer Prevention Research.2021; 14(2): 195. CrossRef
Advances and challenges in the treatment of esophageal cancer
Shiming He, Jian Xu, Xiujun Liu, Yongsu Zhen
Acta Pharmaceutica Sinica B.2021; 11(11): 3379. CrossRef
Changes in protein expression due to metformin treatment and hyperinsulinemia in a human endometrial cancer cell line
Carsten Lange, Amanda Machado Weber, Ronny Schmidt, Christoph Schroeder, Thomas Strowitzki, Ariane Germeyer, Jae-Wook Jeong
PLOS ONE.2021; 16(3): e0248103. CrossRef
Glucose and fatty acid metabolism involved in the protective effect of metformin against ulipristal-induced endometrial changes in rats
Marwa S. Hamza, Eman Ramadan, Salama A. Salama
Scientific Reports.2021;[Epub] CrossRef
12-Epi-Napelline Inhibits Leukemia Cell Proliferation via the PI3K/AKT Signaling Pathway In Vitro and In Vivo
Jia Han, Wei Hou, Bi-qing Cai, Fan Zhang, Jian-cai Tang, Xing Li
Evidence-Based Complementary and Alternative Medicine.2021; 2021: 1. CrossRef
Photodynamic therapy induces human esophageal carcinoma cell pyroptosis by targeting the PKM2/caspase-8/caspase-3/GSDME axis
Lisha Li, Dongfeng Song, Ling Qi, Mingxia Jiang, Yiming Wu, Junqing Gan, Kui Cao, Yanjing Li, Yuxian Bai, Tongsen Zheng
Cancer Letters.2021; 520: 143. CrossRef
Retracted: Silence of cZNF292 suppresses the growth, migration, and invasion of human esophageal cancer Eca‐109 cells via upregulating miR‐206
Zengjia Liu, Guiju Hu, Yan Zhao, Zuorun Xiao, Mingzhe Yan, Mei Ren
Journal of Cellular Biochemistry.2020; 121(3): 2354. CrossRef
Metformin Promotes Axon Regeneration after Spinal Cord Injury through Inhibiting Oxidative Stress and Stabilizing Microtubule
Haoli Wang, Zhilong Zheng, Wen Han, Yuan Yuan, Yao Li, Kailiang Zhou, Qingqing Wang, Ling Xie, Ke Xu, Hongyu Zhang, Huazi Xu, Yanqing Wu, Jian Xiao
Oxidative Medicine and Cellular Longevity.2020; 2020: 1. CrossRef
The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer
Mingxia Jiang, Ling Qi, Lisha Li, Yanjing Li
Cell Death Discovery.2020;[Epub] CrossRef
Metformin delays AKT/c-Met-driven hepatocarcinogenesis by regulating signaling pathways for de novo lipogenesis and ATP generation
Cong Zhang, Junjie Hu, Lei Sheng, Ming Yuan, Yong Wu, Liang Chen, Guohua Zheng, Zhenpeng Qiu
Toxicology and Applied Pharmacology.2019; 365: 51. CrossRef
Enhanced penetration and cytotoxicity of metformin and collagenase conjugated gold nanoparticles in breast cancer spheroids
Elaheh Dalir Abdolahinia, Samad Nadri, Reza Rahbarghazi, Jaleh Barar, Ayoub Aghanejad, Yadollah Omidi
Life Sciences.2019; 231: 116545. CrossRef
Biguanides Exert Antitumoral Actions in Pituitary Tumor Cells Through AMPK-Dependent and -Independent Mechanisms
Mari C Vázquez-Borrego, Antonio C Fuentes-Fayos, Aura D Herrera-Martínez, Fernando L-López, Alejandro Ibáñez-Costa, Paloma Moreno-Moreno, María R Alhambra-Expósito, Ana Barrera-Martín, Cristóbal Blanco-Acevedo, Elena Dios, Eva Venegas-Moreno, Juan Soliver
The Journal of Clinical Endocrinology & Metabolism.2019; 104(8): 3501. CrossRef
Metformin induces TPC-1 cell apoptosis through endoplasmic reticulum stress-associated pathways in vitro and in vivo
Jianwen Ye, Lei Qi, Kunlun Chen, Renfeng Li, Shengping Song, Chuang Zhou, Wenlong Zhai
International Journal of Oncology.2019;[Epub] CrossRef
AKT2 contributes to increase ovarian cancer cell migration and invasion through the AKT2-PKM2-STAT3/NF-κB axis
Bin Zheng, Li Geng, Li Zeng, Fangfang Liu, Qiaojia Huang
Cellular Signalling.2018; 45: 122. CrossRef
Antitumor effects of metformin are a result of inhibiting nuclear factor kappa B nuclear translocation in esophageal squamous cell carcinoma
Nobufumi Sekino, Masayuki Kano, Yasunori Matsumoto, Haruhito Sakata, Yasunori Akutsu, Naoyuki Hanari, Kentaro Murakami, Takeshi Toyozumi, Masahiko Takahashi, Ryota Otsuka, Masaya Yokoyama, Tadashi Shiraishi, Koichiro Okada, Isamu Hoshino, Keiko Iida, Aki
Cancer Science.2018; 109(4): 1066. CrossRef
Down‐regulation of intracellular anti‐apoptotic proteins, particularly c‐FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL
Ali Hassanzadeh, Majid Farshdousti Hagh, Mohammad Reza Alivand, Ali Akbar Movassaghpour Akbari, Karim Shams Asenjan, Raedeh Saraei, Saeed Solali
Journal of Cellular Physiology.2018; 233(10): 6470. CrossRef
Interaction Between Prediabetes and the ABO Blood Types in Predicting Postsurgical Esophageal Squamous Cell Carcinoma-Specific Mortality: The FIESTA Study
Guohui Fan, Dan Hu, Xinran Zhang, Feng Peng, Xiandong Lin, Gang Chen, Binying Liang, Hejun Zhang, Yan Xia, Xiongwei Zheng, Jianzheng Jie, Wenquan Niu
Frontiers in Oncology.2018;[Epub] CrossRef
Obesity, Diabetes and Gastrointestinal Malignancy: The role of Metformin and other Anti-diabetic Therapy
McFarlane Samy I
Global Journal of Obesity, Diabetes and Metabolic Syndrome.2018; : 008. CrossRef

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The Expression of c-myc, bcl-2 and p53 Proteins in Adenocarcinomas of Lung: Jinyoung Yoo, Ji Han Jung, Hyun Joo Choi, Seok Jin Kang, Chang Suk Kang; Cancer Res Treat. 2004;36(2):146-150. Published online April 30, 2004; DOI: https://doi.org/10.4143/crt.2004.36.2.146

Abstract PDF PubReader ePub

Purpose

c-myc, bcl-2 and p53 are known to regulate apoptosis. There has been growing interest in analyzing their contribution to the pathogenesis and prognosis in a variety of human cancers. This study was undertaken to investigate the expression of these proteins in pulmonary adenocarcinomas and to determine their relationship with clinicopathologic parameters and survival.

Materials and Methods

Archival tumor tissues from 61 patients with adenocarcinoma of lung were analyzed by immunohistochemistry for the expression of c-myc, bcl-2 and p53 proteins. Clinical information was obtained through the computerized retrospect database from the tumor registry.

Results

Of 61 patients, 32 were men and 29 women with the median age 63 years. 4 had stage I disease, 2 had stage II disease and 55 had stage III disease. The expression of c-myc protein was identified in 13% (8/61) tumors, bcl-2 protein was detected in 1.6% tumors (1/61) and p53 was detected in 77% (47/71) tumors. The association of the expression of c-myc, bcl-2 and p53 was not detected. The survival time was longer in patients expressing c-myc protein than in patients without the c-myc protein expression (p=.045). Neither bcl-2 nor p53 showed the correlation to clinicopathologic variables.

Conclusion

Our data suggest the involvement of p53 alteration in the pathogenesis of lung adenocarcinoma. The c-myc expression in some tumors indicates that c-myc alone may not contribute critically to the development and/or the progression of these tumors. It, however, correlated to the survival time, suggesting the c-myc expression as a favorable prognostic factor possibly through the apoptosis pathway.

Citations

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The transcriptional repression activity of STAF65γ is facilitated by promoter tethering and nuclear import of class IIa histone deacetylases
Feng-Shu Hsieh, Nai-Tzu Chen, Ya-Li Yao, Shi-Yun Wang, Jeremy J.W. Chen, Chien-Chen Lai, Wen-Ming Yang
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms.2014; 1839(7): 579. CrossRef
Expression of Matrix Metalloproteinase-9 Correlates with Poor Prognosis in Human Malignant Fibrous Histiocytoma
Jinyoung Yoo, Ji Han Jung, Seok Jin Kang, Chang Suk Kang
Cancer Research and Treatment.2004; 36(6): 384. CrossRef

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Expression of P53, Bcl-2, Bax, and P-glycoprotein in Relation to Chemotherapeutic Response in Patients with Advanced Non-Small-Cell Lung Cance: Suk Young Park, Eun Hee Lee, Kee Won Kim, Chul Seung Kay, Seok Chan Kim, Ji Won Suhr, Kyung Shick Lee; J Korean Cancer Assoc. 2001;33(2):158-162.

Abstract PDF: PURPOSE
To evaluate the relationship between the expressions of p53, bcl-2, bax, and p-glycoprotein and the chemotherapeutic response seen in patients with advanced NSCLC.
MATERIALS AND METHODS
Forty-four patients pathologically proven as NSCLC were reviewed. They had undergone at least two cycles of the same chemotherapeutic agents (cisplatin 60 mg/m2 day 1+ vinorelbine 25 mg/m2 day 1, 8, 21-day cycle) and the clinical response was evaluated by WHO criteria. The expressions of p53, bcl-2, bax, and p-glycoprotein were determined by immunohistochemistry.
RESULTS
Patients recorded as CR (2/44) and PR (20/44) were classified as the responder group (22/44) and stable (17/44) and progression (5/44) as the non-responder group (22/44). Positive expression of p53, bcl-2, bax, and p-glycoprotein were 84.1%, 65.9%, 88.6%, and 61.4% respectively. The expression score of p53 was significantly higher in the non-responder group than that seen in the responder group (8.59+/-1.89 vs 5.32+/-2.15, p<0.05). However, the expression scores of bcl-2, bax, and p-glycoprotein were not significantly correlated with the clinical response.
CONCLUSION
This study suggests that p53 gene mutation plays an important role in the clinical response to chemotherapy including cisplatin and vinorelbine. In future investigations, the correlation with the survival time will be studied.

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Expression of p53, bcl-2 Protein in Small Cell Lung Cancer (SCLC) Cell Lines in Relation to Sensitivity to Chemotherapy: In Sook Woo, Myung Jae Park, Young Seok Park, Sung Won Jung, Mi Ae Yeo, Soo Hyun Park, Si Young Kim, Hwi Joong Yoon, Kyung Sam Cho, Jae Kyung Park, Young Il Kim; J Korean Cancer Assoc. 2000;32(5):904-910.

Abstract PDF: PURPOSE
Sensitivity of tumor cells to chemotherapeutic regimen may be accentuated by their abnormal expression of oncogene. p53 is required for the efficient activation of apoptosis following irradiation or treatment with chemotherapeutic agents. The aim of this study was to evaluate the relationship between chemosensitivity and apoptosis related proteins such as p53, bcl-2 in small cell lung cancer cell lines. MATERIAL AND METHODS: Six human small cell lung cancer cell lines, NCI-H69, NCI-H128, NCI-H1436, NCI-H1092, derived from untreated and treated patients were tested for chemo sensitivity and the expression of the p53, bcl-2 genes were examined in each cell lines with western blot analysis. We used 4 drugs including adriamycin, cisplatin, vincristine and VP-16.
RESULTS
NCI-H128 was the most sensitive cell line to four drugs. NCI-H82 and NCI-H1092 were highly resistant to VP-16, adriamycin and vincristine and determination of an IC50 was not possible. In western blot analysis, NCI-H128 alone was strong positive to p53 monoclonal antibody and the rest of cell lines were negative. All but NCI-H128 were positive to bcl-2 monoclonal antibody. NCI-H128 which was strong positive to p53 and negative to bcl-2. NCI-H1092 was strong positive to bcl-2 and negative to p53 monoclonal antibody.
CONCLUSION
We were not able to explain the expression of p53 in small cell lung cancer cell lines in relation to senitivity to anti-cancer chemotherapeutic agents. But the expression of bcl-2 in small cell lung cancer cell lines was correlated with the chemosensitivity well.

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Frequency of bcl-2/JH Rearrangement in Benign Lymphoid Hyperplasia: Young A Yoo, Seung Ho Lee, Mi Na Son, Zeung Kun Cho, Kun Choi, Jong Wook Choi, Sang Won Shin, Byung Soo Kim, Jun Suk Kim, In Sun Kim, Yeul Hong Kim; J Korean Cancer Assoc. 2000;32(3):587-594.

Abstract PDF: No abstract available.

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The Role of bcl-2 and p53 in Tamoxifen-Induced Apoptosis of Human Breast Cancer Cell Lines: Woo Chul Noh, Dong Young Noh, Yong Ho Ham, Chang Min Kim, Nam Sun Paik, Nan Mo Moon, Kuk Jin Choe; J Korean Cancer Assoc. 2000;32(3):531-538.

Abstract PDF: PURPOSE
Tamoxifen has been well known as an effective anti-tumor agent against breast cancer. The important role of bcl-2 and p53 proteins in tamoxifen-induced apoptosis of breast cancer cells has been suggested. However, the paradoxical fact that bcl-2 over-expression is assdegrees Ciated with better prognosis in clinic has not yet been clearly explained. To investigate this paradox, we analyzed the effect and dynamics of bcl-2 and p53 on the apoptosis after treatment of breast cancer cells with tamoxifen.
MATERIALS AND METHODS
The human breast cancer cell lines MCF-7 and MB MDA-468 were treated with 17-betaestradiol (E2) and tamoxifen.
RESULTS
Following tamoxifen treatment, MCF-7 cells underwent apoptosis accompanied by reduced bcl-2 expression. E2 pre-treatment led to the inhibition of tamoxifen-mediated apoptosis and bcl-2 down-regulation. When MB MDA-468 cells were treated with E2 or tamoxifen, bcl-2 and p53 protein expression did not change and apoptosis did not develop.
CONCLUSION
We observed that the down-regulation of bcl-2 by tamoxifen treatment can facilitate the apoptosis of breast cancer cells without p53 mutations. This finding was consistent with clinical experiences in which bcl-2 positive tumors were assdegrees Ciated with more indolent phenotypes in breast cancer.

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Expression of p53, p21/WAF1, bcl-2 and Loss of Heterozygosity for the Study of Apoptosis in Gastric Carcinoma: Hang Jong Yu, Joo Ho Lee, Woo Ho Kim, Kuk Jin Choe, Jin Pok Kim; J Korean Cancer Assoc. 2000;32(3):447-457.

Abstract PDF: PURPOSE
The purpose of this study was to correlate the immunohistdegrees Chemical expressions of p53, p21 and bcl-2, with their loss of heterozygosity (LOH) and clinical significance.
MATERIALS AND METHODS
Paraffin-embedded tissue sections from 30 patients with gastric car cinomas were examined for immunohistdegrees Chemical staining and LOH study. Primary antibodies used in immunohistdegrees Chemical staining were mouse mondegrees Clonal antibody to human p53, p21/ WAF1 and bcl-2. For PCR-LOH assays, D6S271, D6S105, D18S386, TP53, D17S796, and D17S786 microsatellite markers were used.
RESULTS
The expression rates of p53, p21 and bcl-2 were 76.7%, 80% and 3.3%, respectively. The expression of p21 was correlated with lymph node metastasis. LOH were found in 20.8% at D6S271, 42.3% at D6S105, 31.6% at D18S386, 39.1% at TP53, 40.9% at D17S796, and 50.0% at D17S786. No correlation was found between the immunohistdegrees Chemical expression and the LOH in these gene sites.
CONCLUSION
p53 and p21 were detected in high rate, whereas bcl-2 expression rate was very low in gastric adendegrees Carcinoma. Of them, overexpression of p21 was correlated with the tumor progression. High incidence rate of LOH may play an important role in gastric carcinogenesis. These findings suggest that the effects on apoptosis and cell cycle by p53 and p21 were important in development and progression of gastric cancer.

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p27Kipl, K-67 and Bcl-2 Expression in Adenoid Cystic Carcinoma of Head and Neck: C S Choi, G Choi, J J Song, K S Hwang, K Y Jung, J O Choi; J Korean Cancer Assoc. 2000;32(2):382-389.

Abstract PDF: PURPOSE
p27Kip1 negatively regulates cell proliferation by mediating cell cycle arrest in Gl and Ki-67 is a reliable cellular proliferative index. Also Bcl-2, an inhibitor of apoptosis, has potential activity toward cell survival. The present study investigated p27Kip1, Ki-67 and Bcl-2 expression in adenoid cystic carcinoma for their usefulness of indicator in tumor progression and aggressiveness.
MATERIALS AND METHODS
Formalin-fixed paraffin-embedded surgical specimens were obtained from seventeen patients with adenoid cystic carcinoma. We performed immunohistochemical staining with p27Kip1, Ki-67 and Bcl-2 monoclonal antibodies and compared with patients clinicopathologic features.
RESULTS
There were significant correlation between low p27Kip1 expression and high grade and T classification, positive nodal status and perineural invasion and high stages. However, Ki-67 and Bcl-2 expression had no significant differences in clinicopathologic features and p27Kip1 expression.
CONCLUSION
p27Kip1 is a good reliable marker of tumor progression and aggressiveness in adenoid cystic carcinomas.

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Association of Tumor Angiogenesis with bcl - 2 Expression in Breast Cancer Patients: Do Yil Kim, Hy De Lee, Woo Hee Jung; J Korean Cancer Assoc. 1999;31(6):1159-1167.

Abstract PDF: PURPOSE
To evaluate the prognostic significances of angiogenesis and bc1-2, and association of each other, we investigated the correlation of microvessel count for angiogenesis and bcl-2 expression in breast cancer.
MATERIALS AND METHODS
We analysed immunohistochemistry staining from paraffin blocks in a series of 145 women with breast cancer. Immunohistochemical staining to detect factor VIII-related antigen highlighted the microvessels within primary invasive breast carcinoma. Using light microscopy, we counted microvessels per 200X field in the most active areas of neovascularization. To determine the bcl-2 immunoreactivity, we used a monoclonal antibody directed against the bcl-2 protein.
RESULTS
The median of microvessel count (MVC) was 31.5, and the proportions of tumors with low and high MVC were 51% and 49%. Eighty (55.2%) cancers showed the bcl-2 immunoreactivity in the cytoplasm. The microvessel count were correlated with lymph node status (p <0.001), tumor size (p=0.001), and lymphatic invasion around tumor (p=0.009). bcl-2 expressions were corelated with estrogen receptor positivity (p<0.001) and progesterone recepter positivity (p=0.029). The microvessel counts were negatively correlated with bcl-2 expression (p=0.006).
CONCLUSION
This study suggest that the angiogenesis which was investigated by micro- vessel counts was negatively correlated with bcl-2 expression.

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Type of Intestinal Metaplasia in the Surrounding Mucosa of Gastric Carcinoma and Expression of bcl-2, p53 and c-erbB-2 Prtein in Gastric Carcinoma: Seung Che Cho, Kun Young Kwon; J Korean Cancer Assoc. 1999;31(5):898-911.

Abstract PDF: PURPOSE
This study was carried out to clarify significance of types of intestinal metaplasia and roles of bcl-2, p53 and c-erbB-2 protein in the development of gastric carcinoma.
MATERIALS AND METHODS
Total one hundred fifty nine cases of surgically resected stomachs with benign ulcer (n=21), dysplasia (n=18) and gastric carcinoma (n=120) were studied histologically, histochemically and immunohistochemically.
RESULTS
Type III intestinal metaplasia was significantly more common in the carcinoma patients in older age group. Bcl-2 expression was found in 94.4% cases of dysplasia and 75.0% cases of carcinoma. Positivity for bcl-2 protein was significantly higher in intestinal type carcinomas than in diffuse type carcinomas (p=0.000). The expression of p53 protein showed 50.0% cases of dysplasia and 49.2% cases of carcinoma. The expression of p53 protein was significantly correlated with depth of invasion (p=0.000), regional lymph node metastasis (p=0.001), and tumor size (p=0.001). C-erbB-2 protein was only expressed in 15.0% cases of carcinoma. The expression of c-erbB-2 protein was found more often in advanced carcinomas (p=0.001) and carcinomas with regional lymph node metastasis (p=0.003).
CONCLUSION
Type III intestinal metaplasia was associated with age, but not with types of gastric carcinoma. Bcl-2 protein is probably involved in dysplastic lesion of gastric carcinogenic sequence and associated with intestinal type carcinoma, and p53 protein is also involved in dysplasia. p53 protein and c-erbB-2 protein may have a role of tumor invasion and nodal metastasis as poor prognostic factors.

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Induction of Apoptosis of Cancer Cells by Inhibition of Bcl-2 Expression: Ho Keun Yi, Myoung Hee Han, Soo Churl Cho, Jung Soo Kim, Young Han Hwang; J Korean Cancer Assoc. 1999;31(4):716-727.

Abstract PDF: PURPOSE
High levels and aberrant patterns of Bcl-2 gene expression have been reported in a variety of human cancers, including prostate, colorectal, lung and gastric cancers, neuroblastoma, non-Hodgkins lymphoma, and both acute and chronic leukemia. The Ewings sarcoma is a common malignant bone tumor in children and adolescents. Nearly all Ewings sarcomas have a t(11;22) chromosomal translocations which involves EWS gene and Fli-1 of ETS family transcription factors. The patterns of Bcl-2 gene expression in Ewings sarcoma is less well known. The inhibition of Bcl-2 gene expression leads to increase a apoptosis in several cancer cells. This study was undertaken to characterize the patterns of Bcl-2 gene expression in Ewings sarcoma cell (TC135) expressing fusion protein, EWS-Fli-l, and to induce the apoptosis of Ewings sarcoma cell by targeting Bcl-2 gene expression using antisense strategy.
MATERIALS AND METHODS
We used two types of antisense EWS-Fli-1 and Bcl-2 expression vectors. These vectors were transfected to TC135 cells by calcium phosphate method, and transformed cells were selected using G418. The transformed cells were stimulated with apoptosis-inducing reagents, and changes of Bcl-2 expression were analyzed by Western and Northern blot analyses. To confirm the increased apoptosis, we checked DNA fragmentation, cell viability assay by MTT and ICE (interleuldn converting enzyme) activity.
RESULTS
The TC135 cells transfected with antisense EWS-Fli-1 expression vector showed negatively regulated Bcl-2 protein and mRNA expression, but those transfected with control vector (pcDNA3) revealed no change of Bcl-2 gene expression. These results strongly suggested that the EWS-Fli-1 fusion protein directly regulate Bcl-2 gene expression on the Bcl-2 gene promotor region. And the TC135 cells transfected with antisense Bcl-2 expression vector showed increased apoptosis. These results suggested that the apoptosis pathway of Ewings sarcoma is regulated by EWS-Fli-1 fusion protein and following Bcl-2 gene. Finally, TC135 cells transfected with antisense Bcl-2 expression vector did not form colonies in soft agar, which may infer the loss of tumorigenicity.
CONCLUSION
The targeting of Bcl-2 gene in the TC135 cells using antisense strategy lead to an increased apoptosis in .Ewings sarcoma cells. This approach can be considered as an efficient candidate strategy of cancer gene therapy.

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p53 and bcl-2 Gene Expression in Gastational Trophoblastic Disease: Noh Hyun Park, Ju Won Roh, Jae Weom Kim, Yong Sang Song, In Ae Park, Soon Beom Kang, Hyo Pyo Lee; J Korean Cancer Assoc. 1999;31(3):582-589.

Abstract PDF: PURPOSE
p53 and bcl-2 expressions are known as important cell survival factors and their levels of expression are related with patients prognosis in various human malignancies. But there are few data about p53 and bcl-2 expression and their role in the genesis of gestational trophoblastic disease (GTD). The aims of this study are to describe p53 and bcl-2 expression in normal trophoblast and hydatidifonn mole (HM), and to identify the role of p53 and bcl-2 in the genesis of gestational trophoblastic tumor (GlTI from HM.
MATERIALS AND METHODS
Paraffin-embedded tissue sections from 32 cases of HM and 9 cases of normal early pregnancy placentas were obtained. Of 32 HM patients, 15 cases were cured after molar evacuation (group A), and 17 cases progressed to GT1' (group B). p53 and bcl-2 immunohistochemical stainings were done and their reactivity were graded. The positive rates of p53 and bcl-2 overexpression among normal placenta, group A, and group B were compared and analyzed.
RESULTS
p53 mutant gene overexpression was more frequently detected in HM (68%) than in normal placentas (22%)(p<0.05). bcl-2 was overexpressed in 31% of HM and 11% of normal placenta, but the difference was statistically insignificant (P > 0.05). The difference in bcl-2 and p53 expression between group A and group B was not observed (P>0.05). There was no inverse relationship between p53 and bcl-2 expression in group A, and group B (P>0.05).
CONCLUSIONS
p53 gene mutation may play a mle in the process of HM development, but p53 and bcl-2 were not associated with the genesis of GTI' from H-mole. More studies are needed to identify the molecular process in the progression of the GTD.

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Strain - Specific Differences in Radiation - Induced Apoptosis in Murine Tissues: Jinsil Seong, Sung Hee Kim, Won Jae Lee, Chang Ok Suh, Jin Sik Min; J Korean Cancer Assoc. 1998;30(6):1259-1268.

Abstract PDF: PURPOSE
To characterize strain-specific differences in radiation response in murine tissues with different radiosensitivity.
MATERIALS AND METHODS
Six-week old male mice of 2 strains, C57Bl/6J and C3H/HeJ, were given whole body gamma-radiation with a single dose of 10 or 25 Gy. At different times after irradiation, mice were killed and tissues with different radiosensitivity, thymus and liver, were collected. Each tissue sample was stained with hematoxylin and eosin and apoptotic cells were scored. Expression of p53, Bcl-2, Bcl-x, and Bax was analysed by western blotting and densitometry.
RESULTS
Radiation induced massive apoptosis in thymus with a peak level at 8 h after radiation. With 10 Gy irradiation, apoptotic indices in C57Bl/6J and C3H/HeJ were 81.0 2.5% and 59.4 4.0%, respectively (p<0.05). Radiation upregulated the expression of p53, Bcl-x, and Bax, but not Bcl-2; p53 with a peak level of 2.5 fold (C57Bl/6J) and 1.4 fold (C3H/HeJ) at 4 h, Bax with a peak level of 2.6 fold (C57Bl/6J) and 1.3 fold (C3H/HeJ) at 8 h, and Bcl-x with a peak level of 11.1 fold (C57Bl/6J) and 8.2 fold (C3H/HeJ) at 8 h after radiation. In liver, however, radiation-induced apoptosis was minimal (peak apoptotic index of 2.1% in C57Bl/6J and 1.7% in C3H/HeJ). None of p53, Bcl-2, Bcl-x, and Bax was significantly increased.
CONCLUSIONS
Induction of apoptosis and regulation of related genes by radiation were tissue specific. Strain difference of radiation-induced apoptosis was well coupled with theinduction of related genes in thymus, a radiosensitive tissue. This study shows that quantitative difference of radiation induced apoptosis by strain is regulated at the gene level with the involvement of multiple genes.

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Bcl-2 Expression in Endometrial Hyperplasia and Carcinoma: Jong Hyeok Kim, Chang Won Koh, Joor Yung Huh, Bong Hee Kim, Hun Sik Kong, Jun Hee Na, Yong Nam Kim, Young Tak Kim, Joo Hyun Nam; J Korean Cancer Assoc. 1998;30(6):1207-1218.

Abstract PDF: PURPOSE
To speculate the role of bcl-2 protooncogene in endometrial carcinogenesis by determination of the expression of bcl-2 in endometrial hyperplasia and carcinoma.
MATERIALS AND METHODS
We studied bcl-2 expression by an immunohistochemical method in the paraffin-embedded blocks of 78 patients with endometrial hyperplasia, 64 with simple hyperpasia, 9 with complex hyperplasia and 5 with atypical hyperplasia respectively, and 33 endometrial carcinoma treated at Asan Medical Center from June, 1989 to May, 1997. Intensity of bcl-2 staining was scored on a scale of 0 to 4, calibrated by comparison with stromal lymphocytes, which always received a score of 4.
RESULTS
The results of this study showed that bcl-2 was relatively highly expressed in simple (n= 64), complex (n=9) and atypical hyperplasias (n=5) with mean staining scores of 2.95+/-1.09 (Mean+Standard Deviation), 2.78+/-1.20 and 3.60+/-0.89 respectively, which showed no difference among histologic types. In endometrial carcinoma, the expression of bcl-2 was significantly down regulated (mean score=1.76+/-1.35) compared with that of hyperplasia, and did not conelate with FIGO surgical stage. However, grade III tumor showed significantly lower expression that grade I or II tumor.
CONCLUSION
Bcl-2 expression is down regulated in endometrial carcinoma than endo- metrial hyperplasia, and correlates with tumor grade, which suggest that bcl-2 expression might be the result of carcinogenesis or bcl-2 plays only an adjunctive role in the endometrial carcinogenesis.

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Status of Bcl-2 expression and Its Relationship to the Other Prognostic Factors in Breast Cancer: Gun Young Roh, Dong Ha Shin, Yong Lae Park, Jun Ho Shin, Heung Dae Kim, Yong Sin Kim, Won Kon Han, Joo Seob Keum, Myung Sook Kim, Gu Kong, Myung Suk Kim; J Korean Cancer Assoc. 1998;30(6):1131-1139.

Abstract PDF: PURPOSE
There are several well-established prognostic factors to predict the course of breast cancer. Recently, a new category of genes that control the process of programmed cell death, also called apoptosis, has been identified. It includes the bcl-2 proto-oncogene which actively blocks apoptosis. The purpose of this retrospective study is to investigate the relationship between Bcl-2 protein expression in primary breast cancers and other markers of prognostic value.
MATERIALS AND METHODS
We analyzed 43 cases of invasive ductal carcinoma of breast cancer, which were consecutively operated in the period from January 1990 to December 1994. Analysis of Bcl-2 protein, ER and PgR expression was carried out using immunohistochemistry on the paraffin-embedded tissue section. The following indices were measured.; size of the tumor, number of axillary metastasis, histological grade, menopausal status, ER, PgR, and Bcl-2 status.
RESULTS
Expression of the bcl-2 proto-oncogene was found in 28 cases of 43 patients (65.1%). No relationship could be observed between Bcl-2 status and tumor grade, TNM staging and menopausal status. A strong positive relationship was demonstrated between Bcl-2 immunoreactivity and ER status (P 0.001) and PgR status (P=0.014). A favorable prognostic value was demonstrated for Bcl-2 expression on overall survival (P=0.0427), but no prognostic value was demonstrated on disease-free survival (P=0.1587).
CONCLUSION
Our results suggest that the Bcl-2 expression may be a favorable prognostic marker and its important role may be a modulator of response to adjuvant therapy in breast cancer.

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bcl-2 and p53 Gene Expression in Colonic Adenoma and Carcinoma: Chang Young Lim, Jeong Won Kim, Il Han Song, Young Joo Jin, Im Whan Rho, Dong Kook Park, Jeong Hee Cho, Sung Bae Choi; J Korean Cancer Assoc. 1998;30(1):89-99.

Abstract PDF: PURPOSE
Recently, it is suggested that the inhibitian of apoptosis is associated with tumorigenesis of colon. Bcl-2 gene is an important inhibitory regulator of apoptosis, and bcl-2 acts antagonistly with the wild type p53 gene, one of the tumor suppressor genes, in apoptosis. To detnmine the role of bcl-2 and p53 gene in colonic tumorigenesis, we performed the study.
MATERIALS AND METHODS
We tested the tissue obtained by polypectomy and surgical resection by immunohistochemical staining for Bcl-2 and p53.
RESULTS
We found that in normal colonic tissue, the Bcl-2 was sparcely expressed, and the p53 was expressed sporadically. The rate of positivity of staining was below 5%. However, in colonic adenoma and colon cancer tissue, Bcl-2 and p53 were expressed more than in nonnal colonic tissue(p<0.05). (Scoring in Colonic adenoma: Bcl-2 6.2+/-1.1, p53 5.7+/-1.0; Scoring in Colonic carcinoma: Bcl-2 4.7+/-1.0, p53 8.3+/-0.9) CONCLUSION: Our results suggested that the bcl-2 and p53 play an important role in colonic tumorigenesis.

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A Study of Apoptosis, and bcl-2 and p53 Expressions in Breast Cancer: Dong Won Kim, So Young Jin, Dong Wha Lee; J Korean Cancer Assoc. 1997;29(3):412-421.

Abstract PDF: PURPOSE
This study was undertaken for evaluation of the extent of apoptosis and expression of the bcl-2 gene and p53 gene as prognostic factors in breast cancer.
MATERIALS AND METHODS
The extent of apoptosis was determined by the 3' end-labeling method of DNA in tissue sections and the expressions of bcl-2 and p53 was determined by immunohistochemical staining in 41 cases of breast carcinomas.
RESULT
bcl-2 was correlated with ER positivity (p=0.005), with nuclear grade (p=0.001), and with tumor size (p=0.019), whereas it was inversely correlated with apoptosis (p= 0.018). No association was found with axillary nodal status. Apoptosis was not associated with clinicopathological parameters, such as ER positivity, nuclear grade, tumor size, and lymph node status. p53 was not associated with above clinicopathological parameters. No relationship between the expression of bcl-2 and p53 was found.
CONCLUSION
These results suggest that bcl-2 protein inhibit apoptosis, and its expression is associated with favorable clinicopathological features.

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Clinicopathological Correlation of Bcl-2 and p53 Immunohistochemistry in Breast Cancer: Ja Yun Koo, Hy De Lee, Woo Hee Jung; J Korean Cancer Assoc. 1997;29(3):404-411.

Abstract PDF: PURPOSE
Bcl-2 and p53 are known to act as a regulator of apoptosis in breast cancer and we evaluated the significance of these gene expressions and correlation with prognostic factors in breast cancer.
MATERIALS AND METHODS
In order to investigate the expression of Bcl-2 and p53, we analyzed immunochemistry staining from paraffin blocks in a series of 80 women with breast cancer. Expression was then compared with the established indicators of prognosis.
RESULTS
Bcl-2 positivity was 45% and p53 was 32.2%. No relationships could be observed between bcl-2 and node status,tumor size and also between p53 and node status, differentiation,tumor size. Strong positive relationships were seen between bcl-2 and estrogen receptor (ER) (p<0.0001), progesterone receptor (PR) (p<0.001). p53 also showed relationships with ER and PR (p<0.05) Histologic (p<0.05) and nuclear grade (p<0.05) showed relationships with bcl-2 but not with p53. Inverse relationship was noted between p53 and ER, PR (p<0.05). Inverse relationship was also found between bcl-2 and p53 expression (p<0.001).
CONCLUSION
This study suggest that there may be a possibility that bcl-2 and p53 expressions can affect tumor growth and prognosis in breast cancer patients.

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Fraquency and Clinical Implication of bcl-2 / JH Rearrangement in Korean Non - Hodgkin's Lymphoma: Yeul Hong Kim, In Sun Kim, Jin Hai Hyun; J Korean Cancer Assoc. 1994;26(2):262-274.

Abstract PDF: The translocation of 14q32 with 18q21 is the most common chromosomal abnormality in human non-Hodgkins lymphomas. The translocation is commonly associated with the follicu- lar lymphoma which is relatively rare in Korean. About 30% of large cell lymphomas in West- ern countries have same translocation and this finding suggests that this subset of large cell lymphoma would be evolved from foilicular lymphoma. Recently, the translocation breakpoint has been cloned and polymerase chain reaction(PCR) for detecting bcl-2/JH(immunoglobulin heavy chain gene joining segment) rearrangement, the crossover site of trans1ocation, was in- troduced. Detection of bcl-2/JH rearrangement in Korean large cell lymphoma tissue should lead to better understanding of the biology of lymphomas in Korea. So, this study was designed to evaluate the frequency of bcl-2/JH rearrangement in Korean non-Hodgkins lymphomas and to compare the result with those of other countries. The DNA from total 22 cases of non-Hodg- kin's lymphomas were examined with PCR and Southern hybridization with radiolabeled oligonucleotide probes. DNAs were extrated from 15 unfixed frozen and 7 formalin-fixed parffin-embedded biopsy specimens. The t(14; 18) chromosomal translocation, resulting in bcl-2/ JH fusion gene, was detected in 1(9%) of 1 1 diffuse large cell lymphomas and 2(14.3%) of 14 B cell lymphomas. The low frequency of bcl-2/JH rearrangement suggests different genetic consequences in lymphomagenesis of Asian. However, the clinical implication of bcl-2/JH rear- rangement is doubtful in Korean due to quite low frequency.

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Immunologic and Oncogenic Study on the Cervical Neoplasia: Eun Yeong Seol, Sung Chul Lim; J Korean Cancer Assoc. 1996;28(6):1071-1083.

Abstract PDF: Immune response commonly is cited as a determining factor in the development or clearance of various neoplasias, but the immunobiology of neoplastic progression is poorly understood. The cervix has the largest concentration of lymphocytes found in the female genital tract and as a component of the common mucosal immune system guards against ascending infection from the microbial-laiden vagina, but cervical immunocytes have not been well characterized in the neoplasia itself. The objective of this study is to characterize the subpopulations of lymphocytes that infiltrate various grades of cervical neoplasia including metaplasia to invasive carcinoma. To establish the correlation I examined 60 cases of uterine cervix which were divided 4 categories according to the Bethesda Classification system; normal cervix(15), low grade squamous intraepithelial lesions(SILs)(15), high grade SILs(15), and invasive squamous cell carcinomas(15 cases). The degrees of T-lymphocyte infiltration were assessed after immunohistochemical staining by UCHL1, and compared to stainability of aberrant p53 and bcl-2 protein. There were significant increasing number and proportion of T-cells of invaisve cancers compared with that of preinvasive lesions. Aberrant p53 expression of invasive cancer was a little more intensive than that of low grade and high grade SILs, and there was no correlation between T-cell infiltration and aberrant p53 and/or bcl-2 expression. Bcl-2 was expressed in most of basal layer and some cases of parabasal layer of low and high grade SILs, and some minute foci of invasive cancer. In the adjacent areas of SILs and invasive lesions strong bcl-2 expression was noted in parabasal, intermediate or superficial cells case by case. In conclusion, the UCHLl-positive T cell infiltrate far exceeded in the invasive, but not in the preinvasive lesions, a finding that suggests that T cells are recruited preferentially to cervical lesions with progression to invasion. It is suggested that the T cell recruitment is not related to p53 or bc1-2, but the unknown third factors, and the bcl-2 overexpression is involved in the early step of epithelial neoplastic transforrnation and followed by recurrent overexposure to various oncogenic factors.

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