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Study on CEACAM1 Mediated Cell Death and Antitumor Effects of Metformin in 5-Fluorouracil Resistant Gastrointestinal Cancer Cells
DC Field | Value | Language |
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dc.contributor.advisor | 구자록 | - |
dc.contributor.author | 김성희 | - |
dc.date.accessioned | 2017-07-14T01:15:53Z | - |
dc.date.available | 2017-07-14T01:15:53Z | - |
dc.date.issued | 2017-02 | - |
dc.identifier.other | 000000140918 | - |
dc.identifier.uri | https://hdl.handle.net/10371/121782 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 종양생물학전공, 2017. 2. 구자록. | - |
dc.description.abstract | Gastrointestinal (GI) cancer has high incidence and death rate in Korea. Thus to understand about tumorigenesis mechanisms and develop the new therapeutic strategies of GI cancer are important for reducing cancer risk. Conventional therapeutic strategies of GI cancers are surgery with chemotherapy, and chemo-radiotherapy. 5-fluorouracil (5-Fu), oxaliplatin, and irinotecan are most widely used for GI cancer. The combination of 5-Fu with oxaliplatin or irinotecan has improved response rate about up to 40-50% for GI cancer patients. However, still the metastasis and recurrence that related with 5-Fu resistance are occurred, it might be needed of basic research about resistance mechanisms and new strategies for improve of therapeutic effects. In this paper, sensitivity to 5-Fu and gene expression pattern as treated with 5-Fu in parental cancer cell lines, SNU-638, SNU-C5, and their 5-Fu resistant cancer cell lines were investigated.
Based on this study, the purpose of paper is suggestion of adjuvant 5-Fu to recover the resistance. Because of Carcinoembryonic antigen-related cell adhesion molecule1 (CEACAM1), known as tumor suppressor gene, expression level was changed as treated with 5-Fu dose-, and time dependent manner in parental cell lines, I was supposed to that CEACAM1 might be correlated with 5-Fu sensitivity. However, oxaliplatin, irinotecan, and radiation affected to CEACAM1 expression level only in parental cancer cell lines. Through this, I suggested that increased CEACAM1 was one of the phenotypes of cell death regulated by chemotherapeutic agents. As a results, I suggested that CEACAM1 could be used as an indicator of chemotherapeutic agents mediated cell death. Metformin, one of the type II diabetics therapeutic agent that was recently reported about anticancer effect. It was also induce CEACAM1 expression level in GI cancer cell lines. Beside of this, metformin has synergistic effect with 5-Fu especially in 5-Fu resistant cancer cell line. In addition, metformin inhibits cell proliferation, increase cell death and cell cycle arrest, and downregulation of cancer stem cell marker genes. These effects of metformin were concomitant of inhibition of DNA replication machinery and mitotic cell cycle genes. According to series of results, I proposed that use of metformin as adjuvant of 5-Fu that might be reduction of 5-Fu resistance, with less clinical severe adverse effects. | - |
dc.description.tableofcontents | GENERAL BACKGROUND 1
Gastrointestinal cancer 1 Gastric cancer 1 Colorectal cancer 3 Molecular pathway of therapeutic agents for GI cancer 8 5-Fluoriuracil (5-Fu) 8 Oxaliplatin 10 Irinotecan 11 OBJECTIVES 13 PART Ⅰ. Study of expression level of CEACAM1 and overcome the 5-Fu resistance in human gastrointestinal cancer cell lines 14 Abstract 15 Introduction 16 Materials and methods 20 Cell culture and Chemicals 20 PCR and Western blot analysis 23 Cell proliferation assay 25 Establishment of shCEACAM1 cell lines 25 Cell cycle analysis 26 Wound healing assay 27 Statistical analysis 27 Results 28 CEACAM1 expression level in gastrointestinal cancer cell lines 28 CEACAM1 expression level was correlated with 5-Fu sensitivity 31 CEACAM1 was not directly correlated with 5-Fu mediated cell death 34 CEACAM1 expression was increased by treatment of chemotherapeutic agents and irradiation 45 Metformin inhibits cell proliferation and increased CEACAM1 expression 48 Discussion 53 PART Ⅱ. Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells 59 Abstract 60 Introduction 62 Materials and methods 64 Cell culture and Chemicals 64 Cell proliferation, Migration, and Clonogenic assay 64 Apoptotic analysis 66 Cell cycle analysis 66 Reverse transcriptase (RT) - PCR and quantitative real-time RT-PCR 67 Western blot analysis 68 Immunophenotyping 69 Statistical analysis 69 RNA Sequencing 69 Results 74 Metformin reduced cell proliferation and increased G1 arrest in colon cancer cell line 74 Metformin influenced cell migration, clonogenicity and angiogenesis 84 Metformins effect on AMPK/mTOR axis and NF-ƙB pathway 89 Metformin influenced cancer stem cell population and tumor sphere formation 91 Metformin reduced DNA replication machinery genes in 5-Fu resistant cancer cell line 95 Discussion 99 GENERAL DISCUSSION AND CONCLUSION 106 REFERENCES 108 국문초록 122 | - |
dc.format | application/pdf | - |
dc.format.extent | 7069579 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | ko | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Gastrointestinal (GI) cancer | - |
dc.subject | 5-Fluorouracil (5-Fu) | - |
dc.subject | oxaliplatin | - |
dc.subject | irinotecan | - |
dc.subject | 5-Fu resistance | - |
dc.subject | Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) | - |
dc.subject | Metformin | - |
dc.subject.ddc | 616 | - |
dc.title | Study on CEACAM1 Mediated Cell Death and Antitumor Effects of Metformin in 5-Fluorouracil Resistant Gastrointestinal Cancer Cells | - |
dc.type | Thesis | - |
dc.description.degree | Doctor | - |
dc.citation.pages | 122 | - |
dc.contributor.affiliation | 의과대학 협동과정 종양생물학전공 | - |
dc.date.awarded | 2017-02 | - |
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