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Study on epigenetic mechanism of DNA methylation gene in colorectal cancer 원문보기

  • 저자

    문지욱

  • 학위수여기관

    고려대학교 대학원

  • 학위구분

    국내박사

  • 학과

    의학과 분자인체유전학전공

  • 지도교수

    박선화

  • 발행년도

    2014

  • 총페이지

    xv, 138 p.

  • 키워드

    5-Aza-2'-deoxycytidine ADHFE1 AKR1B1 CHST10 Colorectal cancer Demethylating effect DNA methylation ELOVL4 Epigenetics Invasion MT3-MMP Proliferation RUNX3 SOX5 STK33 vincristine ZNF304;

  • 언어

    eng

  • 원문 URL

    http://www.riss.kr/link?id=T13541894&outLink=K  

  • 초록

    The colorectal cancer (CRC) is a disease originated from the epithelial cells lining the gastrointestinal tract. It is the third most common cancer in Korea. CRC arises as a consequence of genetic events such as gene mutation and epigenetic alteration. DNA methylation is one of the epigenetic mechanisms. Methylation-mediated inactivation of tumor-suppressor genes is a critical event during the pathogenesis of many malignancies. The aim of this study was to identify new hypermethylated genes and to identify methylation-based therapeutic target genes by vincristine in CRC cells. In chapter 1, the epigenetic mechanism of hypermethylated genes were described. First, hypermethylation of runt-related transcription factor 3 (RUNX3) was frequently presented in CRC and greater in colon cancer tissues than in rectal cancer tissues. Vincristine, anti-cancer drug, demethylates RUNX3 in colorectal adenocarcinoma cells, restoring its expression. Second, the promoter hypermethylation of alcohol dehydrogenase iron containing 1 (ADHFE1) is frequently present in CRC and alcohol induces methylation-mediated down expression of ADHFE1 and proliferation of CRC cells. Third, membrane type 3 matrix metallopeptidase (MT3-MMP) was frequently hypermethyated in CRC, and mRNA expression levels of MT3-MMP was inversely correlated the methylation status. MT3-MMP was associated with invasion of CRC cells. In chapter 2, the new hypermethylated genes and methylation-based therapeutic target genes using vincristine were described. Twenty-one hypermethylated candidate genes in CRC were selected by methylation chip. Among these genes, AKR1B1, CHST10, ELOVL4, SOX5, STK33, and ZNF304 identified novel hypermethylated genes in CRC tissue compared with normal tissues. In addition, vincristine induced demethylation of methylated genes in CRC cells to the same extent as 5-aza-2'-deoxycytidine. Twenty of 29 hypermethyated gene were significantly demethylated by vincristine treatment in two more CRC cell lines. These results suggest that methylation-mediated down expression of RUNX3, ADHFE1, and MT3-MMP plays an important role in colorectal carcinogenesis. In addition, these results provide insights into the potential functional impact of vincristine on methylated genes in CRC and 6 novel hypermethylated genes AKR1B1, CHST10, ELOVL4, SOX5, STK33, and ZNF304 may be potential methylation biomarkers and therapeutic targets of vincristine in CRC.


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