자궁근종에서 도파민수용체와 전달체의 발현 증가와 도파민전달체 유전자의 메칠화 감소
Increased expression of dopamine receptors and transporterand hypomethylation of dopamine transporter genein uterine leiomyoma
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목적: 도파민은 민무늬근육세포의 증식을 조절함에 있어 중요한 역할을 한다. 이 연구에서는 자궁근종과 정상자궁근육조직에서 도파민 D1과 D2 수용체와 도파민전달체 (DAT)의 발현정도와 DAT 발현 조절에 메칠화의 작용을 알아보고자 하였다. 연구 방법: 자궁근종으로 자궁절제술을 받은 20명의 환자로부터 정상자궁근육과 자궁근종조직을 얻었다. 이들 조직에서 도파민 D1과 D2 수용체와 DAT의 발현정도를 RT-PCR과 면역조직화학법으로 조사하였다. DAT 유전자의 메칠화는 DNA를 HpaII 제한효소로 자른 후 methylation-sensitive PCR을 시행하여 분석하였다. 결과: 도파민 D1 수용체의 mRNA의 수준은 정상자궁근육에서 D2 수용체 보다 높은 상태였으며 이것은 자궁근종에서 변화가가 없었다. 이에 비해 도파민 D2 수용체와 DAT의 mRNA 수준은 정상자궁근육조직에서 보다 자궁근종에서 증가되어 있었다. 이러한 mRNA의 발현양상은 면역조직화학염색의 결과와 일치하였다. 자궁근종에서 DAT 유전자의 CpG island의 intron1 부분 (전사시작부위를 기준으로 +377-+888)에서만 메칠화가 감소되어 있었다. 결론: 도파민 D2 수용체와 DAT의 발현의 증가가 자궁근종세포의 증식과 관련이 있을 것으로 생각되며, DAT의 발현은 이 유전자의 CpG island의 메칠화 양상에 의해 조절될 것으로 생각된다.
Abstract
Objective: Dopamine plays a key role in the proliferation regulation of the smooth muscle cells. The purpose of this study was to observe the degree of expression of dopamine D1 and D2 receptors and dopamine transporter (DAT) and to evaluate the influence of methylation about control of expression of DAT in uterine leiomyoma and normal myometrial tissue. Methods: In 20 patients who underwent hysterectomy due to uterine leiomyoma, normal myometrial and leiomyoma specimens were obtained. The expression of dopamine D1 and D2 receptors and DAT was demonstrated by using RT-PCR and immunohistochemistry in each normal myometrium and leiomyoma. Analysis of the DNA methylation status of DAT was conducted using HpaII digestion and the methylation-sensitive PCR. Results: The mRNA level of dopamine D1 receptor was relatively higher in normal myometrium than D2 receptor and it was also unchanged in leiomyomas. However, the mRNA levels of dopamine D2 receptor and DAT in leiomyomas were much higher than normal myometrium. Consistent with elevated mRNA levels, high levels of dopamine receptors protein expression were detected by immunohistochemistry in leiomyomas. The degree of methylation at CpG sites of the area intron 1 of DAT (genomic position, +377-+888) was decreased in leiomyomas. Conclusion: These results suggest that overexpressed dopamine D2 receptor and DAT would be associated with proliferation of human uterine leiomyomas and the methylation status of the CpG island of DAT determines its expression.
참고문헌 (26)
- "Genetic and epigenetic aspects of DNA methylation on genome expression", 18, pp.869~882 (1997)
- "Cancer as an epigenetic disease DNA methylation and chromatin alterations in human tumours", 196, pp.1~7 (2002)
- "DNA hypermethylation in tumorigenesis", 16, pp.168~174 (2000)
- "A gene hypermethylation profile of human cancer", 61, pp.3225~3229 (2001)
- "Analysis of CpG island hypermethylation in human ovarian cancer using differential methylation hybridization", 82, pp.261~268 (2001)
- "Promoter hypermethylation of multiple genes in carcinoma of the uterine cervix", 7, pp.1982~1986 (2001), Clin Cancer Res
- "Identification and charaterization of differentially methylated regions of genomic DNA by methylation-sensitive arbitrarily primed PCR", 57, pp.594~599 (1997)
- "Structure and organization of the gene encoding human dopamine transporter", 195, pp.11~18 (1997)
- "Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter", 379, pp.606~612 (1996)
- "Dopamine receptors:From structure to function", 78, pp.189~225 (1998)
- "Biogenic amines as regulator of the proliferative activity of normal and neoplastic cells", 17, pp.1~12 (1987)
- "inhibits proliferation and cytotoxicity of CD4+ and CD8+ T cells by D1 dopamine receptors an in vitro analysis", 1, pp.1363~1374 (2001)
- "Alteration of dopamine D2 receptors in human malignant stomach tissue", 42, pp.1260~1264 (1997)
- "Decreased dopamine receptor expression and its second-messenger cAMP in malignant human colon tissue", 44, pp.916~921 (1999)
- "Anti- proliferative effects and cell death mediated by two isoforms of dopamine D2 receptors in pituitary tumor cells", 206, pp.49~62 (2003)
- "Dopamine as a novel antimigration and antiproliferative factor of vascular smooth muscel cells through dopamine D1-like receptors", 17, pp.3164~3173 (1997)
- "Expression of dopamine receptors and transporter in neuroendocrine gastrointestinal tumor cells", 71, pp.667~678 (2002)
- "Expression of the D2 subfamily of dopamine receptor genes in kidney", 266, pp.646~50 (1994)
- "Localization of dopamine receptor subtypes in systemic arteries", 22, pp.277~288 (2000)
- "D2 dopamine-receptor- mediated inhibition of proliferation of rat lactotropes in culture is accompanied by changes in cell shape", 69, pp.163~171 (1998)
- "D2 dopamine receptors stimulate mitogenesis through pertussis toxin-sensitive G proteins and Ras-involved ERK and SAP", JNK pathways in rat C6- D2L glioma cells, 1998, pp.71, 980~990
- "Distinct roles for Gαi2 and Gβ in signaling to DNA synthesis and Gαi3 in cellular transfor-mation by dopamine D2S receptor activation in BALB", c 3T3 cells, 2000, pp.20, 1497~1506
- "도파민과 세로토닌 운반체 및 수용체 영상을 위한 방사선리간드", 34, pp.159~168 (2000)
- "Dopamine transporter:Basic aspects and neuroimaging", 18, pp.3~8 (2003)
- "Alterantions in DNA methylation:A fundamental aspect of neoplasia", 72, pp.141~196 (1998)
- "Specific methylation status of the entire CpG island is not a prerequisite for the formation of an inactive chromatin at the promoter region in cancer cells", 26, pp.127~128 (2003)