卵巢亮細胞癌中腫瘤抑制基因 SFRP 基因啟動子甲基化之分析
腫瘤抑制基因啟動子高度甲基化是造成基因不正常表現的機制之一。
SFRPs (secreted frizzled-related proteins) 是細胞外的分子能拮抗 Wnt
訊息傳遞。本研究針對在台灣發生率佔卵巢癌 12% 的卵巢亮細胞癌
探討 SFRP 基因群啟動子甲基化的情形以了解此種癌症形成的分子機
制。結果顯示 SFRP5 基因啟動子甲基化在卵巢亮細胞癌檢體中的比
例為 42% (5/12) ，在卵巢亮細胞癌細胞株的比例為 100% (5/5) ，但
於良性卵巢囊腫檢體的比例為 0% (0/15) ，漿液性卵巢癌檢體的比例
為 20% (3/15) 。而 SFRP1 啟動子只有在 40% (2/5) 的卵巢亮細胞癌
細胞株呈現甲基化的情形，於卵巢亮細胞癌檢體、良性卵巢囊腫檢體
及漿液性卵巢癌檢體 SFRP1 啟動子都是沒有甲基化。以正常淋巴球
細胞中的 SFRP5 表現量為基準，在測試的卵巢亮細胞癌細胞株中有 8
0% (4/5) 有 SFRP5 的表現。且以去甲基藥物 5’-aza-2’-deoxycytidine
(5-aza-dC) 處理十五天後， SFRP5 的 mRNA 在卵巢亮細胞癌細胞株
中有 60% (3/5) 會上升。 SFRP1 在卵巢亮細胞癌細胞株有 40% (2/5)
是沒有表現，但在去甲基藥物處理十五天後， SFRP1 的表現量並無
差異。此外，實驗結果也顯示加入去甲基藥物，可以抑制卵巢亮細胞
癌細胞株的生長速度 (cell proliferation) 及移行能力 (migration) 。
Analysis of the methylation status of the SFRP genes in ovarian clear c
ell carcinoma
Tumor suppressor genes are known to be inactivated by epigenetic modifications in
cluding promoter methylation. Secreted frizzled-related proteins (SFRPs) are extrac
ellular signaling molecules that antagonize the Wnt signaling pathway. Ovarian cle
ar cell carcinoma constitutes 12% of surface epithelial ovarian cancer in Taiwan. H
owever, the role of SFRP genes in ovarian clear cell carcinoma molecular mechanis
m remains unknown. We investigated the SFRP1 and SFRP5 promoter status and d
emonstrated that SFRP5 gene promoter was methylated in 42% (5/12) ovarian clear
cell carcinoma tissues and in 100% (5/5) ovarian clear cell carcinoma cell lines, co
mpared with 0% (0/15) benign ovarian cyst and 20% (3/15) serous ovarian carcino
ma tissues. And the SFRP1 gene promoter methylated only in 40% (2/5) ovarian cl
ear cell carcinoma cell lines. Our results show that endogenous SFRP5 mRNA expr
ession can be detected in four (80%) of the five ovarian clear cell carcinoma cell lin
es and is higher than that detected in normal lymphocytes. Treatment with the deme
thylating agent 5-aza-2'- deoxycytidine for 15 days rescued SFRP5 mRNA expressi
on (60%, 3/5). Endogeous SFRP1 mRNA expression is absent in two (40%) of the f
ive ovarian clear cell carcinoma cell lines. But treatment with the demethylating ag
ent did not rescue SFRP1 mRNA expression nor restore SFRP1 promoter methylati
on atatus. We also find that suppressed ovarian cell carcinoma cell growth and migr
ation ability.
