http://news.chinatimes.com/2009Cti/Channel/Life/life-article/0,5047,11051801+112009052800079,00.html
發現抑癌基因 絕症將有藥救
* 2009-05-28
* 中國時報
* 李宗祐／台北報導
▲中研院院士楊泮池（左二）領導研究團隊（右二為其指導的博士班畢業生，同時也是
研究論文第一作者王書品）研究肺癌轉移機制出現重大突破，為抗癌新藥研發開啟曙光！
（李宗祐攝）
肺癌高居國人癌症致死率首位，高達八成病患會在五年內發生癌細胞轉移，中央研
究院院士楊泮池領導研究團隊長期觀察研究肺癌轉移機制，最近出現重大突破，揭開抑癌
基因Ｐ５３調控肺癌細胞轉移機制及途徑，是抗癌新藥研發的重大突破。
這項研究由國科會與衛生署共同支持，團隊成員包括台大醫學院院長楊泮池、成大
醫學院副教授洪澤民及國防醫學院教授司徒惠康、博士班畢業生王書品等人，論文已發表
在國際頂尖學術期刊《自然─細胞生物學》。
Ｐ５３ 可控制癌細胞轉移
楊泮池指出，國人普遍施打肝炎疫苗後，肺癌近年成為台灣新國病，尤其是連續十
年居女性癌症死亡率首位。研究團隊經長期觀察研究發現，超過五成肺癌病患出現抑癌基
因Ｐ５３突變，顯示Ｐ５３與癌細胞入侵及轉移關係密切；研究團隊最重要的突破是，證
實Ｐ５３具有控制癌細胞轉移的功能，為標靶治療開啟新方向。
研究團隊利用七十九名肺癌病患的病理切片，進行Ｐ５３基因定序，發現Ｐ５３正
常的病患五年後平均存活率超過六○％，Ｐ５３突變者降到三○％左右，兩者相差很大。
研究團隊並分析Ｐ５３與其下游蛋白質分子ＭＤＭ２與Ｓｌｕｇ的基因圖譜表現，
發現Ｐ５３正常者的ＭＤＭ２劑量相對較高，Ｓｌｕｇ偏低；Ｐ５３則相反，前者低後者
高，證實ＭＤＭ２受Ｐ５３影響，進而影響Ｓｌｕｇ的表現。
基因正常 五年存活率六成
王書品表示，正常細胞中，Ｐ５３及ＭＤＭ２可調控促癌轉移分子Ｓｌｕｇ，維持
Ｓｌｕｇ的穩定性，抑制癌細胞侵襲與轉移能力。當Ｐ５３突變，就喪失控制Ｓｌｕｇ蛋
白質的功能，細胞內不斷累積Ｓｌｕｇ，使癌細胞逐漸壯大，最終導致腫瘤轉移至身體各
處。
研究團隊也發現，Ｐ５３突變、ＭＤＭ２表現劑量偏低及Ｓｌｕｇ劑量較高的肺癌
病患存活率明顯偏低。王書品指出，這項發現可以作為新藥開發參考，未來也可提供醫學
界據此預測病患是否會發生癌細胞轉移及存活率高低，採取最合適的醫療措施，讓病患擁
有更好的生活品質。
http://www.nature.com/ncb/journal/vaop/ncurrent/abs/ncb1875.html
Nature Cell Biology
Published online: 17 May 2009 | Corrected online: 19 May 2009 |
doi:10.1038/ncb1875
p53 controls cancer cell invasion by inducing the MDM2-mediated degradation
of Slug
Shu-Ping Wang1, Wen-Lung Wang1, Yih-Leong Chang2, Chen-Tu Wu2, Yu-Chih Chao1,
Shih-Han Kao3, Ang Yuan4, Chung-Wu Lin5, Shuenn-Chen Yang6, Wing-Kai Chan7,
Ker-Chau Li8, Tse-Ming Hong9,11 & Pan-Chyr Yang4,6,10,11
Abstract
The tumour suppressor p53 is known to prevent cancer progression by
inhibiting proliferation and inducing apoptosis of tumour cells. Slug, an
invasion promoter, exerts its effects by repressing E-cadherin transcription.
Here we show that wild-type p53 (wtp53) suppresses cancer invasion by
inducing Slug degradation, whereas mutant p53 may stabilize Slug protein. In
non-small-cell lung cancer (NSCLC), mutation of p53 correlates with low MDM2,
high Slug and low E-cadherin expression. This expression profile is
associated with poor overall survival and short metastasis-free survival in
patients with NSCLC. wtp53 upregulates MDM2 and forms a wtp53–MDM2–Slug
complex that facilitates MDM2-mediated Slug degradation. Downregulation of
Slug by wtp53 or MDM2 enhances E-cadherin expression and represses cancer
cell invasiveness. In contrast, mutant p53 inactivates Slug degradation and
leads to Slug accumulation and increased cancer cell invasiveness. Our
findings indicate that wtp53 and p53 mutants may differentially control
cancer invasion and metastasis through the p53–MDM2–Slug pathway.
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1. Graduate Institute of Life Sciences, National Defense Medical Center,
Taipei 11490, Taiwan.
2. Department of Pathology and Graduate Institute of Pathology, National
Taiwan University, Taipei 10043, Taiwan.
3. Graduate Institute of Molecular Biology, College of Medicine, National
Taiwan University, Taipei 10043, Taiwan.
4. Department of Internal Medicine, National Taiwan University Hospital,
Taipei 10043, Taiwan.
5. Department of Pathology, National Taiwan University Hospital, Taipei
10043, Taiwan.
6. Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
7. Department of Medical Research, National Taiwan University Hospital,
Taipei 10043, Taiwan.
8. Institute of Statistical Science, Academia Sinica, Taipei, 11529,
Taiwan.
9. Institute of Clinical Medicine, National Cheng Kung University, Tainan
70101, Taiwan.
10. NTU Center for Genomic Medicine, College of Medicine, National Taiwan
University, Taipei 10043, Taiwan.
11. These authors contributed equally to this work.
Correspondence to: Pan-Chyr Yang4,6,10,11 e-mail: pcyang@ntu.edu.tw
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