ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets.
ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets.
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DOI：
10.1002/stem.1193
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发表时间：
2012-10
期刊：
影响因子：
5.2
通讯作者：
Fujita, Mayumi
中科院分区：
文献类型：
--
作者：
Luo, Yuchun;Dallaglio, Katiuscia;Chen, Ying;Robinson, William A.;Robinson, Steven E.;McCarter, Martin D.;Wang, Jianbin;Gonzalez, Rene;Thompson, David C.;Norris, David A.;Roop, Dennis R.;Vasiliou, Vasilis;Fujita, Mayumi
关键词：
虽然癌症干细胞（CSC）的概念在许多肿瘤中被广泛接受，但人类黑色素瘤中是否存在此类细胞一直是争论的主题。在本研究中，我们通过将细胞连续异种移植到NOD/SCID小鼠中，证明了满足CSC（自我更新和分化）标准的人黑色素瘤细胞的存在。这些细胞具有高的醛脱氢酶（ALDH）活性，其中ALDH 1A 1和ALDH 1A 3是主要的ALDH同工酶。在NOD/SCID小鼠和NSG小鼠中，ALDH阳性黑素瘤细胞比ALDH阴性细胞更具致瘤性。ALDH阳性黑色素瘤细胞的生物学分析揭示ALDH同工酶是调节这些细胞功能的关键分子。通过siRNA或shRNA沉默ALDH 1A导致细胞周期停滞、细胞凋亡和体外细胞活力降低，并减少体内肿瘤发生。ALDH阳性黑色素瘤细胞对化疗剂更具抗性，并且通过siRNA沉默ALDH 1A使黑色素瘤细胞对药物诱导的细胞死亡敏感。此外，我们第一次检查了来自患者来源的肿瘤标本的ALDH阳性CSC的分子特征。黑色素瘤CSC的特征包括维甲酸（RA）驱动的靶基因与RA反应元件和基因与干细胞功能。这些发现暗示ALDH同工酶不仅是CSC的生物标志物，而且是人类黑色素瘤的有吸引力的治疗靶点。对这些同工酶和基因的进一步研究将增强我们对CSCs调控的分子机制的理解，并揭示癌症治疗干预的新分子靶点。
Although the concept of cancer stem cells (CSCs) is well accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In the present study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into NOD/SCID mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis and decreased cell viability in vitro and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer.
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影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
DOI：
10.1016/j.jsbmb.2005.05.005
发表时间：
2005-09-01
影响因子：
4.1
作者：
Balmer, JE;Blomhoff, R
通讯作者：
Blomhoff, R
DOI：
10.1073/pnas.0603806103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Chute, John P.;Muramoto, Garrett G.;McDonnell, Donald P.
通讯作者：
McDonnell, Donald P.
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1016/j.bbrc.2009.05.048
发表时间：
2009-07-31
影响因子：
3.1
作者：
Chen, Yu-Chih;Chen, Yi-Wei;Lo, Wen-Liang
通讯作者：
Lo, Wen-Liang