Role of Wnt Signaling in melanoma differentiation and the "stemness" of melanoma

Wnt 信号转导在黑色素瘤分化和黑色素瘤“干性”中的作用

• 批准号: 7732246
• 负责人: Ashani Weeraratna
• 金额: $ 26.54万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732246
• 关键词: ABCG2 gene; Affect; Animals; Carrier Proteins; Cells; Data; Differentiation Antigens; Doxorubicin; Genes; Goals; In Vitro; Laboratories; Link; Maintenance; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Methodology; Mutation; Neoplasm Metastasis; Patients; Pharmaceutical Preparations; Polymerase Chain Reaction; Population; Protein Family; Proteins; RNA Splicing; Role; Series; Signal Transduction; Skin; Skin Aging; Stem Cell Development; Stem cells; Transplantation; Wnt proteins; Wound Healing; Xenograft Model; cancer stem cell; in vivo; interest; melanoma; neoplastic cell; nestin protein; notch protein; novel; self renewing cell; self-renewal; stemness; tumor

The melanoma stem cell can be identified by a few markers such as TIE-1, CD133, nestin and ABCG2. Recently, a novel marker, ABCB5 was identified by Schatton et al. This protein is a transporter protein responsible for the efflux of chemotherapeutic drugs (doxorubicin specifically) from melanoma cells. Schatton et al demonstrated that ABCB5 was expressed in CD133 + cells, and that ABCB5+ cells were capable of self-renewal, and could be serially transplanted in animal xenograft models. ABCB5 was expressed in both primary and metastatic melanomas, and constituted about 2-20% of the tumor cell population. Given recent data that suggested that the Wnt protein, Wnt5A, can affect the proliferation and maintenance of hemaopoietic stem cells, we are trying to determine what the role, if any, of Wnt5A in the maintenance and profileration of the melanoma stem cell might be, using ABCB5+ as a marker of stemness. We have recently shown that Wnt5A can cause the loss of expression of melanoma differentiation antigens (MDAs), while promoting metastasis. Melanoma stem cells give rise to differentiated tumor cells, and so we are currently exploring the link between ABCB5, MDAs and Wnt5A. We have found thus far that cells which express high levels of MDAs tenc to also express high levels of ABCB5. A very interesting finding is that PCR anlaysis indicates, in our less differentiated, more metastatic melanoma cells, ABCB5 is alternatively spliced. We are currently sequencing this gene to determine if this is due to mutation. If it is, we propose to analyze a series of patient tumors for the ABCB5 mutation, and then perform a functional anlaysis to uncover the significance of this mutation, using both in vitro and in vivo methodology. Another family of proteins involved in melanoma stem cell development, and melanoma metastasis is the Notch family of proteins. Current data from our laboratory indicates that Wnt5A and Notch proteins may interact to promote wound-healing, and melanoma metastasis. We are exploring this link further, and trying to better understand the interactions between these two families of proteins not just in a cancer setting, but also in the context of normal skin, and skin aging.

黑色素瘤干细胞可以通过一些标记，例如TIE-1，CD133，NESTIN和ABCG2鉴定。最近，Schatton等人确定了一个新颖的标记ABCB5。该蛋白是一种转运蛋白，负责来自黑色素瘤细胞的化学治疗药物外排（特别是阿霉素）的外排。 Schatton等人证明了ABCB5在CD133 +细胞中表达，并且ABCB5 +细胞能够自我更新，并且可以在动物异种移植模型中串行移植。 ABCB5在原发性和转移性黑色素瘤中均表达，约占肿瘤细胞群的2-20％。鉴于最近的数据表明Wnt蛋白Wnt5a会影响血型干细胞的增殖和维持，我们正在尝试确定使用ABCB5+作为干性的标志性的黑色素瘤干细胞的维持和细胞维持中Wnt5a的作用（如果有的话）。我们最近表明，Wnt5a在促进转移时会导致黑色素瘤分化抗原（MDA）的表达丧失。黑色素瘤干细胞产生分化的肿瘤细胞，因此我们目前正在探索ABCB5，MDA和WNT5A之间的联系。到目前为止，我们发现表达高水平的MDA TenC的细胞也表达高水平的ABCB5。一个非常有趣的发现是，PCR Anlaysis表明，在我们较少分化的转移性黑色素瘤细胞中，ABCB5被剪接。我们目前正在对该基因进行测序，以确定这是否是由于突变引起的。如果是这样，我们建议使用体外和体内方法分析一系列的ABCB5突变的患者肿瘤，然后进行功能性Anlaysis来发现该突变的重要性。 另一个参与黑色素瘤干细胞发育的蛋白质家族，黑色素瘤转移是蛋白质的凹陷家族。我们实验室的当前数据表明，Wnt5a和Notch蛋白可能相互作用以促进伤口愈合以及黑色素瘤转移。我们正在进一步探索这种联系，并试图更好地了解这两个蛋白质家族之间的相互作用，不仅在癌症的情况下，而且在正常皮肤和皮肤衰老的背景下。