Functional Characterization of CD133 (Prominin-1) in Head and Neck Cancer Initiating Cells

• Main Authors: Yu-Syuan Chen, 陳煜選
• Other Authors: Jeng-Fan Lo
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/20310127649916287800

博士 === 國立陽明大學 === 口腔生物研究所 === 101 === Head and Neck squamous cell carcinoma (HNSCC) is a lethal cancer with clinical, pathological, phenotypical and biological heterogeneity. In solid tumor, cancer initiating cells (CICs) being the rare population, are responsible for tumor growth, therapy resistance, and coupled with gain of epithelial-mesenchymal transition (EMT), have been identified. CD133 (prominin-1), a 5-transmembrane glycoprotein, is originally recognized as a hematopoietic stem cells marker, and has been considered as an important cell surface marker to represent the subpopulation of cancer-initiating cells. Previously, we have enriched a subpopulation of head and neck cancer initiating cells (HN-CICs) with up-regulation of CD133 and enhancement of EMT. Others demonstrate that Src kinase interacts with and phosphorylates the cytoplasmic domain of CD133. However, the physiological function of CD133/Src signaling in HNSCCs has not been uncovered. In this study, I investigated whether CD133 could regulate cancer initiating cells properties and the molecular mechanism. Initially, down-regulation of CD133 significantly reduced the self-renewal ability and expression of stemness genes, and promoted the differentiation and apoptotic capability of HN-CICs. Additionally, knockdown of CD133 in HN-CICs also lessened both in vitro malignant properties including cell migration/cell invasiveness/anchorage independent growth, and in vivo tumor growth by nude mice xenotransplantation assay. In opposite, overexpression of CD133 enhanced the stemness properties and tumorigenic ability of HNSCCs. Lastly, up-regulation of CD133 increased phosphorylation of Src coupled with EMT transformation in HNSCCs, on the contrary, silence of CD133 or treatment of Src inhibitor inversely abrogated above phenotypic effects, which were induced by CD133 up-regulation in HNSCCs or HN-CICs. I also found point mutation of CD133Y852F could invert the Src activation. I present results suggested that CD133/Src signaling is a regulatory switch to gain of EMT and of stemness properties in HNSCC. In the future, CD133/Src axis might be a potential therapeutic target for HNSCC by a potential therapeutic target for HNSCC by eliminating HN-CICs.