The roles of cell surface markers in cancer stemness, tumorigenicity and metastasis

• Main Authors: Su, Ying-Jhen, 蘇英禎
• Other Authors: Lee, Jia-Lin
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/93153260117901456502

博士 === 國立清華大學 === 分子與細胞生物研究所 === 104 === Cancer progression is commonly segregated into processes of primary tumor growth and metastasis. Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in cancer. However, the role of CSCs in cancer metastasis is unclear. Although CD44 and CD133 cell surface markers are widely used to isolate cancer stem cells (CSCs), the functional aspects of maintaining CSCs have yet to be determined. In this study, we found that the C terminus of CD44 contributes to sphere formation in vitro via the CD44-SRC-integrin axis. In addition, nuclear CD44/acetylated-STAT3 is required for clonal formation in vitro and tumourigenicity in vivo. In order to get more details of the molecular mechanism, we utilized chromatin immunoprecipitation assays to demonstrate that nuclear CD44 binds to various promoters including c‐myc and Twist1, leading to cell fate change through transcriptional reprogramming. In the second part of my study, we also found that beta-catenin could be activated by CD133 thus binding to the proximal promoter regions of ITGA2-4 and ITGA10-11 in brain, colon and lung cancer cell lines, and β-catenin also bound to the proximal promoter regions of ITGB6 and ITGB8 in cell lines from gastric and breast cancers. Moreover, cell migration triggered by wounding CD133+ cells cultured on ECM-coated dishes can induce polarity and lipid raft coalescence, enhancing CD133/integrin signaling and asymmetric cell division. Taken together, in response to this signal cascade, we propose that nuclear CD44/acetylated-STAT3 and CD133/integrin/Src/Akt/GSK3-beta/ beta-catenin may be a regulatory switch to increase drug resistance, stemness properties, and metastasis leading to poor prognosis. Collectively, the results of current study not only reveal molecular mechanism leading to CD44 and CD133 function, but also provide the potential targets for inhibition of CD44 and CD133 as therapeutic strategy in cancer treatment.