研究表明食管鳞癌存在肿瘤干细胞并与复发转移、耐药等密切相关，但其调控机制不明。申请者已发现过表达Numb-p72能抑制食管鳞癌细胞间充质转换、细胞增殖及裸鼠体内成瘤性等（Oncotarget 2014）。进一步实验证明过表达Numb-p72使干细胞标志物表达下调，侧群比例下降，提示其可能与食管鳞癌干细胞表型相关。为探索Numb-p72调控肿瘤干细胞的分子机制，我们实验显示Numb-p72可抑制Notch1表达并与p53相互作用；生物信息学分析显示Numb-p72中存在可能调控Notch1和p53的多个功能域。基于以上发现，我们提出假设：Numb-p72可能通过调控Notch和/或p53通路抑制食管鳞癌干细胞干性。本研究将进一步阐明上述通路在Numb-p72调控食管鳞癌干细胞干性中的作用，明确Numb-p72调控Notch/p53的特异性功能域。为针对食管鳞癌干细胞治疗提供新的理论依据。

Increasing evidences have demonstrated the existence of cancer stem cells (CSCs) in esophageal squamous cell carcinoma (ESCC) which contribute to tumor recurrence, metastasis, and chemotherapy resistance, however, the cellular and molecular pathways that control the stemness of CSCs remain largely unknown. Previous studies from our group have demonstrated that ectopic expression of Numb-p72 prevented ESCC proliferation, epithelial-mesenchymal transition, migration and invasion in cell culture system, as well as in vivo tumorigenicity in xenograft model (Oncotarget 2014). Further studies indicated overexpression of Numb-p72 could downregulate CSCs markers, such as SOX2, OCT4, ABCG2, decrease side population in ESCCs, suggesting Numb-p72 may play a role on regulating stemness of CSCs in ESCC. To further dissect molecular pathways that are involved in Numb-p72 mediated inhibition of CSCs, We found Numb-p72 could negatively regulate Notch1 pathway and interact with p53. Bioinformatic analysis revealed that Numb-p72 harbors functional domains that could potentially regulate Notch and p53 signaling pathways, which have been shown to play an important role on regulation of CSCs. Based on these discoveries, we hypothesized that Numb-p72 inhibits stemness of CSCs in ESCC through regulating Notch and/or p53 pathways. Accomplishment of the proposed studies in this application will not only shade light on the current understanding of regulation of CSCs in ESCC, but also provide novel target for treatment of human patients with ESCC.