TZAP靶向GNT-V调控鼻咽癌细胞增殖和干性的研究

肿瘤干细胞的治疗抗性是肿瘤复发和转移的根源，寻找有效抑制癌干性的靶点对提高其疗效至关重要。我们前期发现，TZAP在鼻咽癌组织中表达下调且与进展期临床病理特征相关；TZAP负向调控鼻咽癌细胞增殖，TZAP敲除显著增强鼻咽癌细胞干性；癌基因GNT-V(GV)的转录受转录因子TZAP负向调控，GV过表达促进鼻咽癌细胞增殖。据此提出TZAP靶向GV调控鼻咽癌细胞增殖、干性和放疗敏感性的假说。本项目拟进一步阐明TZAP和GV对鼻咽癌细胞增殖、干性和放疗敏感性的影响，并确证GV是否介导了TZAP的功能；采用RNA seq揭示TZAP过表达或敲除后的鼻咽癌细胞的基因表达谱，预测TZAP参与相关调控的机制与调控网络，并进行功能验证。最后评价GV抑制剂单药或联合放疗的体内抑瘤效果；临床标本验证TZAP、GV与干性相关基因和辐射抗性基因表达的相关性及临床病理意义。预期成果将为寻找鼻咽癌新的治疗靶点提供依据。

Therapeutic resistances of cancer stem cells stand at the root of tumor recurrence and metastasis. Exploring effective targets to suppress cancer stemness is essential to improve therapeutic efficacy of malignancies. Previously, we found that TZAP downregulated in nasopharyngeal carcinoma (NPC) tissues and downregulated TZAP associated with advanced clinicopathological characters. In vitro analysis showed that TZAP negatively modulated proliferation and stemness of NPC cells. In addition, the transcription of GNT-V was negatively modulated by transcriptional factor TZAP. Overexpression of GNT-V promoted the proliferation of NPC cells. Thus, the hypothesis of TZAP targeting GNT-V to regulate proliferation, stemness and radiosensitivity of NPC cells was proposed. This project aims to further elucidate the effects of TZAP and GNT-V on proliferation, stemness and radiosensitivity of NPC and to confirm whether GNT-V mediated the function of TZAP. RNA sequence would be used to reveal gene expression profiles in TZAP overexpressed or knockout NPC cells. The mechanisms and regulatory networks involved in TZAP-related regulation would be predicted, and functional validation be performed. Finally, tumor suppression effect of GNT-V inhibitor monotherapy or combined radiotherapy in vivo would be evaluated. Expression of TZAP, GNT-V, stemness related gene and radiation resistance associated gene would be detected in clinical pathological tissues and their clinicopathological significance would be explored. The expected results will provide a basis for finding new therapeutic targets for NPC.