斯钙素2在鼻咽癌放疗抵抗及远处转移中的作用及分子机制研究

Chemoradiotherapy is the main treatment modality of Nasopharyngeal carcinoma (NPC)，two major obstacles to the therapeutic success are distant metastasis and radiation resistance. Stanniocalcin 2（STC2), a member of the stanniocalcin family, is among the most upregulated genes of tumor cells in response to hypoxia, glutamine or glucose deprivation. Since microenvironment of solid tumors is frequently characterized by hypoxia, low glucose and glutamine supply, which leads to adaptive gene expression reprogramming to sustain the tumor progression, STC2 has been proposed to facilitate tumor survival and progression under stress conditions. We have recently found that STC2 is overexpressed in the majority of NPC and its overexpression correlates to poor prognosis including resistance to radiation therapy and risk of distant metastasis. A better understanding of the role of STC2 in NPC tumor progression, resistance to radiation and distant metastasis will bring in new opportunities for improved prognosis and treatment of NPC. In this study, we will address three critical questions: 1)What are the molecular mechanisms that mediate STC2 overexpression in NPC? Considering the well-established NPC etiology, we will investigate the effect of EB virus infection, in addition to nutrient insufficiency, on STC2 overexpression in NPC. Particularly we will test the hypotheses that: latent membrane protein 1 (LMP1) triggers HIF-1 activation, which in turn, transactivates STC2 in NPC; 2)Does STC2 overexpression facilitate NPC radioresistence and how? We will use a combination of molecular, cell biology and biochemical approaches to investigate how loss of STC2 function may affect NPC cell behavior, including cell cycle, apotosis and DNA repair, in response to nutrient deprivation and radiation. Human tissues, NPC cell lines and xenograft mouse model will be used.Considering cell behaviors are controlled by gene expression, we propose to explore how loss of STC2 function may affect gene expression reprograming of NPC cells upon nutrient deprivation and radiation. Specific attention will be given to gene clusters that are involved in cell cycle, cell survival and DNA repair. 3)Does STC2 overexpression increase metastatic potential of NPC cells and how? We will detect how loss of STC2 may affect invasiveness and migration capability of NPC. Similar, we propose to explore how loss of STC2 function may affect gene expression reprogramming which was related to metastasis, upon nutrient deprivation and radiation. We expect that this series of studies will elucidate the role of STC2 in radioresistence and metastasis in NPC, paving the way to an improved management of NPC. We also expect that our study will shed light on the regulatory pathway downstream of STC2, which so far remains elusive.

放化疗综合治疗是鼻咽癌的主要治疗手段，治疗后出现远处转移及部分病人存在放疗抵抗是鼻咽癌治疗失败的主要原因。斯钙素2（Stanniocalcin 2，STC2）是肿瘤在乏氧、葡萄糖缺乏、谷氨酰胺缺乏环境下表达显著异常的基因之一, 与肿瘤的预后有关。前期研究发现STC2在鼻咽癌中存在过表达现象，且与放疗抵抗及远处转移有关。本研究拟采用分子生物学等方法，在前期研究的基础上从人体组织学、细胞学及裸鼠移植瘤水平围绕以下问题展开：1）STC2对鼻咽癌放疗敏感性的影响及机制，探讨放疗对STC2表达的影响，及STC2对细胞周期、凋亡及DNA损伤修复的影响及机制；2）STC2对鼻咽癌转移潜能的影响及其可能的分子机制。