c2orf48调控HMGB1促进鼻咽癌侵袭转移的机制研究

Distant metastasis and recurrence remain the major reason of treatment failure for nasopharyngeal carcinoma (NPC) patients, but its molecular mechanism is still unknown, lacking of effective therapeutic target. Our previous studies found that the open reading frame of new chimera RRM2-c2orf48 is different from that of wild type c2orf48, and their encoded protein is also different. The role and mechanism of c2orf48 in development of NPC is still unclear. Preliminary experiments demonstrated that c2orf48 was unregulated in NPC cells and specimens. Further immunohistochemical assay and prognostic analysis demonstrated that high expression of c2orf48 might contribute to distant metastasis and poor prognosis. In vitro, overexpression of c2orf48 could upregulate the expression of stemness genes, induce epithelial-mesenchymal transition, and enhance cell self-renewal, invasion and metastasis potency; meanwhile, c2orf48 could increase expression of High Morbidity Group Box 1(HMGB1). Knockdown of c2orf48 could decrease the expression of HMGB1. Accordingly, it was hypothesized that c2orf48 should enhance the stemness and promote invasion and metastasis through HMGB1 in nasopharyngeal carcinoma cells. In this project, cell and molecular biology experiments and animal models could be used to study the function and mechanism of c2orf48 in NPC metastasis, hereby providing a new insight into the effective therapeutic target of NPC.

鼻咽癌治疗失败的主要原因是复发和远处转移，但其机制不明。我们前期研究发现新嵌合体RRM2-c2orf48的开放读码框架有别于野生型c2orf48，所编码蛋白不同，且c2orf48在鼻咽癌发生发展中的作用及机制不清。新近的预实验发现c2orf48在鼻咽癌细胞和组织中高表达，且鼻咽癌组织c2orf48高表达与患者发生远处转移和临床预后不良有关。进一步的研究显示，鼻咽癌细胞过表达c2orf48可上调肿瘤相关的转录因子、促进上皮-间质转化，增强细胞自我更新、迁移和侵袭能力。此外，c2orf48可上调高迁移率族蛋白B1（HMGB1），干扰c2orf48可下调HMGB1表达。据此，我们提出假设：c2orf48可能通过上调HMGB1增强鼻咽癌细胞干性，继而促进侵袭转移。本课题拟通过细胞、分子生物学及动物实验深入探讨c2orf48在鼻咽癌侵袭转移中的作用和分子机制，为寻找鼻咽癌转移有效治疗靶点提供依据。

鼻咽癌治疗失败的主要原因是复发和远处转移，但其机制不明。我们前期研究发现c2orf48在鼻咽癌中高表达，且鼻咽癌组织c2orf48高表达与患者发生远处转移和临床预后不良有关。研究发现，鼻咽癌细胞过表达c2orf48可促进肿瘤的增殖、侵袭转移及顺铂化疗耐药。进一步蛋白质谱发现c2orf48可上调HMGA2的表达。且发现c2orf48可通过调节HMGA2影响鼻咽癌的增殖、侵袭迁移及顺铂化疗耐药。因此，我们证实以下假说：c2orf48通过上调HMGA2增强鼻咽癌细胞增殖、侵袭迁移及顺铂化疗耐药。本课题通过细胞、分子生物学实验深入探讨c2orf48在鼻咽癌侵袭转移及化疗耐药中的作用和分子机制，为寻找鼻咽癌的有效治疗靶点提供依据。