eIF5A2基因在口腔鳞状细胞癌化疗耐药中的作用及机制研究

It is well known that chemoresistance is one of the main reasons for extremely low 5-year survival rate in oral squamous cell carcinoma (OSCC) patients, and how to effectively reverse the chemoresistance to OSCC has become the bottleneck in the existing phase of treatment. Eukaryotic translation initiation factor-5A2 (eIF-5A2) is a newly found oncogene in ovarian cancers, which plays an key role in maintaining cell proliferation and promoting invasion of tumor cells. Recent researches have revealed that overexpression of eIF5A2 are also intimately associated with tumor malignancy and chemoresistance. Numerous studies focused on tumor chemosistance have shown that epithelial-mesenchymal transformation (EMT), occurs frequently in the process of tumor progression, is an important mechanism to mediate tumor cell chemoresistance. The EMT theory provides a new insight in how to overcome the severe chemosistance in OSCC. This study is intended to clarify the role of eIF5A2 in OSCC cells and investigate whether the chemoresistance in OSCC are mediated by EMT regulated by expression of eIF5A2 through in vitro and in vivo experiments. This study is not only to enrich the understanding of mechanism in OSCC chemoresistance, but also provide a strong theoretical basis for looking for new chemotherapy targets.

化疗耐药是口腔鳞癌（oral squamous cell carcinoma，OSCC）患者5年生存率低的公认主要原因之一。如何有效地逆转其对现有化疗药物的耐药性已经成为现有阶段治疗OSCC的瓶颈。真核翻译起始因子-5A2 (eukaryotic initiation factor-5A2, eIF-5A2)是在卵巢癌中最新发现的一个肿瘤基因，其在维持细胞特别是肿瘤细胞的增殖及侵袭方面起到了不可代替的作用。eIF5A2的过表达与肿瘤的恶性程度及化疗耐药性密切相关。研究表明，肿瘤进展过程中经常发生的上皮间质转换（EMT）是介导肿瘤细胞化疗耐药的关键步骤，这为研究OSCC的化疗耐药机制提供了一条崭新的思路。本课题旨在研究eIF5A2是否可以通过调节EMT过程来介导OSCC的化疗耐药。研究结果不但能够丰富OSCC化疗耐药的机制，更为寻找新的化疗靶点提供强有力的理论依据。

如何克服化疗耐药是目前晚期或复发口腔鳞癌（oral squamous cell carcinoma，OSCC）患者综合治疗的热点和难点之一。真核翻译起始因子-5A2 (eukaryotic initiation factor-5A2, eIF-5A2)是最新发现的一个肿瘤基因，其在维持细胞特别是肿瘤细胞的增殖及侵袭方面起到了不可代替的作用。本研究探讨了eIF5A2与口腔鳞癌细胞株HN30，HN4，Tca8113及Cal27细胞对常用化疗药顺铂与多柔比星敏感性的关系及分子调控机制。我们研究发现，通过与eIF5A2活化的特异性抑制剂GC7联用，可显著增加口腔鳞癌细胞株对顺铂或多柔比星的敏感性。体内荷瘤裸鼠治疗干预模型研究也证实，顺铂或多柔比星GC7联用可显著增强顺铂或多柔比星的抑瘤作用。随后对eIF5A2调控OSCC顺铂或多柔比星化疗耐药的分子机制研究发现，GC7增强口腔鳞癌细胞株对顺铂的敏感性与上皮间质表型转换无关，其可能通过抑制eIF5A2活化进而抑制stat3信号转导通路的机制增强口腔鳞癌细胞对顺铂的敏感性。另一方面，GC7则通过逆转多柔比星诱导的OSCC细胞EMT的发生，显著增强口腔鳞癌细胞株对多柔比星的敏感性。研究表明，肿瘤进展过程中经常发生的上皮间质转换是介导肿瘤细胞化疗耐药的关键步骤，通过本研究为OSCC的化疗耐药机制提供了一条崭新的思路，阐明了eIF5A2在调控介导OSCC的化疗耐药中的关键性作用。本课题研究结果不但能够丰富OSCC化疗耐药的机制，更为寻找新的化疗靶点提供强有力的理论依据。