EIF5A2诱导食管癌细胞EMT促进肿瘤浸润转移的机制

Esophageal cancer (EC) is one of the most common malignancies,with high incidence of metastasis and poor prognosis. Recently, our preliminary results showed that overexpression of eukaryotic initiation factor 5A2 (EIF5A2) protein was correlated with metastasis and poor prognosis of EC and silencing of EIF5A2 could reverse the phenotype of EC cell epithelial-mesenchymal transition (EMT). Our data suggested that expression of EIF5A2 could induce EC cell EMT to promote tumor invasiveness and metastasis. However, its potential regulation mechanisms of EIF5A2 in EC are unclear. In this study, the methods of adenovirus-mediated gene transfer, lentivirus vector-mediated RNA interference, and cDNA microarray are utilized to find the downstream molecule and explore the downstream signal transducer, and identify the molecular mechanisms of EIF5A2 in promoting EC invasiveness and metastasis by inducing EC cell EMT. Also, the role and clinicopathologic significance of EIF5A2-targeted downstream molecule in EC were investigated in this study. The completion of this investigation could help to identify the new mechanism of EIF5A2 in promoting EC invasiveness and metastasis via EMT in molecular level and its clinicopathologic significance. Our study will provide the evidence that EIF5A2 could be employed as a novel prognostic biomarker and as an therapeutic target for EC patients.

食管癌是转移率高、预后差的常见恶性肿瘤之一。最近，我们预实验结果发现真核翻译起始因子5A2（EIF5A2）蛋白高表达与食管癌转移及预后差相关，并且沉默EIF5A2基因后食管癌细胞的上皮-间质转化（EMT）表型被逆转。这些结果提示EIF5A2表达能够诱导食管癌细胞发生EMT促进肿瘤浸润转移，然而，其潜在调节机制尚未清楚。本项目拟通过腺病毒的基因导入、慢病毒为载体的RNA干扰及cDNA芯片等技术筛选和探讨EIF5A2促进食管癌细胞发生EMT的下游分子和潜在信号传导通路，明确EIF5A2基因诱导食管癌细胞EMT促进食管癌浸润转移的分子机制，以及其下游分子在促进食管癌侵袭和转移中的作用和临床病理学意义。本研究的完成将有助于从分子水平阐明EIF5A2通过EMT促进食管癌浸润转移的新机制及临床病理学意义；为食管癌预后评价提供新的生物标记物和临床靶向治疗食管癌提供新的科学依据。

真核翻译起始因子5A2（EIF5A2）在肿瘤细胞恶性转化、增殖、转移起着非常重要作用，但是其具体作用机制尚未完全明确。首先，我们利用免疫组化检测EIF5A2在肿瘤组织芯片中的表达及其临床病理学意义；其次，本项目通过体内外试验探讨RNA干扰和外源性过表达EIF5A2对肿瘤细胞新生血管形成、浸润转移生物学行为的影响。随后，我们采用荧光免疫染色、透射电子显微镜、肿瘤灌注化验肿瘤缺氧化验方法检查EIF5A2对肿瘤血管重塑的影响。进一步，在基因表达调控方面阐述EIF5A2调控肿瘤血管形成及重塑的作用机理。研究结果显示：外源性地过表达EIF5A2能够促进肿瘤细胞移动侵袭能力、血管形成及重塑、与诱导细胞上皮间质转化（EMT）。敲降EIF5A2表达能够抑制肿瘤细胞侵袭、血管形成及重塑、与抑制EMT；并且发现EIF5A2可能通过MMP-2基因发挥这些恶性生物学功能；同时，我们证明了EIF5A2可能通过P38 MAPK和JNK/c-Jun通路增强MMP-2发挥这些功能；此外，我们发现去除EIF5A2能增强了肿瘤细胞对5-氟尿嘧啶（5-FU）的化学敏感性。综上所述，我们的研究结果表明EIF5A2基因在肿瘤的侵袭转移、血管形成及重塑中发挥着重要的作用，为恶性肿瘤预后评价提供新的生物标记物和临床靶向治疗提供新的科学依据。