HOTAIR作为miR-218的竞争性内源RNA调控宫颈癌侵袭/转移的机制

Local and (or) distant metastasis are the major reasons for the cervical cancer related-deaths, unfortunately, the underlying molecular mechanism is largely unknown. We previously demonstrated a negative correlation between the expression of long non-coding RNA HOTAIR and miR-218, and both of the non-coding RNAs were significantly associated with the invasion and metastasis of cervical cancer. In vitro studies proved that HOTAIR and miR-218 executed opposite functions on the invasion and metastasis of cervical cancer. Moreover, we also found HOTAIR and miR-218 could negatively regulate each other. The bioinformatical analysis predicted two miR-218 binding sites within the sequence of HOTAIR, indicating that HOTAIR may serve as a competitive endogenous RNA to inhibit the function of miR-218 and subsequently promoted the invasion and metastasis of cervical cancer. In the present project, we aim to further investigate the direct interaction between HOTAIR and miR-218 and elucidate the roles of HOTAIR/miR-218 axis in cervical cancer through performing a series of in vitro and in vivo experiments (such as plasmids construction/transfection, RNA immunoprecipitation, dual-luciferase reporter assay, peritoneal metastasis mice model in-vivo imaging system). Our findings may provide solid evidences to develop novel non-coding RNAs-targeting therapies for metastatic cervical cancer.

肿瘤转移是宫颈癌致死的主要原因，但其分子机制尚不明确。课题组前期研究发现：长链非编码RNA HOTAIR和miR-218均与宫颈癌的侵袭转移密切相关，且两者表达呈显著负相关；体外实验证实两者对宫颈癌细胞迁移侵袭的调控截然相反；敲低HOTAIR导致miR-218表达升高，序列分析提示HOTAIR包含两个可与miR-218特异结合的种子序列。由此我们推测HOTAIR可能为一竞争性内源RNA，通过拮抗miR-218来促进宫颈癌的侵袭转移。本课题以前期研究为基础，借助多种体外（宫颈细胞原代培养、荧光素酶报告系统、RNA免疫沉淀）、体内（腹腔转移模型、静脉转移模型、小鼠活体成像）实验技术，探讨HOTAIR与miR-218的相互作用模式，揭示HOTAIR/miR-218轴在宫颈癌侵袭转移中的功能及潜在机制，可为以HOTAIR/miR-218为靶点治疗转移性宫颈癌提供坚实的理论基础和实验依据。

肿瘤转移是宫颈癌致死的主要原因，但其分子机制尚不明确。课题组前期研究发现：长链.非编码RNA HOTAIR和miR-218均与宫颈癌的侵袭转移密切相关，且两者表达呈显著负相关；体外实验证实两者对宫颈癌细胞迁移侵袭的调控截然相反；敲低HOTAIR导致miR-218表达升高，序列分析提示HOTAIR包含两个可与miR-218特异结合的种子序列。在本项目中，借助多种体外（宫颈细胞原代培养、荧光素酶报告系统、RNA免疫沉淀）、体内（腹腔转移模型、静脉转移模型、小鼠活体成像）实验技术，我们证实：HOTAIR作为ceRNA来拮抗miR-218的抑癌功能，进而促进宫颈癌的侵袭转移。本项目揭示了HOTAIR与miR-218的相互作用模式，证明了HOTAIR/miR-218轴在宫颈癌侵袭转移中的功能及潜在治疗价值。