染色体9q31.1-33.1区microRNAs群对宫颈癌中PI3K活性的调控及其临床意义研究

The molecular mechanism involved in the development of cervical cancer remains to be elucidated. Previous studies indicated extensive genomic alterations occur on chromosome 9 (chr9q31.1-33.1) in cervical cancer. Moreover, activation of the PI3K pathway is believed to play a key role in the pathogenesis of cervical cancer. Our study is worked on explanation of mechanism linked to chr9q31.1-33.1 and the PI3K pathway. We discovered low-level expression of miR-32/181a/181b in cervical cancer, which are located on chr9q31.1-33.1, and this is corresponded with the deletion of this chromosome region. Our data will showed that constitutive expression of miR-32/181a/181b degraded in vitro and in vivo oncogenicity, modulates cell survival, and robustly repress growth of cervical cancer cell. Remarkably, absent of expression of miR-32/181a/181b will activate the PI3K pathway by directly targeting the PIK3R3, the regulatory subunit of PI3 kinase, resulted in enhanced growth and low frequency of apoptosis of cervical cancer cell. Our data will deletion of chr9q31.1-33.1 and miR-32/181a/181b as an attractive candidate biomarker and therapeutic target for cervical cancers, and support an emerging theme that chr9q31.1-33.1/miR-32-181a-181b /PI3K pathway are important determinants of cervical cancer biology.

资料显示染色体9q31.1-33.1区域改变与宫颈癌发生直接相关，而PI3K信号通路的过度激活参与了宫颈癌的发生，但两者的作用机制均不明确。通过基因数据库的扫描分析，我们发现miR-32、181a、181b共同定位于此区域；细胞与组织水平的初步研究提示这些miRNAs分子在宫颈癌中表达缺失；数据库分析与相关实验证实它们可协同作用于靶基因PIK3R3。基于此我们拟开展：1）验证宫颈癌细胞中miR-32、181a、181b 对PI3K信号活性的协同调控；2）阐明miRNAs表达缺失可通过调控PI3K信号影响宫颈癌细胞存活；3）鉴定宫颈癌样本中该染色体区域的变化及miRNAs分子等位基因的表达调控；4）miRNAs对PI3K通路协同调控的组织水平鉴定及临床病理意义研究。本项目将通过miRNAs将染色体9q31.1- 33.1区域局限性改变与PI3K通路相联系，有助于宫颈癌治疗新靶点的识别。

资料显示染色体9q31.1-33.1区域改变与宫颈癌发生直接相关，而PI3K信号通路的过度激活参与了宫颈癌的发生，但两者的作用机制均不明确。通过基因数据库的扫描分析，我们发现miR-21、181a、181b共同定位于此区域；细胞与组织水平的初步研究提示这些microRNAs分子在宫颈癌中表达缺失；数据库分析与相关实验证实它们协同作用于靶基因PIK3R3。基于此我们拟开展：1）验证宫颈癌细胞中miR-32、181a、181b对PI3K信号活性的协同调控；2）阐明miRNAs表达缺失可通过调控PI3K信号影响宫颈癌细胞存活；3）鉴定宫颈癌样本中该染色体区域的变化及miRNAs分子等位基因的表达调控；4）miRNAs对PI3K通路协同调控的组织水平鉴定及临床病理意义研究。本项目通过miRNAs将染色体9q31.1-33.1区域局限性改变与PI3K通路相联系，有助于宫颈癌治疗新靶点的识别。