miR-5188/Foxo1/β-catenin/TCF4/c-Jun反馈环路在肝癌中介导MYH9/GSK3β复合物促进肿瘤干性和耐药

The newly discovered mir-5188 have not been studied. We performed microarray analysis in Cancer Stem Cells (CSCs) derived from hepatocellular carcinoma (HCC) cells and the wild type HCC cells to screen for specific microRNAs (miRNAs) regulating CSC properties, and identified mir-5188 as an oncomir. mir-5188 was notably upregulated in CSCs derived from HCC cells, and promoted renewal of HCC stem cells and chemoresistance of HCC. The preliminary mechanism study showed that miR-5188 directly targeted the classic tumor-suppressor gene-FOXO1. Furthermore, the interaction between FOXO1 and β-catenin regulated the effect of β-catenin/TCF4 on c-Jun activation, and the activation induced mir-5188 to form a positive feedback loop which controlled Wnt/β-catenin signaling to affect the CSC properties and chemoresistance in HCC. MYH9 mostly serves as an oncogene in cancers, however, its functions in HCC have not been elucidated. Preliminary studies suggested that MYH9 could promote renewal of HCC stem cells and chemoresistance of HCC, and induced the expression of mir-5188. MYH9-mediated ubiquitination of GSK3β promoted Wnt/β-catenin signaling to facilitate the activation of mir-5188/c-Jun feedback loop through which MYH9 affected the CSC properties and chemoresistance in HCC. If the project is successfully implemented, we will clarify the novel mechanism of CSC properties and resistance to chemotherapy in HCC and it may provide a new theoretical basis for the treatment of HCC.

miR-5188是新近发现的miRNA，尚未见任何报导。我们前期通过芯片汇总分析肝癌细胞培养的肿瘤球与野生型肝癌细胞中差异表达的miRNAs，初步筛选出候选促癌基因miR-5188；其在肝癌肿瘤球中高表达，并能促进肿瘤干性和耐药；机制初步研究显示miR-5188可直接靶向FOXO1，FOXO1与β-catenin相互作用后调控TCF4对c-Jun的转录激活，c-Jun又能诱导miR-5188的表达，从而正反馈调控Wnt通路对干性和耐药的激活。MYH9在肿瘤中大多发挥促癌作用，其在肝癌中未见研究；初步研究显示MYH9在肝癌中亦发挥促进肿瘤干性和耐药的作用，并能诱导miR-5188的表达；MYH9可介导GSK3β的泛素化，从而促进Wnt/β-catenin/c-Jun激活miR-5188介导的环路，实现MYH9对干性和耐药的激活。若本项目顺利实施，将在肝癌中揭示调控肿瘤干性和耐药新的分子机制。

miR-5188是新近发现的miRNA，尚未见任何报导。我们前期通过生物信息学分析筛选出候选促癌基因miR-5188，其表达可能受经典癌基因c-Jun的转录调控；进一步发现miR-5188在体内外通过Wnt/β-catenin 信号促进肝癌干性、 侵袭转移和化疗耐药；机制研究显示miR-5188可直接靶向FOXO1，FOXO1与β-catenin相互作用后调控TCF4对c-Jun的转录激活，c-Jun又能诱导miR-5188的表达，从而正反馈调控Wnt通路对干性和耐药的激活。MYH9在肿瘤中大多发挥促癌作用，其在肝癌中未见研究；我们发现MYH9亦能在体内外发挥促进肝癌干性、侵袭转移、耐药的作用；机制研究显示MYH9与β-catenin降解复合物相互作用从而促进GSK3β的泛素化降解并激活β-catenin/c-Jun信号，c-Jun又能诱导MYH9的表达，从而正反馈调控Wnt通路对干性和耐药的激活。有意思的是，我们发现HBX通过Wnt/β-catenin/c-Jun信号调控miR-5188促进肝癌发展，HBX也能够与MYH9相互作用激活Wnt/β-catenin/c-Jun信号调控MYH9促进肝癌发展。 同时，在肝癌组织样本中通过生物信息学分析、原位杂交、免疫组化等证实了miR-5188和MYH9的高表达提示肝癌患者的不良预后。本项目的实施为肝癌的诊断、治疗和预后评估提供了坚实的基础。