肺腺癌中致癌基因miRNA-10a*和YAP1在轉移過程 及腫瘤生成過程之機制探討

Abstract

越來越多的證據指出小分子核糖核酸在癌症形成的形成與侵襲過程中扮演重要的角色。經由我們將十六個肺腺癌細胞株各自所有的小分子核糖核酸 (miRNA) 表現以及細胞本身侵襲能力綜合比較之後，發現六個和細胞侵襲能力相關的miRNA，接者，藉由一個包含九十八個肺腺癌病人的臨床試驗我們發現miR-10a*是一個以細胞侵襲能力為依據的預後指標基因。另外，我們是目前第一個驗證組蛋白去乙醯酶5 (HDAC5) 是miR-10a*的直接目標物。HDAC5可能是藉由抑制轉錄因子AP-1的表現來達到負向調控基質金屬蛋白酵素-2和基質金屬蛋白酵素-9的表現。此外，我們讓細胞過度表現miR-10a*之後可以藉由其基因微陣列晶片結果發現排名第四名的訊息路徑是和YAP相關，我們先前研究發現在有高度家族顯性的肺腺癌中YAP1 R331W會是個容易罹患的對偶基因點突變，在此篇研究裡面我們發現YAP1 R331W本身和WT組別比較之後可能是藉由增加YAP1在細胞核內的累積量、降低YAP1 S127磷酸化程度、增強YAP1-TEAD4的相互作用和提高YAP1蛋白的穩定程度等多項因素來達成在動物實驗中觀察到YAP1 R331W具有較強的腫瘤生成能力。我們在此篇研究清楚地驗證出致癌性基因miR-10a*和YAP1在肺腺癌中的致癌機制。

The growing evidences implied that miRNAs play important roles in different states of cancers as well as cancer invasion. Comparison between the miRNA expression profiles and the invasiveness of 16 lung adenocarcinoma cells, 6 invasion-related miRNAs were found. Using a cohort of 98-lung adenocarcinoma patients, we identified miR-10a* is an invasion-based prognostic gene in lung adenocarcinoma. Besides, we firstly found that histone deacetylases 5 (HDAC5) is a direct target of miR-10a* and it also is important for miR-10a*-promoted invasiveness. HDAC5 might down-regulate MMP-2 and MMP-9 expression through down-regulation of transcription factor AP-1. Besides, YAP signaling pathway was ranked number 4 of the array result of miR-10a* overexpressing cells. Before, we identified that YAP1 R331W is an allele predisposed for lung adenocarcinoma with high familial penetrance. We found YAP1 R331W might increase tumorigenesis in vitro and in vivo through higher YAP1 nuclear accumulation, lower phosphorylation of YAP1 Ser127, stronger YAP1-TEAD4 interaction and better protein stability than WT group. We clearly demonstrated the mechanism of oncogenic miRNA-10a* and YAP1 in metastasis and tumorigenesis in lung adenocarcinoma.