Yang Wen-Bin, Chen Ping-Hsin, Hsu Tsung, Fu Tzu-Fun, Su Wu-Chou, Liaw Hungjiun, Chang Wen-Chang, Hung Jan-Jong
Institute of Bioinformatics and Biosignal Transduction, College of Bioscience in Biotechnology, National Cheng Kung University, Tainan 701, Taiwan.
Oncotarget. 2014 Feb 15;5(3):740-53. doi: 10.18632/oncotarget.1608.
Our recent study indicated that overexpression of Sp1 enhances the proliferation of lung cancer cells, while represses metastasis. In this study, we found that the transcriptional activity of FOXO3 was increased, but its protein levels decreased following Sp1 expression. Sp1 increased expression of miR-182, which was then recruited to the 3'-untranslated region of FOXO3 mRNA to silence its translational activity. Knockdown of miR-182 inhibited lung cancer cells growth, but enhanced the invasive and migratory abilities of these cells through increased N-cadherin expression. Repression of FOXO3 expression in the miR-182 knockdown cells partially reversed this effect, suggesting that miR-182 promotes cancer cell growth and inhibits cancer metastatic activity by regulating the expression of FOXO3. The expression of several cancer metastasis-related genes such as ADAM9, CDH9 and CD44 was increased following miR-182 knockdown. In conclusion, in the early stages of lung cancer progression, Sp1 stimulates miR-182 expression, which in turn decreases FOXO3 expression. This stimulates proliferation and tumor growth. In the late stages, Sp1 and miR-182 decline, thus increasing FOXO3 expression, which leads to lung metastasis.
我们最近的研究表明，Sp1的过表达增强了肺癌细胞的增殖，同时抑制了转移。在本研究中，我们发现FOXO3的转录活性增加，但其蛋白水平在Sp1表达后降低。Sp1增加了miR-182的表达，然后miR-182被募集到FOXO3 mRNA的3'非翻译区以沉默其翻译活性。敲低miR-182可抑制肺癌细胞生长，但通过增加N-钙黏蛋白的表达增强了这些细胞的侵袭和迁移能力。在miR-182敲低的细胞中抑制FOXO3表达可部分逆转这种效应，表明miR-182通过调节FOXO3的表达促进癌细胞生长并抑制癌症转移活性。在敲低miR-182后，几种癌症转移相关基因如ADAM9、CDH9和CD44的表达增加。总之，在肺癌进展的早期阶段，Sp1刺激miR-182表达，进而降低FOXO3表达。这刺激了增殖和肿瘤生长。在晚期，Sp1和miR-182下降，从而增加FOXO3表达，导致肺转移。
