| Summary: | 博士 === 國立成功大學 === 生物資訊與訊息傳遞研究所 === 103 === Our recent study indicated that the expression of Sp1 at a high level enhances the proliferation of lung cancer cells, but represses the metastatic activity of lung cancer. In this study, we found that the transcriptional activity of the FOXO3 was increased, but its protein levels decreased following Sp1 expression. Further studies revealed that Sp1 increased the expression of the miRNA, 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. The 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. Furthermore, we found that Sp1 may regulate the expression of a cluster of miRNAs (miR-106a, miR-150, miR-182, miR-183*, miR-193a-5p and miR-212-5p) to negatively regulate CD44 through 3'-UTR regulation. Clinical relevance indicated that Sp1 expression is negatively correlated with CD44 expression. Enhancement of CD44 expression promoted lung cancer cell migration and invasion abilities. These findings could verify why Sp1 suppresses lung cancer metastasis. Finally, we performed chromatin immunoprecipitation coupled to next-generation sequencing combining with small RNA sequencing technology to identify 50 of mature miRNAs which were potential directly regulated by Sp1. Functional analysis also indicated that these miRNAs were involved in apoptotic process and cell proliferation. In conclusion, our findings provide a new insight of Sp1 regulated lung cancer progression through miRNAs regulation. 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 Sp1-regulated miRNAs decline, thus increasing FOXO3 and CD44 expression, which leads to lung metastasis, thereby highlighting the importance of miRNAs biosynthesis in cancer.
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