Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Int J Oncol. 2010 Jul;37(1):61-9. doi: 10.3892/ijo_00000653.
The MUC1 oncoprotein is aberrantly overexpressed in human carcinomas and hematologic malignancies. Micro-RNAs (miRNAs) have been implicated in the suppression and induction of oncogenesis. The present studies demonstrate that the MUC1 mRNA 3' untranslated region (3'UTR) contains a highly conserved motif for binding of a novel miRNA, miR-1226, that has no known targets. The results show that miR-1226 is expressed in human breast cancer cell lines and non-malignant mammary epithelial cells. We also show that miR-1226 interacts with the MUC1 mRNA 3'UTR and that miR-1226 downregulates endogenous MUC1 protein levels. Consistent with miR-1226-induced downregulation of MUC1 expression, the results demonstrate that miR-1226 induces i) an increase in reactive oxygen species, ii) loss of the mitochondrial transmembrane potential, and iii) a decrease in cell survival. These findings indicate that expression of the MUC1 oncoprotein is downregulated by miR-1226 and that miR-1226 thereby functions as a tumor suppressor by promoting the induction of cell death.
MUC1 癌蛋白在人类癌和血液恶性肿瘤中异常过表达。微小 RNA（miRNA）被认为参与了肿瘤抑制和诱导。本研究表明，MUC1 mRNA 3'非翻译区（3'UTR）含有一个高度保守的基序，用于结合一种新型 miRNA，miR-1226，其没有已知的靶标。结果表明，miR-1226 在人乳腺癌细胞系和非恶性乳腺上皮细胞中表达。我们还表明，miR-1226 与 MUC1 mRNA 3'UTR 相互作用，并且 miR-1226 下调内源性 MUC1 蛋白水平。与 miR-1226 诱导的 MUC1 表达下调一致，结果表明 miR-1226 诱导 i）活性氧的增加，ii）线粒体跨膜电位的丧失，和 iii）细胞存活减少。这些发现表明，MUC1 癌蛋白的表达受 miR-1226 下调，miR-1226 因此通过促进细胞死亡的诱导而作为肿瘤抑制因子发挥作用。
