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Abstract
Both miRNAs (miRs) and connexin 43 (Cx43) were important regulators of the metastasis of breast cancer, whereas the miRs regulating Cx43 expression in breast cancer cells were still obscure. In the present study, we scanned and found miR-1, miR-206, miR-200a, miR-381, miR-23a/b and miR-186 were functional suppressors of human Cx43 mRNA and protein expression. Specially, we demonstrated that only miR-200a could directly target the 3'-untranslated region (3'-UTR) of human Cx43 gene. Functionally, overexpression of Cx43 in MCF cells potentiated the migration activity, whereas additional miR-200a treatment notably prevented this effect. Finally, we demonstrated that decreased levels of miR-200a and elevated expression of Cx43 in the metastatic breast cancer tissues compared with the primary ones. Thus, we are the first to identify miR-200a as a novel and direct suppressor of human Cx43, indicating that miR200a/Cx43 axis might be a useful diagnostic and therapeutic target of metastatic breast cancer.
Highlights
Breast cancer is the most common malignant tumour in women and the second leading cause of cancer-related death among women worldwide [1,2]
The human connexin 43 (Cx43) coding sequence (CDS) exons were subcloned into the pCDNA3.1 vector to construct a human Cx43 overexpression plasmid pCDNA-Cx43, which could not be inhibited by miR-200a due to lack of 3 -untranslated region (UTR)
Prediction of the potential miRs targeting at the 3 -UTR of Cx43 gene in human (A), mouse (B) and rat (C). (D) The conserved miRs targeting at the 3 -UTR of human Cx43 gene. (A–C) The underlined numbers indicated the location of the miR-targeting sites in the 3 -UTR of Cx43 gene
Summary
Breast cancer is the most common malignant tumour in women and the second leading cause of cancer-related death among women worldwide [1,2]. Breast cancer metastasis is associated with an increase in connexin 43 (Cx43) expression and intercellular exchange disorders [4,5,6]. Connexin proteins form the gap junction, a membrane structure between adjacent cells, mediating mutual, direct electric and chemical signal communications. MiRNAs (miRs) form one of the largest groups of posttranscriptional regulatory factors [12]. They had 2–8 bases at the 5 -end that could bind with the 3 -UTR of the target gene so as to repress gene translation and reduce protein expression [13]. Increasing evidences indicated that miRs were important regulators of breast cancer metastasis [16,17,18,19,20]. We suggested that the miR-200a/Cx43 axis might play an important role in the metastasis of breast cancer
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