Abstract 19191: Transfer of MicroRNAs From Cardiomyocytes Prevents the Growth of Cancer Cells
The sporadic incidence of malignancies in the heart led us to test the possibility that translocation of miRs from cardiomyocytes to cancer cells may oppose the expansion of tumors in the myocardium. miR-1, miR-133a, and miR-499 were highly expressed in myocytes but were barely detectable in MCF7 breast cancer cells. To establish whether miRs migrated from myocytes to MCF7 via gap junction channels, the two cell classes were cultured together. In comparison with MCF7 plated alone, the quantity of miR-1 and miR-133a in MCF7 co-cultured with myocytes increased 45-fold and 20-fold, respectively. However, the expression of miR-499 was only 4-fold higher in MCF7 seeded with myocytes. Coupling with cardiomyocytes decreased by 20% the fraction of Ki-67-positive MCF7. To determine the relevance of gap junctions for the translocation of miRs, Cx43 was downregulated in MCF7 by shRNA. The increase in miR-1 and miR-133a in co-cultured MCF7 was attenuated but not abolished following Cx43 silencing. Unexpectedly, silencing of Cx43 did not increase the percentage of Ki67-positive MCF7 co-cultured with myocytes, raising the possibility that other members of the connexin family of proteins may be implicated in the translocation of the miRs. Double silencing for Cx43 and Cx45 (MCF7-shCx43-shCx45) inhibited the formation of gap junctions, resulting in a marked decrease in the expression of the three miRs in cancer cells co-cultured with myocytes. These findings indicate that concomitant downregulation of Cx43 and Cx45 is critical for the transfer of miRs. Following 4 days of co-culture with myocytes, the growth rate of MCF7-shCx43-shCx45 cells was significantly faster than that of MCF7 exposed to scramble shRNA. To identify the mechanism by which miR-1, miR-133a and miR-499 inhibited cancer cell growth, the role of the putative target gene CDK6 was defined. Overexpression of CDK6 restored the proliferative activity of MCF7-miRs with a value of Ki67 labeling comparable to that of control MCF7. In conclusion, miRs highly expressed in cardiomyocytes can translocate to cancer cells via gap junctions, inhibiting their replication through CDK6 repression.
Author Disclosures: L. Graciotti: None. T. Hosoda: None. F. Sanada: None. G. Borghetti: None. C. Arranto: None. R. Kannappan: None. S. Bardelli: None. M. Moccetti: None. M. Rota: None. P. Goichberg: None. P. Anversa: None. T. Moccetti: None. A. Leri: None.
- © 2014 by American Heart Association, Inc.