Estrogenic gper signaling regulates mir144 expression in cancer cells and cancer-associated fibroblasts (cafs).

Abstract

MicroRNAs (miRNAs) are small non coding RNA molecules that play a crucial role in several pathophysiological conditions, including cancer. The stimulation of hormone-sensitive tumors by estrogens are mediated by estrogen receptor (ER)α and G protein estrogen receptor (GPER). Previous studies have reported that ERα regulates miRNA expression, while this ability of GPER remains to be elucidated. Here, we demonstrate that in SkBr3 breast cancer and HepG2 hepatocarcinoma cells, 17β-estradiol (E2) and the selective GPER ligand G-1 induce miR144 expression through GPER and the involvement of the PI3K/ERK1/2/Elk1 transduction pathway. Moreover, we show that E2 and G-1 down-regulate through miR144 the onco-suppressor Runx1 and increase cell cycle progression. The capability of E2 and G-1 in triggering the induction of miR144 and the down-regulation of Runx1 was also confirmed in cancer-associated fibroblasts (CAFs) that are main components of the tumor microenvironment driving cancer progression. Further confirming these results, Runx1 protein levels were found decreased in tumor xenografts upon G-1 treatment. On the basis of our findings miR144 and Runx1 may be included among the oncotargets of GPER action. Moreover, the present data provide new insights regarding the ability of estrogens to trigger the GPER/miR144/Runx1 transduction pathway toward the stimulation of cancer progression.

• Authors: Adele Vivacqua, Paola De Marco, Maria Francesca Santolla, Francesca Cirillo, Michele Pellegrino, Maria Luisa Panno, Sergio Abonante, Marcello Maggiolini
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 18 Pg. 16573-87 (Jun 30 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26030000 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Core Binding Factor Alpha 2 Subunit
• ELK1 protein, human
• Estrogen Receptor alpha
• GPER1 protein, human
• MIRN144 microRNA, human
• MicroRNAs
• RUNX1 protein, human
• Receptors, Estrogen
• Receptors, G-Protein-Coupled
• ets-Domain Protein Elk-1
• Estradiol
• Phosphatidylinositol 3-Kinases
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Cell Line, Tumor
• Core Binding Factor Alpha 2 Subunit (biosynthesis)
• Estradiol (metabolism)
• Estrogen Receptor alpha (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Fibroblasts (pathology)
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Heterografts
• Humans
• MCF-7 Cells
• Mice
• Mice, Nude
• MicroRNAs (biosynthesis, genetics)
• Neoplasm Transplantation
• Neoplasms (genetics, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, G-Protein-Coupled (metabolism)
• Signal Transduction (genetics)
• Tumor Microenvironment (physiology)
• ets-Domain Protein Elk-1 (metabolism)