Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis

Abstract

It is currently known that estrogen plays an important role in breast cancer (BC) development, but the underlying molecular mechanism remains to be elucidated. Accumulating evidence has revealed important roles of microRNAs in various kinds of human cancers, including BC. In this study, we found that among the microRNAs regulated by estrogen, miR-124 was the most prominent downregulated miRNA. miR-124 was downregulated by estradiol (E2) treatment in estrogen receptor (ER) positive BC cells, miR-124 overexpression suppressed cell proliferation, migration and invasion in BC cells; while the suppression of miR-124 using Anti-miR-124 inhibitor had opposite cellular functions. Under the E2 treatment, miR-124 had stronger effect to inhibit cellular functions in MCF7 cells than that in MDA-MB-231 cells. In addition, we identified that ERα, but not ERβ, was required for E2-induced miR-124 downregulation. Furthermore, AKT2, a known oncogene, was a novel direct target of miR-124. AKT2 expression levels were inversely correlated with miR-124 expression levels in human breast cancer specimens. AKT2 was overexpressed in BC specimens, and its expression levels were much higher in ERα positive cancer tissues than those ERα negative cancer tissues. Consistent with miR-124 suppression, E2 treatment increased AKT2 expression levels in MCF7 cells via ERα. Finally, overexpression of miR-124 in MCF7 cells significantly suppressed tumor growth and angiogenesis by targeting AKT2. Our results provide a mechanistic insight into a functional role of new ERα/miR-124/AKT2 signaling pathway in BC development. miR-124 and AKT2 may be used as biomarkers for ERα positive BC and therapeutic effect in the future.

MiR-124 Attenuates Osteoclastogenic Differentiation of Bone Marrow Monocytes Via Targeting Rab27a

“…A strong relationship between miRNA and pathophysiological processes has been reported in the literature [20,21]. As mentioned in the literature review, miR-124 is frequently expressed in multiple tissues to regulate different pathophysiologic processes, for instance, the development of cancer [22][23][24][25][26], as a new therapeutic approach to Parkinson's disease [27], promotes the pathogenesis of Crohn's Disease [28] and contributes to cholangiocyte proliferation in the cholestatic liver [29].…”

miR-148a-3p represses proliferation and EMT by establishing regulatory circuits between ERBB3/AKT2/c-myc and DNMT1 in bladder cancer

“…21 Increasing studies demonstrated AKT2 had an important role in cancers as an oncogene. 22 A previous study demonstrated a mechanistic example of how rewiring signaling pathways after EMT was associated with changes in specific dependencies for proliferation, demonstrating a novel function for ERBB3 in EMT. 19 High levels of NRG1 stimulated the ERBB2-ERBB3-PI3K-AKT signaling pathway, which was related to the efficacy of ERBB2 inhibitor, 23 and RTK activation of PI3K-AKT before EMT was important for cancer cell growth and survival.…”

The regulatory role of microRNAs in angiogenesis‐related diseases

“…Recent studies found that miR‐124‐3p is significantly decreased in ECs from pulmonary arterial hypertension (PAH) patients and in various cancers tissues, associated with poor prognosis in patients,35, 36 whose up‐regulation can attenuate glioma cell proliferation, migration and tumour angiogenesis in vitro and in vivo by NRP‐1‐mediated PI3K/AKT/NFκB pathways and by targeting R‐Ras and N‐Ras 35, 37. Meanwhile, it also inhibits angiogenesis and proliferation by targeting Ets‐1 and AKT2 in breast cancer cells 38. Moreover, increased levels of miR‐124‐5p can inhibit angiogenesis and growth of glioma via suppressing LAMB in vitro and in vivo and may serve as a promising potential target of new therapeutic strategies for glioma 39.…”

“…35,37 Meanwhile, it also inhibits angiogenesis and proliferation by targeting Ets-1 and AKT2 in breast cancer cells. 38 Moreover, increased levels of miR-124-5p can inhibit angiogenesis and growth of glioma via suppressing LAMB in vitro and in vivo and may serve as a promising potential target of new therapeutic strategies for glioma. 39 These studies demonstrate that miR-124 may act as a promising and useful diagnostic/prognostic marker and new therapeutic target for tumour through inhibiting angiogenesis in future.…”