miR-665 expression predicts poor survival and promotes tumor metastasis by targeting NR4A3 in breast cancer

Abstract

Cancer metastasis is the main cause of death in breast cancer (BC) patients. Therefore, prediction and treatment of metastasis is critical for enhancing the survival of BC patients. In this study, we aimed to identify biomarkers that can predict metastasis of BC and elucidate the underlying mechanism of the functional involvement of such markers in metastasis. miRNA expression profile was analyzed using a custom microarray system in 422 BC tissues. The relationship between the upregulated miR-665, metastasis and survival of BC was analyzed and verified in another set of 161 BC samples. The biological function of miR-665 in BC carcinogenesis was explored with in vitro and in vivo methods. The target gene of miR-665 and its signaling cascade were also analyzed. There are 399 differentially expressed miRNAs between BC and noncancerous tissues, of which miR-665 is the most upregulated miRNA in the BC tissues compared with non-tumor breast tissues ( P < 0.001). The expression of miR-665 predicts metastasis and poor survival in 422 BC patients, which is verified in another 161 BC patients and 2323 BC cases from online databases. Ectopic miR-665 expression promotes epithelial–mesenchymal transition (EMT), proliferation, migration and invasion of BC cells, and increases tumor growth and metastasis of BC in mice. Bioinformatics, luciferase assay and other methods showed that nuclear receptor subfamily 4 group A member 3 (NR4A3) is a target of miR-665 in BC. Mechanistically, we demonstrated that miR-665 promotes EMT, invasion and metastasis of BC via inhibiting NR4A3 to activate MAPK/ERK kinase (MEK) signaling pathway. Our study demonstrates that miR-665 upregulation is associated with metastasis and poor survival in BC patients, and mechanistically, miR-665 enhances progression of BC via NR4A3/MEK signaling pathway. This study provides a new potential prognostic biomarker and therapeutic target for BC patients.

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

“…Among these genes, we noted NR4A3, which was up‐regulated after LINC00467 knockdown and inversely associated with LINC00467 in HCC tissues. NR4A3 is a member of nuclear receptors superfamily and frequently reported to act as a tumour suppressor in gastric, breast and lung cancer . Therefore, we further investigated whether LINC00467 regulates NR4A3 and whether the modulation of NR4A3 mediates the oncogenic roles of LINC00467 in HCC.…”

Upregulated miR‑665 expression independently predicts poor prognosis of lung cancer and facilitates tumor cell proliferation, migration and invasion

“…In hepatocellular carcinoma cells, miR-665 can promote cell migration, invasion and proliferation by targeting PTPRB (33). In breast cancer, tumor cell migration and invasion are enhanced by the overexpression of miR-665 by promoting the epithelial-mesenchymal transition process (34). By contrast, miR-665 has been demonstrated to suppress cell proliferation and migration in ovarian cancer cells (35).…”

Knockdown of miR-665 Protects Against Cardiomyocyte Ischemia/Reperfusion Injury-Induced ROS Accumulation and Apoptosis Through the Activation of Pak1/Akt Signaling in Myocardial Infarction

“…24) In breast cancer, miR-665 promotes tumor metastasis by targeting to NR4A3. 25) Prashad, et al have proved that miR-665 inhibits murine neuroblastoma cell growth via targeting c-MYC and HDAC8. 26) Recently, accumulating researches have proved that the recovery of oxidative stress homeostasis is considered to be a promising treatment strategy for cardiac remodeling and failure after AMI.…”