miR‑589‑3p sponged by the lncRNA TINCR inhibits the proliferation, migration and invasion and promotes the apoptosis of breast cancer cells by suppressing the Akt pathway via IGF1R

Abstract

The long non-coding (lnc)RNA named tissue differentiation inducing non-protein coding RNA (TINcR) is a tumor marker that has not been studied in breast cancer. The present study aimed to investigate the TINcR-targeting micro (mi)RNAs and the regulatory mechanisms of TINcR in breast cancer. Following prediction by TargetScan and confirmation by dual-luciferase reporter assay, TINcR was demonstrated to be a target gene for miR-589-3p. The expression of TINcR and miR-589-3p in breast cancer and adjacent tissues was detected by reverse transcription-quantitative (RT-q)PcR, and the correlation between TINcR and miR-589-3p expression was determined by using Spearman correlation analysis. The 5-years survival was analyzed in patients with breast cancer according to TINcR expression (high or low). The effects of TINcR and miR-589-3p on the proliferation, apoptosis, migratory and invasive abilities of some breast cancer cell lines were detected by MTT assay, flow cytometry, wound healing assay and Transwell assay. The target gene of miR-589-3p was predicted and verified by TargetScan and dual-luciferase reporter assay, and the mechanism of miR-589-3p involvement in breast cancer cells was explored by overexpression or downregulation of miR-589-3p in breast cancer cells. RT-qPcR and western blotting were used to determine the expression of the insulin-like growth factor 1 receptor (IGF1R)/AKT pathway-related genes. The results demonstrated that TINcR expression level was negatively correlated with miR-589-3p expression level in breast cancer tissues and that patients with high expression of TINcR presented with lower survival rates. In addition, TINcR overexpression in cancer cells inhibited miR-589-3p expression, and cell transfection with miR-589-3p mimic partially reversed the effect of TINcR overexpression on the promotion of cancer cell proliferation, migration and invasion, and on the inhibition of cancer cell apoptosis. Furthermore, IGF1R, which is a target gene of miR-589-3p, increased cancer cell proliferation, migration and invasion and inhibited cancer cell apoptosis; however, these effects were partially reversed by miR-589-3p mimic. Furthermore, the results demonstrated that miR-589-3p mimic could downregulate the protein expression of IGF1R and p-AKT. In addition, TINcR overexpression downregulated miR-589-3p expression level. miR-589-3p partially reversed the effects of TINcR overexpression on cancer cell proliferation, migration and invasion, and inhibited cancer cell apoptosis by inhibiting the IGF1R-Akt pathway. The results from the present study demonstrated that TINcR may sponge miR-589-3p in order to inhibit IGF1R-Akt pathway activation in breast cancer cells, promoting therefore cancer cell proliferation, migration and invasion.

Breast Cancer and the Other Non-Coding RNAs

“…That work was then complemented by Guo et al’s recent research [ 72 ], which revealed TINCR effect in MCF-7 and MDA-MB-231 BC cell lines. TINCR over-expression there inhibited miR-589-3p activity because TINCR acted as the miR-589’s ceRNA.…”

“…IGFR is a well-known trans-membrane tyrosine kinase receptor important in cell mitosis, proliferation, differentiation, apoptosis and regulation of Akt pathway activity [ 73 , 74 ]. Finally, Guo et al [ 72 ] determined that higher TINCR expression was associated with poor survival rate in a cohort of 68 patients.…”

Long Non-Coding RNAs as Potential Diagnostic and Prognostic Biomarkers in Breast Cancer: Progress and Prospects

“…Insulin-like growth factor receptor 1 (IGFR-1), a tyrosine kinase cell surface receptor, is involved in the development and progression of breast cancer (210). Guo et al showed that TINCR played an oncogenic role in breast cancer through regulation of the miR-589-3p/IGF1R axis (126). Moreover, the expression of TINCR was higher in trastuzumab-resistant tissues than in sensitive tissues owing to enhanced histone acetylation of the TINCR promoter.…”

“…Moreover, TINCR promoted EMT via downregulation of Snail-1 expression, while enhanced Snail-1 expression reversed EMT suppression induced by TINCR silencing in trastuzumab-resistant cell lines (127). Furthermore, Kaplan-Meier survival curves showed that high levels of tissue TINCR correlated with unfavorable prognosis in breast cancer (126). Wang et al found that circulating TINCR was dramatically elevated in breast cancer, particularly in the aggressive triple-negative subtype.…”

“…Guo et al. showed that TINCR played an oncogenic role in breast cancer through regulation of the miR-589-3p/IGF1R axis ( 126 ). Moreover, the expression of TINCR was higher in trastuzumab-resistant tissues than in sensitive tissues owing to enhanced histone acetylation of the TINCR promoter.…”