Imbalance of Molecular Module of TINCR-miR-761 Promotes the Metastatic Potential of Early Triple Negative Breast Cancer and Partially Offsets the Anti-Tumor Activity of Luteolin

Abstract

Background Triple negative breast cancer (TNBC) poses a great threat to patient prognosis. LncRNA-miRNA is a molecular module formed by a long non-coding RNA (LncRNA) and a microRNA (miRNA) that mediates the metastatic potential of tumours such as TNBC, and luteolin (LU) is a natural compound with anti-TNBC activity. Objective We aim to explore the regulatory mechanism of terminal differentiation-induced non-coding RNA (TINCR)-miR-761 molecular module in early TNBC, as well as its influence on anti-tumor activity of LU. Methods The serum was collected from TNBC patients in early stage to detect the expression of TINCR and miR-761 using RT-PCR. Transwell method was applied for the determination of cell migration and invasion, Western blot for epithelial–mesenchymal transition (EMT), flow cytometry (FCM) for cell apoptosis, and dual luciferase reporter and RNA pull-down experiment for the verification of the targeted relationship between TINCR and miR-761. Results Both TINCR and miR-761 were up-regulated in the serum of patients with early TNBC and the area under the curve (AUC) of the two for distinguishing TNBC from BC was not less than 0.850. In the cell function tests, down-regulation of TINCR or miR-761 notably suppressed the metastatic potentials (cell migration, invasion and EMT) of TNBC cells were remarkably inhibited, while up-regulation of TINCR or miR-761 notably promoted the metastatic potentials. We also confirmed that TINCR acts as the molecular sponge of miR-761, and has positive regulation on it. Besides, LU can significantly down-regulate TINCR and miR-761, and partially offset the anti-TNBC activity of LU when they were abnormally up-regulated, which was mainly reflected in the decrease of anti-proliferation and pro-apoptotic ability of LU against TNBC. Conclusion There is an imbalance of TINCR-miR-761 molecular module in early TNBC, which may be a potential new therapeutic target of TNBC.

Blood Circulating Non-Coding RNAs for the Clinical Management of Triple-Negative Breast Cancer

“…Interestingly, Zhang et al, based on the serum TINCR expression, dis-tinguished between BC histological subtypes. TINCR demonstrated a significantly higher expression in TNBC individuals and distinguished TNBC from other BC subtypes with an AUC of 0.868 [72]. Unfortunately, the above-mentioned lncRNAs were also found to be deregulated in other human cancers, suggesting their low cancerspecificity [73,74].…”

“…Circulating lncRNAs demonstrate similar diagnostic accuracy as blood miRNAs, and their combination into diagnostic signatures improves test sensitivity and specificity (Table 1) [66][67][68][69][70][71][72]. In the first reported study, Liu et al, based on MA and qRT-PCR analysis, selected the three following lncRNAs, ANRIL, HIF1A-AS2, and UCA1, as promising markers for TNBC detection (AUC range of 0.827-0.840) [66].…”

Secreted Non-Coding RNAs: Functional Impact on the Tumor Microenvironment and Clinical Relevance in Triple-Negative Breast Cancer

“…High TINCR expression distinguished the subgroup of TNBC patients with cancer relapse. Interestingly, it has been subsequently demonstrated that TINCR and miR-761 act along a functional axis in early TNBC, promoting cell migration, invasion and EMT [ 92 ]. Furthermore, the authors showed that luteolin (LU), a natural compound with anti-TNBC activity, was able to repress the TINCR/miR-761 axis impinging on their metastatic potential [ 92 ].…”

“…Interestingly, it has been subsequently demonstrated that TINCR and miR-761 act along a functional axis in early TNBC, promoting cell migration, invasion and EMT [ 92 ]. Furthermore, the authors showed that luteolin (LU), a natural compound with anti-TNBC activity, was able to repress the TINCR/miR-761 axis impinging on their metastatic potential [ 92 ]. These results indicate that TINCR/miR-761 targeting could represent a potential therapeutic approach for TNBC.…”

The functions of long noncoding RNAs on regulation of F-box proteins in tumorigenesis and progression

“…In HCC cells, TINCR enhanced cell invasion and growth via regulation of STAT3 pathway by binding to TCPTP ( 131 ). In breast cancer, TINCR governed cell metastatic ability and cell growth via regulating miR-761 and targeting OAS1 and EGFR ( 132 – 134 ).…”