MicroRNA-34a Inhibition of the TLR Signaling Pathway Via CXCL10 Suppresses Breast Cancer Cell Invasion and Migration

Abstract

Background/Aims: Breast cancer (BC) starts as a local disease, but it can metastasize to the lymph nodes and distant organs. However, the metastatic process is still poorly understood. The mRNA microarray datasets GSE26910 and GSE33447 show that CXCL10 is up-regulated in BC, and the microRNA microarray dataset GSE38167 and a network meta-analysis of microRNA expression profile studies in human BC suggest that microRNA-34a (miR-34a) is down-regulated in BC. CXCL10 was predicted as a target of miR-34a by microRNA.org. In this study, we uncovered a CXCL10-independent mechanism by which miR-34a exerts its antimetastatic activity in BC. Methods: To investigate the clinical significance of miR-34a in BC, we collected cancer tissues and paracancerous tissues from 258 patients with BC. In addition, a series of inhibitors, mimics, and siRNAs was introduced into MCF-7 and T47D cells to validate the regulatory mechanisms by which miR-34a regulates CXCL10. Next, to better understand the pivotal role of TLR signaling pathway inhibition in MCF-7 and T47D cells, we blocked the TLR signaling pathway using OxPAPC, an antagonist of TLR signaling. Results: Among BC patients, miR-34a was down-regulated, CXCL10 was up-regulated, and the TLR signaling pathway was activated. Determination of luciferase activity revealed that CXCL10 was a target of miR-34a. Through gain- and loss-of-function studies, miR-34a was demonstrated to negatively regulate CXCL10; inhibit activation of the TLR signaling pathway; significantly suppress in vitro cell proliferation, migration, and invasion; and induce apoptosis. Conclusion: Our findings suggest that functional loss or suppression of the tumor suppressor CXCL10 due to induction of miR-34a leads to inhibition of the TLR signaling pathway during breast tumorigenesis, providing a novel target for the molecular treatment of breast malignancies.

TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme—Future Perspectives

“…In their study, the miR-34a molecule was found to inhibit C-X-C motif ligand 10 (CXCL10). The ligand is characterized by a strong affinity to TLR, promoting cancerogenic downsignaling [97,98]. Indirect inhibition of TLR signaling results in the regression of tumor growth and expansion.…”

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

“…In this work, for example, we show that apigenin suppressed the TNFα mediated rise in a potent tumor suppressor: CXCL10. While previous studies consistently that CXCL10 is up-regulated in normal vs. tumor tissue (76,77) this particular protein acts as the major tumor suppressor, evoked by IFN-γ treatment and somehow plays a role in the re-expression of MHC-1, PD-L1, the infiltration of anti-tumoral CD4(+) and CD8(+) T cells (78,79), NK cells, cytotoxic lymphocytes (CTLs) to the tumor to turn on immune surveillance and heighted survival odds in diverse human cancers (80)(81)(82). While the beneficial effects of apigenin in cancer are consistently reported, any compound that would turn off the CXCL9, -10, -11/CXCR3 axis could harm the host immunes system to destroy self-malignant tumor tissue (83).…”

MicroRNA‑34a suppresses breast cancer cell proliferation and invasion by targeting Notch1

“…In recent years, great progress has been made in the investigation of miR-34a in breast cancer ( 19 – 21 ). Previous studies have demonstrated that multiple miRNAs are abnormally expressed in breast cancer and are closely associated with the development of this tumor ( 22 , 23 ).…”