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

Min Xu, Dong Li, Chen Yang, Jian-Song Ji
2018 Cellular Physiology and Biochemistry  
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 downregulated in BC. CXCL10 was predicted as a target of
more » ... 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. Yang et al.: Mir-34a Suppresses BC Cell Invasion and Migration ClusterProfiler installation package from R software to determine the main biochemical metabolic pathway and signaling pathways associated with the identified DEGs [22, 23] . Network meta-analysis Computers were used to retrieve information from English-language databases such as PubMed, the Cochrane Library and Embase. References were manually searched from the founding of the databases to April 2017 by the principle of combining keywords with free words. Key terms included "breast cancer", "miR" and "expression level". The included criteria were as follows: 1) research type: case control study; 2) research subjects: tissue samples of breast cancer; and 3) outcomes: the expression level of miR. The united formulated data collecting form was applied for extraction of data materials from references by two researchers independently, and additional researchers were recruited to discuss discrepancies between the initial two researchers. The fold change was used to calculate the fold change values of miR with the following formula: Log 2 Fold change = Log 2 (expression in breast cancer tissues) -Log 2 (expression in normal tissues). A fold change value > 0 indicated high miR expression in breast cancer tissues, and vice versa. Study subjects A total of 258 patients with pathologically confirmed breast cancer who underwent surgery from
doi:10.1159/000489111 pmid:29689563 fatcat:jgjcw5uttrahzfd2a7agbzfxua