Abstract
MicroRNAs play important roles in tumor metastasis. Recently, we reported that the level of miR-520b is inversely related to the metastatic potential of breast cancer cells. In this study, we investigated the role of miR-520b in breast cancer cell migration. We found that miR-520b suppressed the migration of breast cancer cells with high metastatic potential, including MDA-MB-231 and LM-MCF-7 cells, although the inhibition of miR-520b enhanced the migration of low metastatic potential MCF-7 cells. We further discovered that miR-520b directly targets the 3'-untranslated region (3'UTR) of either hepatitis B X-interacting protein (HBXIP) or interleukin-8 (IL-8), which has been reported to contribute to cell migration. Surprisingly, tissue array assays showed that 75% (38:49) and 94% (36:38) of breast cancer tissues and metastatic lymph tissues, respectively, were positive for HBXIP expression. Moreover, overexpression of HBXIP was able to promote the migration of MCF-7 cells. Interestingly, HBXIP was able to regulate IL-8 transcription by NF-κB, suggesting that the two target genes of miR-520b are functionally connected. In addition, we found that miR-520b could indirectly regulate IL-8 transcription by targeting HBXIP. Thus, we conclude that miR-520b is involved in regulating breast cancer cell migration by targeting HBXIP and IL-8 via a network in which HBXIP promotes migration by stimulating NF-κB-mediated IL-8 expression. These studies point to HBXIP as a potential therapeutic target for breast cancer.
Highlights
Least 700 miRNAs [1, 2]
We previously showed that the expression levels of miR520b were significantly lower in highly metastatic breast cancer cell lines, including MDA-MB-231 and LM-MCF-7, than in poorly invasive MCF-7 cells [23]
Consistent with their metastatic potential, MDA-MB-231 and LM-MCF-7 cells have high migratory potentials compared with MCF-7 cells (Fig. 1A), so we speculated that miR-520b might be involved in breast cancer migration
Summary
Least 700 miRNAs [1, 2]. Emerging evidence has demonstrated that miRNAs can function as oncogenes or tumor suppressors involved in neoplasm development, progression, diagnosis, and prognostication [3, 4]. Overexpression of miR-520b resulted in a significant decrease in cell migration compared with scrambled negative control (Scrambled) in LM-MCF-7 and MDA-MB-231 cells in Boyden’s chamber assays (Fig. 1B). MiR-520b mimics resulted in a significant decrease of luciferase activity of the reporter in LM-MCF-7 cells, whereas expression of the mu-pGL3-HBXIP-3ЈUTR did not (Fig. 2E).
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