Lapatinib enhances migration ability of triple-negative breast cancer cells through induction of
Raf-1/MAPK-dependent interleukin-6 expression by downergulation of microRNA-7
Yu-Chun Hsiao1, Yun-Ju Chen2,3, and Wei-Chien Huang1,4,5,6
1. The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University, Taichung 404, Taiwan 2. Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan
3. Department of Biological Science & Technology, I-Shou University, Kaohsiung 824, Taiwan
4. Department of Biotechnology, College of Health Science, Asia University, Taichung 413, Taiwan
5. Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan 6. Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan
Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. However, its therapeutic efficacy from EGFR inhibition in triple-negative breast cancer (TNBC) patients is limited even though
overexpression of EGFR was frequently found in this disease. On the contrary, the enhancement of metastasis by lapatinib in TNBC cells has been further reported. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6
antibody abolished the lapatinib-induced migration, suggesting that lapatinib enhances TNBC cell migration through induction of IL-6 expression. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to mediate the induction of IL-6 expression. Furthermore, Raf-1 was demonstrated as a direct target of microRNA-7, and the down-regulation of miR-7 by lapatinib accounts for the activation of Raf-1 signaling pathway and the
induction of IL-6 expression. Taken together, our results indicated that lapatinib enhanced the migration ability of TNBC cells through induction of IL-6 expression via the Raf-1, MAPK, JNK, p38, and AP-1 pathways by downregulating microRNA-7 expression.
Abstract
Results
Figure 2. IL-6 was involved in the regulation of lapatinib-enhanced aggressiveness of 231 cells
Figure 1. IL-6 expression was up-regulated in MDA-MB-231 TNBC cells with long-term treatment of lapatinib.
Figure 3. Lapatinib induced IL-6 expression through MAPK signaling pathways
Figure 4. c-Jun activation was involved in lapatinib-induced IL-6 production in TNBC cells Figure 5. Involvement of MAPK/AP-1 axis in mediating lapatinib-induced IL-6 gene transcription
Figure 6. Raf-1 activation mediates IL-6 gene expression in 231/Lap cells
Figure 7. Elevation of Raf-1 expression in response to lapatinib is due to the de-repression from miR-7
Long-term treatment with lapatinib activates Raf-1/MAPK signaling pathways through downregulation of miR-7 expression. Then, the activated MAPKs induces expression and binding of c-Jun to IL-6 promoter, which leads to the production of IL-6. The secreted IL-6 in turn enhances the migration ability of TNBC cells.
