TrkB/C-induced HOXC6 activation enhances the ADAM8-mediated metastasis of chemoresistant colon cancer cells.

ABSTRACT

The abnormal expression of tropomyosin receptor kinase (Trk) serves an important role in the promotion of cancer progression. Homeobox C6 (HOXC6) and A disintegrin and metalloproteinase domain­containing 8 (ADAM8) are associated with the invasiveness of cancer cells. However, the exact relationship between these molecules and their downstream signaling pathways in chemoresistant colon cancer cells are largely unknown. Therefore, the current study investigated the association between TrkB/C with HOXC6 and ADAM8 in the induction of drug­resistant colon cancer cell metastasis. The results demonstrated that chemoresistant colon cancer cells exhibited upregulated TrkB/C, HOXC6 and ADAM8 expression. Additionally, but also chemoresistant colon cancer cells demonstrated higher migratory activities compared with parent colon cancer cells. The pharmacological inhibition of TrkB/C activity reduced the phosphorylation of mitogen­activated protein kinase kinase/ERK and subsequently suppressed HOXC6 and ADAM8 expression. In addition, gene silencing of HOXC6 inhibited ADAM8 and MMP activity, and inhibited the migration and invasion of drug­resistant cancer cells. However, the targeted downregulation of ADAM8 using small interfering RNA failed to suppress TrkB/C­associated ERK­mediated HOXC6 signaling activity. Furthermore, pre­treatment with ADAM10­ and ADAM17­specific inhibitors had no effect on attenuating the invasiveness of chemoresistant colon cancer cells. The results indicated that TrkB/C­mediated ERK activation serves an important role in the metastasis of drug­resistant colon cancer cells through the regulation of HOXC6/ADAM8 activity.