Midkine derived from cancer-associated fibroblasts promotes cisplatin-resistance via up-regulation of the expression of lncRNA ANRIL in tumour cells

Midkine (MK) is a heparin-binding growth factor that promotes carcinogenesis and chemoresistance. The tumour microenvironment (TME) can affect chemotherapy sensitivity. However, the role of stromal-derived MK, especially in cancer-associated fibroblasts (CAFs), is unclear. Here, we confirmed that MK decreased cisplatin-induced cell death in oral squamous cell carcinoma (OSCC) cells, ovarian cancer cells and lung cancer cells. We also isolated primary CAFs (n = 3) from OSCC patients and found that CAFs secreted increased levels of MK, which abrogated cisplatin-induced cell death. Moreover, MK increased the expression of lncRNA ANRIL in the tumour cells. Normal tissues, matched tumour-adjacent tissues and OSCC tissues were analysed (n = 60) and showed that lncRNA ANRIL was indeed overexpressed during carcinogenesis and correlated with both high TNM stage and lymph node metastasis (LNM). Furthermore, lncRNA ANRIL knockdown in tumour cells inhibited proliferation, induced apoptosis and increased cisplatin cytotoxicity of the tumour cells via impairment of the drug transporters MRP1 and ABCC2, which could be restored by treatment with human MK in a caspase-3/BCL-2-dependent manner. In conclusion, we firstly describe that CAFs in the TME contribute to the high level of MK in tumours and that CAF-derived MK can promote cisplatin resistance via the elevated expression of lncRNA ANRIL.