Midkine promotes thyroid cancer cell migration and invasion by activating the phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin pathway.

Objective: Thyroid cancer (TC) therapy, which is routinely used at present, can improve patients' survival rates. However, lymph node metastasis results in a higher degree of TC malignancy in patients who experience recurrence and/or death. The elucidation of new mechanisms of TC metastasis can help identify new therapeutic targets. Midkine (MDK) is expressed aberrantly in various cancers. However, the regulatory mechanisms of MDK in TC remain largely unknown. Hence, this study mainly explores the effect and molecular function of MDK in TC.

Material and methods: MDK gene expression and protein levels were analyzed using the Gene Expression Profiling Interactive Analysis and the Human Protein Atlas online databases. MDK messenger RNA (mRNA) in TC was analyzed by quantitative real-time polymerase chain reaction. MDK, phosphatidylinositol 3 kinase (PI3K), phosphorylated AKT (p-AKT), and phosphorylated mammalian target of rapamycin (p-mTOR) protein in TC were analyzed by Western blotting. Transwell and wound healing assays were performed to evaluate TC cell metastasis.

Results: MDK mRNA was significantly highly expressed in most patients with TC (P < 0.05). Moreover, MDK gene expression levels correlated with different TC stages. MDK protein was negative in normal tissues and positive in TC tissues. MDK mRNA and protein were significantly highly expressed in TC cells (P < 0.01). Compared with metastasis in the control group, that in the MDK group is significantly suppressed by MDK knockdown (P < 0.001). MDK knockdown also significantly inhibited PI3K, p-AKT, and p-mTOR protein expression in TPC-1 and K1 cells (P < 0.001). The activation of PAmT-P significantly enhanced the PI3K, p-AKT, and p-mTOR protein expression in TPC-1 and K1 cells (P < 0.001) and promoted metastasis (P < 0.001), thereby disrupting the inhibitory effect of the MDK knockdown.

Conclusion: Our findings confirmed that MDK promotes TC migration and invasion by activating PAmT-P. MDK is a novel molecular target for the treatment of patients with metastatic TC.