MDK Promotes Lymph Node Metastasis of Cervical Squamous Cell Carcinoma by Activating the PI3K/AKT and p38 MAPK Pathway

Purpose: The mechanism of lymph node metastasis (LNM) of cervical squamous cell carcinoma (CSCC) remains unconfirmed. Here we investigate the effects and mechanisms of midkine (MDK) on CSCC LNM. Methods The expression of MDK in CSCC and normal cervical tissue was analyzed. In vivo and in vitro experiments explored the effects of MDK on LNM. A retrospective study of 134 CSCC and 53 healthy controls on the relationship of serum-MDK(s-MDK) and clinicopathological characteristics was performed to evaluate the clinical value of s-MDK in CSCC LNM. Results MDK was highly expressed in CSCC and overexpression of MDK was associated with CSCC LNM.MDK promoted LNM by enhancing proliferation, migration and invasion capacity of cervical cancer cells, facilitating lymphangiogenesis and down-regulating the expression of tight junction proteins of human lymphatic endothelial cells. MDK exerted these biological effects by interacting with syndecan-1 and activating PI3K/AKT and p38 MAPK pathway. s-MDK was related to LNM, stage, tumor size, vascular invasion and muscle invasion. s-MDK combined with serum-squamous cell carcinoma antigen improved the diagnostic accuracy of CSCC LNM. Conclusions These findings established a new mechanism of LNM and highlighted MDK as a candidate tumor biomarker and therapeutic target in CSCC.