Fei He, Chen Tong, Jiang Hua
Department of Gynecology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
Department of Hematology, Huashan Hospital, Fudan University, Shanghai 200040, China.
iScience. 2024 May 22;27(7):110077. doi: 10.1016/j.isci.2024.110077. eCollection 2024 Jul 19.
Lymph node metastasis (LNM) is the main metastatic pathway of cervical cancer, which is closely related to 5-year survival rate of cervical squamous cell carcinoma (CSCC), yet the underlying mechanism remains unconfirmed. In this study, we show that midkine (MDK) was highly expressed in CSCC and overexpression of MDK was associated with CSCC LNM. Functional investigations demonstrated that 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 (HLECs). MDK exerted these biological effects by interacting with Syndecan-1 and activating PI3K/AKT and p38 MAPK pathways. A retrospective study showed that s-MDK was related to LNM. s-MDK combined with serum-squamous cell carcinoma antigen(s-SCCA) improved the diagnostic accuracy of CSCC LNM. These findings established a new mechanism of LNM and highlighted MDK as a candidate tumor biomarker and therapeutic target in CSCC.
淋巴结转移（LNM）是宫颈癌的主要转移途径，与宫颈鳞状细胞癌（CSCC）的5年生存率密切相关，但其潜在机制仍未得到证实。在本研究中，我们发现中期因子（MDK）在CSCC中高表达，且MDK的过表达与CSCC的LNM相关。功能研究表明，MDK通过增强宫颈癌细胞的增殖、迁移和侵袭能力、促进淋巴管生成以及下调人淋巴管内皮细胞（HLECs）紧密连接蛋白的表达来促进LNM。MDK通过与Syndecan-1相互作用并激活PI3K/AKT和p38 MAPK信号通路发挥这些生物学作用。一项回顾性研究表明，可溶性MDK（s-MDK）与LNM相关。s-MDK联合血清鳞状细胞癌抗原（s-SCCA）提高了CSCC LNM的诊断准确性。这些发现确立了一种新的LNM机制，并突出了MDK作为CSCC中一种候选肿瘤生物标志物和治疗靶点的地位。
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