Overexpression of lipocalin 2 in human cervical cancer enhances tumor invasion

// I-Hsiao Chung 1, * , Tzu-I Wu 1, 3, * , Chia-Jung Liao 1 , Jin-Yo Hu 1 , Yang-Hsiang Lin 1 , Pei-ju Tai 1 , Chyong-Huey Lai 2, 4 , Kwang-Huei Lin 1 1 Department of Biochemistry, School of Medicine, Chang-Gung University and Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333 2 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan 333 3 Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 116 4 Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan 333 * These authors have contributed equally to this work Correspondence to: Kwang-Huei Lin, e-mail: khlin@mail.cgu.edu.tw Keywords: lipocalin2, cervical cancer, invasion, metastasis Received: August 21, 2015      Accepted: January 17, 2016      Published: January 31, 2016 ABSTRACT Cervical carcinoma is the third-most common cause of cancer-related deaths in women worldwide. However, the molecular mechanisms underlying the metastasis of cervical cancer are still unclear. Oligonucleotide microarrays coupled with bioinformatics analysis show that cytoskeletal remodeling and epithelial-to- mesenchymal transition (EMT) are significant pathways in clinical specimens of cervical cancer. In accord with clinical observations demonstrating ectopic expression of lipocalin 2 (LCN2), an oncogenic protein associated with EMT, in malignant tumors, was significantly upregulated in cervical cancer and correlated with lymph node metastasis. Overexpression of LCN2 enhanced tumor cell migration and invasion both in vitro and in vivo . Conversely, knockdown or neutralization of LCN2 reduced tumor cell migration and invasion. LCN2-induced migration was stimulated by activation of the EMT-associated proteins, Snail, Twist, N-cadherin, fibronectin, and MMP-9. Our findings collectively support a potential role of LCN2 in cancer cell invasion through the EMT pathway and suggest that LCN2 could be effectively utilized as a lymph node metastasis marker in cervical cancer.