title: Lipocalin 2 prevents oral cancer metastasis through carbonic anhydrase IX inhibition and is associated with favourable prognosis.
abstract: Lipocalin 2 (LCN2), a secreted glycoprotein, is up- or downregulated in different human cancers. At present, the functional role of LCN2 in the progression of oral squamous cell carcinoma (OSCC), which accounts for most head and neck cancers, remains poorly understood, particularly with respect to its involvement in invasion and metastasis. In this study, we observed that LCN2 expression decreased in patients with OSCC and lymph node metastasis compared with that in patients without metastasis. A higher LCN2 expression correlated with the survival of patients with OSCC. Furthermore, LCN2 overexpression in OSCC cells reduced in vitro migration and invasion and in vivo metastasis, whereas its silencing induced an increase in cell motility. Mechanistically, LCN2 inhibited the cell motility of OSCC cells through hypoxia-inducible factor (HIF)-1α-dependent transcriptional inhibition of the carbonic anhydrase IX (CAIX). CAIX overexpression relieved the migration inhibition imposed by LCN2 overexpression in OSCC cells. Moreover, a microRNA (miR) analysis revealed that LCN2 can suppress CAIX expression and cell migration through miR-4505 induction. Examination of tumour tissues from patients with OSCC and OSCC-transplanted mice revealed an inverse correlation between LCN2 and CAIX expression. Furthermore, patients with LCN2(strong)/CAIX(weak) revealed the lowest frequency of lymph node metastasis and the longest survival. Our findings suggest that LCN2 suppresses tumour metastasis by targeting the transcriptional and post-transcriptional regulation of CAIX in OSCC cells. LCN2 overexpression may be a novel OSCC treatment strategy and a useful biomarker for predicting OSCC progression.
authors.affiliation: Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors.forename: Chiao-Wen
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
authors.forename: Wei-En
authors.initials: WE
authors.lastname: Yang
authors.affiliation: Department of Medical Research, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
authors.forename: Wei-Jiunn
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.affiliation: Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians University, 80539 Munich, Germany.
authors.forename: Feng-Koo
authors.initials: FK
authors.lastname: Hsieh
authors.affiliation: The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Dentistry, Shin-Kong Memorial Hospital, Taipei 111, Taiwan.
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
authors.forename: Jyh-Ming
authors.initials: JM
authors.lastname: Chow
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua 505, Taiwan.
authors.forename: Mu-Kuan
authors.initials: MK
authors.lastname: Chen
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan and.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.affiliation: Department of Medical Research, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.|Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
mesh_terms: D000328:Adult; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D000071231:Carbonic Anhydrase IX / Q000096:biosynthesis* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D000071068:Lipocalin-2 / Q000096:biosynthesis* / Q000235:genetics; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011379:Prognosis
chemical_list: D000951:Antigens, Neoplasm; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071068:Lipocalin-2; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX