Lin Chiao-Wen, Yang Wei-En, Lee Wei-Jiunn, Hua Kuo-Tai, Hsieh Feng-Koo, Hsiao Michael, Chen Chia-Cheng, Chow Jyh-Ming, Chen Mu-Kuan, Yang Shun-Fa, Chien Ming-Hsien
Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan.
Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
Carcinogenesis. 2016 Jul;37(7):712-722. doi: 10.1093/carcin/bgw050. Epub 2016 Apr 27.
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.
脂质运载蛋白2（LCN2）是一种分泌型糖蛋白，在不同的人类癌症中表达上调或下调。目前，LCN2在占大多数头颈癌的口腔鳞状细胞癌（OSCC）进展中的功能作用仍知之甚少，尤其是其在侵袭和转移中的作用。在本研究中，我们观察到与无转移的患者相比，OSCC伴淋巴结转移患者的LCN2表达降低。较高的LCN2表达与OSCC患者的生存率相关。此外，OSCC细胞中LCN2的过表达降低了体外迁移和侵袭以及体内转移，而其沉默则诱导细胞运动性增加。机制上，LCN2通过缺氧诱导因子（HIF）-1α依赖性转录抑制碳酸酐酶IX（CAIX）来抑制OSCC细胞的运动性。CAIX过表达缓解了LCN2过表达对OSCC细胞迁移的抑制作用。此外，一项微小RNA（miR）分析表明，LCN2可通过诱导miR-4505抑制CAIX表达和细胞迁移。对OSCC患者和OSCC移植小鼠的肿瘤组织检查显示，LCN2和CAIX表达呈负相关。此外，LCN2（强）/CAIX（弱）的患者淋巴结转移频率最低，生存期最长。我们的研究结果表明，LCN2通过靶向OSCC细胞中CAIX的转录和转录后调控来抑制肿瘤转移。LCN2过表达可能是一种新的OSCC治疗策略，也是预测OSCC进展的有用生物标志物。
