Lipocalin 2 prevents oral cancer metastasis through carbonic anhydrase IX inhibition and is associated with favourable prognosis
Lipocalin 2 prevents oral cancer metastasis through carbonic anhydrase IX inhibition and is associated with favourable prognosis
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DOI：
10.1093/carcin/bgw050
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发表时间：
2016-07-01
期刊：
影响因子：
4.7
通讯作者：
Chien, Ming-Hsien
中科院分区：
文献类型：
--
作者：
Lin, Chiao-Wen;Yang, Wei-En;Chien, Ming-Hsien
我们的研究阐明了Lcn2在台湾人群口腔鳞癌中的临床和预后意义。此外，我们观察到Lcn2通过HIF-1α介导的转录调控和miR-4505介导的转录后调控下调CAIX蛋白水平，从而抑制细胞运动。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在口腔鳞状细胞癌(OSCC)发生发展中的作用尚不清楚，尤其是其在侵袭和转移中的作用。在本研究中，我们观察到Lcn2在有淋巴结转移的口腔鳞癌患者中的表达低于无转移者。Lcn2的高表达与口腔鳞癌患者的生存相关。此外，Lcn2在口腔鳞癌细胞中的过表达减少了体外迁移、侵袭和体内转移，而沉默Lcn2则导致细胞运动增加。Lcn2通过低氧诱导因子(HIF)-1α依赖的转录抑制碳酸酐酶IX(CAIX)抑制口腔鳞状细胞癌细胞的运动。CAIX过表达可解除Lcn2过表达对口腔鳞癌细胞迁移的抑制作用。此外，microRNA(MiR)分析表明，Lcn2可以通过诱导miR-4505抑制CAIX的表达和细胞迁移。对口腔鳞癌患者和口腔鳞癌移植小鼠肿瘤组织的检查显示，Lcn2和CAIX的表达呈负相关。此外，Lcn2(强)/CAIX(弱)患者的淋巴转移率最低，生存时间最长。我们的研究结果表明，Lcn2通过靶向口腔鳞癌细胞中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口腔鳞癌治疗策略和预测口腔鳞癌进展的有用的生物标志物。
Our study elucidated the clinical and prognostic significance of LCN2 in OSCC among the Taiwanese population. Moreover, we observed that LCN2 suppresses cell motility by downregulating CAIX protein level via HIF-1 alpha-mediated transcriptional regulation and miR-4505-mediated post-transcriptional regulation.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)-1 alpha-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.