Shi Wei, Ye Zhihua, Zhuang Li, Li Yingchang, Shuai Wendi, Zuo Zhixiang, Mao Xueli, Liu Ranyi, Wu Jiangxue, Chen Shuai, Huang Wenlin
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
The Second Department of Internal Medicine, The Third Affiliated Hospital of Kunming Medical University, Yunnan Tumour Hospital, Kunming, Yunnan, PR China.
J Pathol. 2016 Nov;240(3):352-365. doi: 10.1002/path.4784.
Uncontrolled growth and distant metastasis are hallmarks of colorectal cancer (CRC), but the mechanisms are poorly understood. Olfactomedin 1 (OLFM1), a member of the olfactomedin domain-containing protein family, plays an important role in the development of neurogenic tissues. Recently, OLFM1 deregulation was frequently observed in several cancers, and it was induced in colon cell lines after treatment with the demethylating agent 5-aza-2'-deoxycytidine. However, the function of OLFM1 in CRC remains unknown. In this study, we reanalysed published microarray data and found that OLFM1 was significantly down-regulated in primary CRC samples compared to adjacent non-cancerous tissues. The results of immunohistochemistry indicated that decreased OLFM1 expression was significantly associated with lymph node status (p = 0.023), distant metastasis (p < 0.001), and AJCC/TNM stage (p = 0.013), and CRC patients with low OLFM1 expression had consistently poor overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). Further analysis demonstrated that OLFM1 was epigenetically silenced in CRC tissues and cell lines via promoter hypermethylation. Overexpression and knockdown of OLFM1 attenuated and increased, respectively, CRC cells' proliferation, migration, and invasion in vitro and metastasis to the lung and liver in vivo. Mechanistically, the promotion of growth and metastasis of CRC cells by silencing of OLFM1 was associated with the activation of the non-canonical NF-κB signalling pathway. OLFM1 interacted with NF-κB-inducing kinase (NIK; MAP3K14) and repressed the phosphorylation of its downstream substrate Ikappa B kinase alpha (IKKα). OLFM1 expression was negatively correlated with the phosphorylation level of IKKα in CRC tissue samples. Knockdown of NIK impaired the ability of OLFM1 to repress NF-κB signalling, cell growth or migration. Thus, OLFM1 may be a valuable biomarker and therapeutic target for CRC patients. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
不受控制的生长和远处转移是结直肠癌（CRC）的标志，但其中的机制尚不清楚。嗅觉介质1（OLFM1）是含嗅觉介质结构域蛋白家族的成员，在神经组织发育中起重要作用。最近，在几种癌症中经常观察到OLFM1失调，并且在用去甲基化剂5-氮杂-2'-脱氧胞苷处理后在结肠细胞系中被诱导。然而，OLFM1在CRC中的功能仍然未知。在本研究中，我们重新分析了已发表的微阵列数据，发现与相邻的非癌组织相比，OLFM1在原发性CRC样本中显著下调。免疫组织化学结果表明，OLFM1表达降低与淋巴结状态（p = 0.023）、远处转移（p < 0.001）和AJCC/TNM分期（p = 0.013）显著相关，并且OLFM1表达低的CRC患者总体生存率（OS；p < 0.001）和无进展生存率（PFS；p < 0.001）一直较差。进一步分析表明，OLFM1在CRC组织和细胞系中通过启动子高甲基化在表观遗传上被沉默。OLFM1的过表达和敲低分别减弱和增加了CRC细胞在体外的增殖、迁移和侵袭以及在体内向肺和肝的转移。从机制上讲，通过沉默OLFM1促进CRC细胞的生长和转移与非经典NF-κB信号通路的激活有关。OLFM1与NF-κB诱导激酶（NIK；MAP3K14）相互作用并抑制其下游底物IκB激酶α（IKKα）的磷酸化。在CRC组织样本中，OLFM1表达与IKKα的磷酸化水平呈负相关。敲低NIK会损害OLFM1抑制NF-κB信号传导、细胞生长或迁移的能力。因此，OLFM1可能是CRC患者的一个有价值的生物标志物和治疗靶点。版权所有©2016英国和爱尔兰病理学会。由John Wiley & Sons, Ltd.出版。
