title: Olfactomedin 1 negatively regulates NF-κB signalling and suppresses the growth and metastasis of colorectal cancer cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Ye
authors.affiliation: The Second Department of Internal Medicine, The Third Affiliated Hospital of Kunming Medical University, Yunnan Tumour Hospital, Kunming, Yunnan, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
authors.forename: Yingchang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
authors.forename: Wendi
authors.initials: W
authors.lastname: Shuai
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Mao
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
authors.forename: Ranyi
authors.initials: R
authors.lastname: Liu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China.
authors.forename: Jiangxue
authors.initials: J
authors.lastname: Wu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China. chenshuai@sysucc.org.cn.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, PR China. hwenl@mail.sysu.edu.cn.|Guangdong Provincial Key Laboratory of Tumour Targeted Drugs and Guangzhou Enterprise Key Laboratory of Gene Medicine, Guangzhou Double Bioproducts Co Ltd, Guangzhou, PR China. hwenl@mail.sysu.edu.cn.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D000077209:Decitabine; D018572:Disease-Free Survival; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D001374:Azacitidine; D015415:Biomarkers; D000077209:Decitabine; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C081451:olfactomedin
keywords: NF-κB pathway; NIK; OLFM1; colorectal cancer; metastasis