title: Loss of TIMP-3 promotes tumor invasion via elevated IL-6 production and predicts poor survival and relapse in HPV-infected non-small cell lung cancer.
abstract: Human papillomavirus (HPV) 16/18 E6 oncoprotein is expressed in lung tumors and is associated with p53 inactivation. The tissue inhibitor of metalloproteinase 3 (TIMP-3) is essential for limiting inflammation; therefore, we expected that TIMP-3 loss might induce chronic inflammation, thereby promoting tumor malignancy as well as poor survival and relapse in patients with HPV-infected non-small cell lung cancer. In this study, the loss of TIMP-3 by loss of heterozygosity and/or promoter hypermethylation was more frequent in HPV16/18 E6-positive tumors than in E6-negative tumors. To explore the possible underlying mechanism, E6-negative TL4 and CL1-0 cells were transfected with an E6 cDNA plasmid. A marked decrease in TIMP-3 expression was caused by promoter hypermethylation via increased DNA (cytosine-5-)-methyltransferase 1 (DNMT1) expression. Mechanistic studies indicated that TIMP-3 loss promoted interleukin-6 (IL-6) production, which led to cell invasion and anchorage-independent growth on soft agar plates. Kaplan-Meier and Cox regression models showed that patients with low-TIMP-3/high-IL-6 tumors had shorter overall survival and relapse-free survival periods when compared with patients with high-TIMP-3/low-IL-6 tumors. In summary, loss of TIMP-3 may increase IL-6 production via the tumor necrosis factor α/nuclear factor κB axis, thereby promoting tumor malignancy and subsequent relapse and poor survival in patients with HPV-infected non-small cell lung cancer.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taiwan.
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Wu
authors.forename: Lung-Hung
authors.initials: LH
authors.lastname: Tsai
authors.forename: Po-Ming
authors.initials: PM
authors.lastname: Chen
authors.forename: Ming-Ching
authors.initials: MC
authors.lastname: Lee
authors.forename: Lee
authors.initials: L
authors.lastname: Wang
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Cheng
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D052162:Human papillomavirus 16 / Q000502:physiology; D052161:Human papillomavirus 18 / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D030361:Papillomavirus Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology / Q000821:virology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D012008:Recurrence; D012907:Smoking / Q000009:adverse effects; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency* / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D009856:Oncogene Proteins, Viral; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3