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

De Wei Wu, Lung Hung Tsai, Po Ming Chen, Ming Ching Lee, Lee Wang, Chih Yi Chen, Ya Wen Cheng, Huei Lee

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1796-1806
Number of pages11
JournalAmerican Journal of Pathology
Volume181
Issue number5
DOIs
Publication statusPublished - Nov 2012

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Tissue Inhibitor of Metalloproteinase-3
Non-Small Cell Lung Carcinoma
Interleukin-6
Recurrence
Survival
Neoplasms
Inflammation
Human papillomavirus 18
Human papillomavirus 16
Loss of Heterozygosity
Oncogene Proteins
Proportional Hazards Models
Agar
Plasmids
Complementary DNA
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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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. / Wu, De Wei; Tsai, Lung Hung; Chen, Po Ming; Lee, Ming Ching; Wang, Lee; Chen, Chih Yi; Cheng, Ya Wen; Lee, Huei.

In: American Journal of Pathology, Vol. 181, No. 5, 11.2012, p. 1796-1806.

Research output: Contribution to journalArticle

Wu, De Wei ; Tsai, Lung Hung ; Chen, Po Ming ; Lee, Ming Ching ; Wang, Lee ; Chen, Chih Yi ; Cheng, Ya Wen ; Lee, Huei. / 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. In: American Journal of Pathology. 2012 ; Vol. 181, No. 5. pp. 1796-1806.
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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.",
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