Oncotarget

Research Papers:

Increased S100A15 expression and decreased DNA methylation of its gene promoter are involved in high metastasis potential and poor outcome of lung adenocarcinoma

Yung-Che Chen _, Meng-Chih Lin, Chang-Chun Hsiao, Yi-Xin Zheng, Kuang-Den Chen, Ming-Tse Sung, Chung-Jen Chen, Ting-Ya Wang, Yong-Yong Lin, Huang-Chih Chang, Yu-Mu Chen and Jen-Chieh Chang

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Oncotarget. 2017; 8:45710-45724. https://doi.org/10.18632/oncotarget.17391

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Abstract

Yung-Che Chen1,6,*, Meng-Chih Lin1,6,*, Chang-Chun Hsiao6,7, Yi-Xin Zheng1, Kuang-Den Chen2, Ming-Tse Sung3, Chung-Jen Chen4, Ting-Ya Wang1, Yong-Yong Lin1, Huang-Chih Chang1,6, Yu-Mu Chen1 and Jen-Chieh Chang5

1Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

2Center of Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

3Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

4Division of Rheumatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

5Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

6Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

7Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Yung-Che Chen, email: [email protected]

Meng-Chih Lin, email: [email protected]

Chang-Chun Hsiao, email: [email protected]

Keywords: lung adenocarcinoma, S100A15, DNA methylation, next generation sequencing

Received: November 02, 2016    Accepted: April 10, 2017    Published: April 24, 2017

ABSTRACT

Purpose: This study aims to determine the functional role of S100A15 and its promoter DNA methylation patterns in lung cancer progression.

Experimental Design: We analyzed 178 formalin-fixed paraffin embedded specimens from lung cancer patients, including 24 early stage and 91 advanced stage adenocarcinoma. S100A15 protein expression was evaluated by immunohistochemistry stain, and its DNA methylation levels were measured by pyrosequencing.

Results: S100A15 nuclear staining was increased in lung adenocarcinoma patients with distant metastasis versus those without distant metastasis. There was reduced one/three-year overall survival in adenocarcinoma patients receiving first line target therapy and harboring high nuclear expressions of S100A15. Both DNA methylation levels over -423 and -248 CpG sites of the S100A15 gene promoter were decreased in adenocarcinoma patients with distant metastasis, and the former was associated with lower one-year overall survival. The highly invasive CL1-5 cell lines display decreased DNA methylation over –412/-248/-56 CpG sites of the S100A15 gene promoter and increased S100A15 gene/protein expressions as compared with the less invasive CL1-0 cell lines. Knockdown of S100A15 in CL1-5 cell line inhibited cell proliferation, migration, and invasion, while over-expression of S100A15 in CL1-0 cell line promoted cell proliferation, migration, and invasion. RNA sequencing analysis revealed potential biological effects of S100A15 over-expression and knock-down with CTNNB1, ZEB1, CDC42, HSP90AA1, BST2, and PCNA being the pivotal down-stream mediators.

Conclusions: Increased S100A15 expression and decreased DNA methylation of its gene promoter region were associated with high metastasis potential and poor outcome in lung adenocarcinoma, probably through triggering CTNNB1 -centered pathways.


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