Abstract
// Mian Xie 1 , Xiaojun Wu 2 , Chaosheng He 3 , Jiexia Zhang 1 , Jinjun Zhang 4 1 China State Key Laboratory of Respiratory Disease and Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 2 State Key Laboratory of Oncology in Southern China, Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China 3 Department of Internal Medicine, Guangdong General Hospital, Guangzhou, China 4 Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China Correspondence to: Mian Xie, e-mail: mianxie@gird.cn Keywords: lung cancer, Ski, DNA methylation, prognosis Received: July 20, 2015 Accepted: November 22, 2015 Published: December 12, 2015 ABSTRACT Epigenetic silencing of tumor suppressors contributes to the development and progression of lung cancer. We recently found that Ski was hypermethylated in lung cancer. This study aimed to clarify its epigenetic alteration, molecular mechanisms and clinical significance in lung cancer. Ski methylation was evaluated by methylation-specific PCR (MS-PCR) and bisulfite sequencing. mRNA level of Ski was measured by RT-PCR and compared with the methylation status. Ski methylation correlated with decreased mRNA expression in human lung cancer cell lines. Ski hypermethylation was detected in 56.0% of primary lung tumors and associated with poor differentiation and late tumor stage. Demethylation agent 5-aza-2′-deoxycytidine (5-aza-2′dC) restored Ski expression. Re-expression of Ski in lung cancer cells inhibited cell proliferation, clonogenicity, migration, invasion and tumor formation. Ski decreased transcriptional activities of Smads and TAZ. Multivariate analysis showed that patients with Ski positive expression had a better overall survival in resected non-small cell lung cancer (NSCLC) patients. Our results revealed that Ski acts as a tumor suppressor inactivated by DNA methylation and is an independent prognostic factor of lung cancer.
Highlights
Ski was originally described as the oncogene present in the avian Sloan-Kettering viruses [1]; its oncogenic activity was rationalized upon discovering that Ski directly interacts with Smad2, Smad3 and Smad4 [2,3,4,5]
The results showed that NCI-H358, A549, NCI-H1299, HCC827, and NCI-H1838 lung cancer cell lines exhibited methylation, while no methylation was found in HBE-154 cell line and other three lung cancer cell lines NCI-H1975, NCI-H292, and SK-MES-1 (Figure 1B)
The result of BSP was in accordance with methylationspecific PCR (MS-PCR), with Ski densely methylated in five lung cancer cells and unmethylated in the other three lung cancer cell lines and normal bronchial epithelial cell line (Figure 1C)
Summary
Ski was originally described as the oncogene present in the avian Sloan-Kettering viruses [1]; its oncogenic activity was rationalized upon discovering that Ski directly interacts with Smad, Smad and Smad4 [2,3,4,5]. Ski acts in opposition to TGF-β-induced transcriptional activation by functioning as a Smad-dependent corepressor [6]. Ski contains both pro-oncogenic and antioncogenic activities in mammalian cells [7]. Shinagawa et al found that Ski directly binds to and recruits the HDAC complex to Smads, leading to inhibition of tumor growth factor-β (TGF-β) signaling. Our previous study proved that overexpression of TAZ is associated with poor prognosis in resected non-small cell lung cancer (NSCLC) [19]. Rashidian et al identified Ski as a repressor of TAZ during breast cancer progression [20]. Additional molecules or pathways regulated by Ski should be better elucidated in lung cancer
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