Abstract
BackgroundLung cancer is a common cancer and the leading cause of cancer-related death worldwide. SIX3 is a human homologue of the highly conserved sine oculis gene family essential during embryonic development in vertebrates, and encodes a homeo-domain containing transcription factor. Little is known about the role of SIX3 in human tumorigenesis. This study is to assess the expression/function of SIX3 and the significance of SIX3 as a prognostic biomarker in lung adenocarcinoma.MethodsQuantitative real-time RT-PCR was used to analyze SIX3 mRNA expression and quantitative methylation specific PCR (MSP) was used to examine promoter methylation. MTS and colony formation assays were performed to examine cell proliferation. Wound healing assays were used to assess cell migration, and microarrays were utilized to examine genes regulated by SIX3 in lung cancer cells. Association of SIX3 expression levels with clinical outcomes of patients with lung adenocarcinoma was evaluated using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model.ResultsSIX3 was down-regulated in lung adenocarcinoma tissues compared to their matched adjacent normal tissues, and this down-regulation was associated with methylation of the SIX3 promoter. SIX3 was also methylation-silenced in lung cancer cell lines. Restoration of SIX3 in lung cancer cells lacking endogenous SIX3 suppressed cell proliferation and migration, and downregulated a number of genes involved in proliferation and metastasis such as S100P, TGFB3, GINS3 and BAG1. Moreover, SIX3 mRNA expression was associated with significantly improved overall survival (OS) and progression-free survival (PFS) in adenocarcinoma patients and patients with bronchioloalveolar carcinoma (BAC) features.ConclusionsSIX3 may play an important role as a novel suppressor in human lung cancer. SIX3 has potential as a novel prognostic biomarker for patients with lung adenocarcinomas.
Highlights
Lung cancer is one of the most common cancers and the leading cause of cancer-related death worldwide [1]
We observed that 9 of the 12 Non-small-cell lung cancer (NSCLC) cell lines that we examined lacked SIX3 expression and the other three cell lines (H1703, H460 and H522) had downregulated SIX3 expression, compared to that in normal adult lung tissues (Fig. 1a)
We examined methylation status of the SIX3 promoter by methylation-specific PCR (MSP) in these NSCLC cell lines
Summary
Lung cancer is one of the most common cancers and the leading cause of cancer-related death worldwide [1]. Despite recent development of cancer treatments based on TNM staging, prognosis of lung cancer patients has limited improvement. SIX3 belongs to the sine oculis family and is a highly conserved gene that is required for the initiation of eye development in vertebrates. SIX family genes code for transcription factors that are characterized by a homeo domain and a SIX domain [11]. In this study we intend to investigate the expression and function of SIX3 in human lung. SIX3 is a human homologue of the highly conserved sine oculis gene family essential during embryonic development in vertebrates, and encodes a homeo-domain containing transcription factor. This study is to assess the expression/function of SIX3 and the significance of SIX3 as a prognostic biomarker in lung adenocarcinoma
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