Down-Regulation of SIX3 is Associated with Clinical Outcome in Lung Adenocarcinoma

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.

Integrated bioinformatics analysis of miRNA expression in osteosarcoma

“…Study showed that SIX3 might play an important role as a novel suppressor in human lung cancer. SIX3 had potential as a novel prognostic biomarker for patients with lung adenocarcinomas (Mo et al 2013). In our study, transcription factor SIX3 had high cross ratio, indicating that the identification of transcription factors were reliable.…”

“…SIX3 was a human homologue of the highly conserved sine oculis gene family essential during embryonic development in vertebrates, and encoded a homeo-domain containing transcription factor (Mo et al 2013). Researches were reported that the homeotic protein Six3 was a co-activator of the nuclear receptor NOR-1 and a co-repressor of the fusion protein EWS/NOR-1 in human extraskeletal myxoid chondrosarcomas (Laflamme et al 2003).…”

The expression profile and clinic significance of the SIX family in non-small cell lung cancer

“…Min-Li Mo et al demonstrated for the first time that SIX3 over-expression repressed a number of oncogenic genes related to proliferation and metastasis during lung carcinogenesis [18]. Furthermore, SIX3 expression was identified to be associated with improved RFS and OS in the early stage of ADC patients [18].…”

“…However, another critical member of SIX family, SIX3, was reported to act as a repressor in ADC cell proliferation and migration. More importantly, SIX3 could remarkably improve overall survival (OS) and progression-free survival (PFS) in early stage ADC patients [18]. To comprehensively explore the effect of different SIX family members in NSCLC, we analyzed relevant datasets and performed a systemic review and a meta-analysis to assess the profile of SIX family members in NSCLC and evaluate their importance as biomarkers for diagnosis and prediction of NSCLC.…”

Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer

“…48 The four most significantly enriched transcription factor families, SIX3, TF2B, TCFF, and ZFHX, have known associations with human cancers. 49–52 Of particular interest, dysregulation of two members of the ZFHX family, zinc finger E-box binding homeobox 1 (Zeb1) and zinc finger E-box binding homeobox 2 (Zeb2), has been associated with bladder cancer. 52,53 Overall, the extensive overlap between transcription factor binding sites within genes with differential methylation associated with EUC As and bladder cancer indicates that similar transcription factors may mediate both exposure and disease-related epigenetic effects.…”