J Cancer 2017; 8(13):2561-2574. doi:10.7150/jca.19972

Research Paper

LHX6, An Independent Prognostic Factor, Inhibits Lung Adenocarcinoma Progression through Transcriptional Silencing of β-catenin

Juntang Yang1, Fei Han1, Wenbin Liu1, Mingqian Zhang2, Yongsheng Huang1, Xianglin Hao1, Xiao Jiang1, Li Yin1, Hongqiang Chen1, Jia Cao1, Huidong Zhang1✉, Jinyi Liu1✉

1. Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, PR China;
2. Department of emergency, Yan'an Hospital, Kunming Medical University, Kunming 650500, PR China.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Yang J, Han F, Liu W, Zhang M, Huang Y, Hao X, Jiang X, Yin L, Chen H, Cao J, Zhang H, Liu J. LHX6, An Independent Prognostic Factor, Inhibits Lung Adenocarcinoma Progression through Transcriptional Silencing of β-catenin. J Cancer 2017; 8(13):2561-2574. doi:10.7150/jca.19972. Available from https://www.jcancer.org/v08p2561.htm

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Introduction: Our previous study identified LIM homeobox domain 6 (LHX6) as a frequently epigenetically silenced tumor-suppressor gene in lung cancer. However, its clinical value has never been evaluated, and the in-depth anti-tumor mechanism remains unclear.

Methods: Public database was used for lung cancer, lung adenocarcinoma and lung squamous carcinoma patients and tissue microarray data was used for lung adenocarcinoma patients to study prognostic outcome of LHX6 expression by Kaplan-Meier and Cox-regression analysis. In vitro proliferation, metastasis and in vivo nude mice model were used to evaluate the anti-tumor effect of LHX6 on lung adenocarcinoma cell lines. The mechanisms were explored using western blot, TOP/FOP flash assays and luciferase reporter assays. LHX6 expression and clinical stages data were collected from The Cancer Genome Atlas database (TCGA).

Results: Expression of LHX6 was found to be a favorable independent prognostic factor for overall survival (OS) of total lung adenocarcinoma patients (P=0.014) and patients with negative lymph nodes status (P=0.014) but not related the prognostic outcome of lung squamous cell carcinoma patients. The expression status of LHX6 significantly correlated to histological grade (P<0.01), tumor size (P=0.026), lymph node status (P=0.039) and clinical stages (P<0.01) of lung adenocarcinoma patients. Functionally, LHX6 inhibited the proliferation and metastasis of lung adenocarcinoma cells in vitro and in vivo. Furthermore, LHX6 suppressed the Wnt/β-catenin pathway through transcriptionally silencing the expression of β-catenin, and the promoter region (-1161 bp to +27 bp) was crucial for its inhibitory activity.

Conclusions: Our data indicate that the expression of LHX6 may serve as a favorable prognostic biomarker for lung adenocarcinoma patients and provide a novel mechanism of LHX6 involving in the tumorigenesis of lung adenocarcinoma.

Keywords: LHX6, lung adenocarcinoma, prognostic factor, β-catenin.