Abstract
Epigenetic modification is considered a major mechanism of the inactivation of tumor suppressor genes that finally contributes to carcinogenesis. LIM homeobox transcription factor 1α (LMX1A) is one of the LIM-homeobox-containing genes that is a critical regulator of growth and differentiation. Recently, LMX1A was shown to be hypermethylated and functioned as a tumor suppressor in cervical cancer, ovarian cancer, and gastric cancer. However, its role in lung cancer has not yet been clarified. In this study, we used public databases, methylation-specific PCR (MSP), reverse transcription PCR (RT-PCR), and bisulfite genomic sequencing to show that LMX1A was downregulated or silenced due to promoter hypermethylation in lung cancers. Treatment of lung cancer cells with the demethylating agent 5-aza-2’-deoxycytidine restored LMX1A expression. In the lung cancer cell lines H23 and H1299, overexpression of LMX1A did not affect cell proliferation but suppressed colony formation and invasion. These suppressive effects were reversed after inhibition of LMX1A expression in an inducible expression system in H23 cells. The quantitative RT-PCR (qRT-PCR) data showed that LMX1A could modulate epithelial mesenchymal transition (EMT) through E-cadherin (CDH1) and fibronectin (FN1). NanoString gene expression analysis revealed that all aberrantly expressed genes were associated with processes related to cancer progression, including angiogenesis, extracellular matrix (ECM) remodeling, EMT, cancer metastasis, and hypoxia-related gene expression. Taken together, these data demonstrated that LMX1A is inactivated through promoter hypermethylation and functions as a tumor suppressor. Furthermore, LMX1A inhibits non-small cell lung cancer (NSCLC) cell invasion partly through modulation of EMT, angiogenesis, and ECM remodeling.
Highlights
Lung cancer is the most common cause of cancer-related death worldwide, and survival is largely dependent on the tumor stage [1,2]
A similar phenomenon was observed in lung squamous cell carcinoma (LUSC) (p < 0.0001)
The data showed that LMX1A was frequently hypermethylated and downregulated in non-small cell lung cancer (NSCLC) cells
Summary
Lung cancer is the most common cause of cancer-related death worldwide, and survival is largely dependent on the tumor stage [1,2]. Major efforts are being made to identify molecular markers, including aberrant DNA methylation, circulating cell-free tumor DNA, noncoding RNA, and proteomic markers, to facilitate early detection of lung cancer to improve prognosis and survival [3,4,5,6,7]. The progression of lung cancer is a complicated process, involving a series of genetic and epigenetic changes [8,9,10]. In addition to genetic mutations, aberrant DNA methylation is another mechanism for inactivation of tumor suppressor genes to promote the occurrence and progression of lung cancer [18,19,20]. The identification of genetic mutations and epigenetic changes will further improve biomarker-driven precision treatment for lung cancer patients
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