Abstract
Whole-genome and transcriptome sequencing of non-small cell lung cancer (NSCLC) identified that DACH1, is a human homolog of drosophila gene dac, is involved in NSCLC. Here we showed that expression of DACH1 was significantly decreased in human NSCLC tissues and DACH1 abundance was inversely correlated with tumor stages and grades. Restoration of DACH1 expression in NSCLC cells significantly reduced cellular proliferation, clone formation, migration and invasion in vitro, as well as tumor growth in vivo. Unbiased screen and functional study suggested that DACH1 mediated effects were dependent in part on suppression of CXCL5. There was an inverse correlation between DACH1 mRNA levels and CXCL5 in both lung cancer cell lines and human NSCLC tissues. Kaplan-Mier analysis of human NSCLC samples demonstrated that high DACH1 mRNA levels predicted favorable prognosis for relapse-free and overall survival. In agreement, high CXCL5 expression predicted a worse prognosis for survival.
Highlights
DACH1 is a human homolog of drosophila gene dac, a key member of the Retinal Determination Gene Network (RDGN)
To determine whether loss of DACH1 occurred in the early stage, we analyzed a gene expression dataset of 226 primary lung adenocarcinoma with pathological stage I-II, the result showed that expression of DACH1 mRNA was reduced in tumor tissues (Fig. 1E) and inversely correlated with tumor stage (Fig. 1F)
Survival analysis demonstrated that patients with high expression of DACH1 had 90% relapse-free survival (RFS) at 100 months follow-up, while RFS rate for patients in lower DACH1 expression group were only 60% (Fig.1H)
Summary
DACH1 is a human homolog of drosophila gene dac, a key member of the Retinal Determination Gene Network (RDGN). Through gene-specific recruitment of coactivator or corepressor that control precursor cell proliferation and survival, mamalian homologues, DACH1/SIX1/EYA network determines the development of many organs, including lung [2,3]. In this respect, transgenic model demonstrates that Six and Eya are required for maintaining epithelial progenitor cell, regulating epithelial branching, mesenchymal development as well as alveolarization during the saccular phase of lung morphogenesis [3,4]. Functional studies have identified DACH1 as a negative regulator of TGF-β and Wnt signaling to repress cancer cell migration and invasion [11,12]. High expressions of CXCL5 is associated with worse prognosis
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