Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

Abstract

We investigated the clinical implications of lung developmental transcription factors ( TTF-1 , NKX2–8 , and PAX9 ) that we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the 3 genes were determined and used to risk stratify a non-small-cell lung cancer (NSCLC) clinical data set consisting of 91 early stage tumors. Coactivation of the TTF-1 and NKX2–8 pathways identified a cluster of patients with poor survival, representing ≈20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with coactivation of TTF-1 and NKX2–8 was validated in 2 other independent clinical data sets. Furthermore, lung cancer cell lines showing coactivation of the TTF-1 and NKX2–8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. This suggests that the cohort of patients with coactivation of TTF-1 and NKX2–8 pathways appears to be resistant to standard cisplatin therapy, suggesting the need for alternative therapies in this cohort of high-risk patients.

Bronchial-pulmonary adenocarcinoma subtyping relates with different molecular pathways

“…It is said that MAPKinase, JAK/STAT and Wnt are important in activation of TTF1 and NKX8, connected with EGFR and Her2. 46 The expression of cyclin D1 was higher in tumoral than in normal tissue and RB expression had no statistical difference when compared to normal tissue. This fact may indicate a tendency to proliferate, because once cyclin D1 is in high concentration, it could phosphorylate more RB protein and release E2F, involved in the regulation of genes with implications in cell cycle progression (G1 to S phase).…”

Nkx2-1: a novel tumor biomarker of lung cancer

“…Nkx2-1, Nkx2-8 (Nkx homeobox-8 gene), and PAX9 (paired box gene 9), the three transcription factors known to mediate lung development and maturation, were recently characterized as cooperating oncogenes located together on chromosome 14q13 (Hsu et al, 2009). NSCLC patients with early stage tumors that expressed both Nkx2-1 and Nkx2-8 had poor survival.…”

NKX2-1 Activation by SMAD2 Signaling After Definitive Endoderm Differentiation in Human Embryonic Stem Cell

“…3). We also detected a significant increase in transcript levels for other pulmonary epithelial transcription factors in hESC-H9 progeny, including GATA6 and PAX9 [21,26,27], but not PAX8, expressed by thyroid epithelium [28,29]. Immunostaining demonstrated that > 80% of hESC-H9 progeny stained positive for FOXA2, of which approximately 6% co-stained with antibodies against NKX2-1 (Fig.…”