Upregulation of Notch2 and Six1 Is Associated with Progression of Early-Stage Lung Adenocarcinoma and a More Aggressive Phenotype at Advanced Stages

Abstract

Purpose: Lung adenocarcinoma often manifests as tumors with mainly lepidic growth. The size of invasive foci determines a diagnosis of in situ, minimally invasive adenocarcinoma, or invasive types and suggests that some adenocarcinomas undergo malignant progression in that order. This study investigates how transcriptional aberrations in adenocarcinoma cells at the early stage define the clinical phenotypes of adenocarcinoma tumors at the advanced stage.Experimental Design: We comprehensively searched for differentially expressed genes between preinvasive and invasive cancer cells in one minimally invasive adenocarcinoma using laser capture microdissection and DNA microarrays. We screened expression of candidate genes in 11 minimally invasive adenocarcinomas by reverse transcriptase PCR and examined their involvement in preinvasive-to-invasive progression by transfection studies. We then immunohistochemically investigated the presence of candidate molecules in 64 samples of advanced adenocarcinoma and statistically analyzed the findings, together with clinicopathologic variables.Results: The transcription factors Notch2 and Six1 were upregulated in invasive cancer cells in all 11 minimally invasive adenocarcinomas. Exogenous Notch2 transactivated Six1 followed by Smad3, Smad4, and vimentin, and enlarged the nuclei of NCI-H441 lung epithelial cells. Immunochemical staining for the transcription factors was double positive in the invasive, but not in the lepidic growth component of a third of advanced Ads, and the disease-free survival rates were lower in such tumors.Conclusions: Paired upregulation of Notch2 and Six1 is a transcriptional aberration that contributes to preinvasive-to-invasive adenocarcinoma progression by inducing epithelial-mesenchymal transition and nuclear atypia. This aberration persisted in a considerable subset of advanced adenocarcinoma and conferred a more malignant phenotype on the subset. Clin Cancer Res; 18(4); 945-55. Ó2011 AACR.

MiR-134/487b/655 Cluster Regulates TGF-β–Induced Epithelial–Mesenchymal Transition and Drug Resistance to Gefitinib by Targeting MAGI2 in Lung Adenocarcinoma Cells

“…Moreover, we evaluated miR-134/478b/655 expression levels in eight lung adenocarcinoma cells without TGF-b1 stimulation, previously performed by the TaqMan MicroRNA Array (24). Previous reports demonstrated that RERF-LC-KJ and RERF-LC-MS were recognized as EMT-positive cells (25,26). Four EMT-positive cells exhibited higher expression levels of three miRNAs than did those of four EMT-negative cells (Supplementary Fig.…”

DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling

“…2D-F). DS domain of DACH1 protein was required for inhibition of growth in breast and prostate cancer cells [20,24,26,27]. To examine whether this domain also plays an essential role in NSCLC, sublines expressing DACH1 without DS domian (ΔDS) were established.…”

“…Clinically, a decreased expression of DACH1 in breast and endometrial cancer correlates with tumor progression, poor differentiation [23] and predicts a short survival [13,24,25]. In human lung adenocarcinoma, the transcription factor SIX1 is upregulated during preinvasive to invasive transition and that results in EMT and conferring a more malignant phenotype [26]. In contrast, DACH1 expression was reduced in human NSCLC.…”

MicroRNA-30a regulates zebrafish myogenesis via targeting the transcription factor Six1

“…Interestingly, the expression of miR30a decreases with the progression of lymphoma, leukemia, lung, ovarian, breast and colon cancer (Cheng et al, 2012;González-Gugel et al, 2013;Guan et al, 2012;Lee et al, 2012;Liu et al, 2013;Ma et al, 2012;Võsa et al, 2013), all cancers in which SIX1 overexpression has been detected (Behbakht et al, 2007;Ford et al, 1998;Mimae et al, 2012;Ono et al, 2012;Wang et al, 2011). Importantly, increased SIX1 expression enhances progression of RMS and several additional tumor types by re-activating many of the same signaling networks that SIX1 turns on developmentally to promote cell survival, proliferation and migration (Christensen et al, 2008;Khan et al, 1999;Yu et al, 2006;Yu et al, 2004).…”