Identification of Gene Signatures and Molecular Markers for Human Lung Cancer Prognosis using anIn vitroLung Carcinogenesis System

Abstract

Lung cancer continues to be a major deadly malignancy. The mortality of this disease could be reduced by improving the ability to predict cancer patients' survival. We hypothesized that genes differentially expressed among cells constituting an in vitro human lung carcinogenesis model consisting of normal, immortalized, transformed, and tumorigenic bronchial epithelial cells are relevant to the clinical outcome of non–small cell lung cancer (NSCLC). Multidimensional scaling, microarray, and functional pathways analyses of the transcriptomes of the above cells were done and combined with integrative genomics to incorporate the microarray data with published NSCLC data sets. Up-regulated (n = 301) and down-regulated genes (n = 358) displayed expression level variation across the in vitro model with progressive changes in cancer-related molecular functions. A subset of these genes (n = 584) separated lung adenocarcinoma clinical samples (n = 361) into two clusters with significant survival differences. Six genes, UBE2C, TPX2, MCM2, MCM6, FEN1, and SFN, selected by functional array analysis, were also effective in prognosis. The mRNA and protein levels of one these genes—UBE2C—were significantly up-regulated in NSCLC tissue relative to normal lung and increased progressively in lung lesions. Moreover, stage I NSCLC patients with positive UBE2C expression exhibited significantly poorer overall and progression-free survival than patients with negative expression. Our studies with this in vitro model have lead to the identification of a robust six-gene signature, which may be valuable for predicting the survival of lung adenocarcinoma patients. Moreover, one of those genes, UBE2C, seems to be a powerful biomarker for NSCLC survival prediction.

TPX2 (TPX2, microtubule-associated, homolog (Xenopus laevis))

“…Prognosis Three studies indicate the prognostic value of TPX2 overexpression in adenocarcinomas (Kadara et al, 2009;Li et al, 2013) and squamous cell carcinoma (Ma et al, 2006): TPX2 expression is associated with tumor grade and stage and poor survival rates. In particular, TPX2 is among the top genes in prognostic TPX2 (TPX2, microtubule-associated, homolog (Xenopus laevis)) Asteriti IA, Guarguaglini G Atlas Genet Cytogenet Oncol Haematol.…”

“…In particular, TPX2 is among the top genes in prognostic TPX2 (TPX2, microtubule-associated, homolog (Xenopus laevis)) Asteriti IA, Guarguaglini G Atlas Genet Cytogenet Oncol Haematol. 2013;17(9) signatures identified as classifiers for overall survival of patients (Kadara et al, 2009;Li et al 2013). Oncogenesis Several studies report increased TPX2 expression levels in primary lung tumors (adenocarcinomas, squamous cell carcinoma, small cell carcinoma) and lung cancer cell lines, compared to controls (Manda et al, 1999;Tonon et al, 2005;Ma et al, 2006;Zhang et al, 2008;Kadara et al, 2009;Li et al, 2013).…”

Prediction of Survival in Resected Non–Small Cell Lung Cancer Using a Protein Expression–Based Risk Model: Implications for Personalized Chemoprevention and Therapy

“…These markers have been investigated using in vitro and in vivo early carcinogenesis models, and were found to be key to the pathogenesis of NSCLC, both adenocarcinoma and squamous cell carcinoma. The markers chosen relate to cell adhesion and extracellular matrix interactions (CASK, CD51 (8), EpCAM (9), SPP1 (10)), inflammation (CXCR2 (11)), growth factors and effector pathways (IGF-1R(12), IGFBP3 (13), insulin receptor (14), pIGF-1R, pEGFR (15, 16)), growth and metabolism (pAkt (17, 18), pSrc (19), pmTor (18), pAMPK (20), pS6 (17), SFN (21), UBE2C), and DNA replication and repair (FEN1, MCM2, MCM6, TPX2 (21, 22)). We then aimed to investigate these biomarkers in early stage lung cancer and to gain a better understanding of the cellular and molecular processes that drive lung carcinogenesis.…”

Dominant negative Ubiquitin-conjugating enzyme E2C sensitizes cervical cancer cells to radiation

“…Overexpression of UBE2C has been demonstrated in a variety of malignancies such as colorectal, thyroid, lung, breast, ovary and lymphomas corresponding to their normal tissues (Warrenfeltz et al 630 M. V. Bose et al . 2004, Kadara et al 2009, Loussouarn et al 2009, Troncone et al 2009, Chen et al 2010, Guerriero et al 2010.…”