Identification of Gene Expression Differences between Lymphangiogenic and Non-Lymphangiogenic Non-Small Cell Lung Cancer Cell Lines

Regan, Erin; Sibley, Robert C.; Cenik, Bercin Kutluk; Silva, Asitha; Girard, Luc; Minna, John D.; Dellinger, Michael T.

doi:10.1371/journal.pone.0150963

Cited by 13 publications

(16 citation statements)

References 40 publications

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“…Therefore, biomarkers that can help to predict prevalence of lymph node metastasis may be helpful for the clinical evaluation. VEGF-C, a subtype of VEGF family, has been reported to participate in the lymphatic metastasis of various solid tumors including ovarian cancers (Bednarek et al 2008;Wu et al 2012;Regan et al 2016;Wang et al 2016). Interestingly, our study revealed that the mRNA expression of VEGF-C was positively correlated with TBL1XR1 levels in clinical tumor tissues.…”

Section: Discussionsupporting

confidence: 44%

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

2017

Tohoku J. Exp. Med.

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Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is a core component of the NCoR/SMRT transcription co-repressor complex, and its role in regulating cancer progression has been reported. Serous epithelial ovarian cancer (EOC) is the most common histological type of EOC. Here we explored the significance of TBL1XR1 expression in predicting outcomes of patients with serous EOC. Real-time quantitative PCR analysis showed that the expression level of TBL1XR1 mRNA was significantly higher in EOC tissues compared with adjacent non-tumorous tissues. The protein levels of TBL1XR1 in EOC tissues were assessed by immunohistochemistry, and the patients were classified into low-expression group (n = 62) and high-expression group (n = 54) according to the immunoreactivity. Prognostic significance of TBL1XR1 was evaluated by univariate and multivariate analyses, showing that over-expression of TBL1XR1 was correlated with poor prognosis. In addition, TBL1XR1 was positively associated with the lymph node metastasis of EOC. Because vascular endothelial growth factor (VEGF)-C is known as a critical mediator of lymph node metastasis, we measured the expression level of VEGF-C mRNA in EOC tissues and thus identified a positive correlation between TBL1XR1 and VEGF-C mRNA levels. Subsequently, using human EOC cell lines, we showed that silencing of TBL1XR1 decreased VEGF-C expression, suggesting that TBL1XR1 may function as an upstream regulator of VEGF-C in EOC. Furthermore, the proliferation and invasion of EOC cells were inhibited by TBL1XR1 silencing. In conclusion, TBL1XR1 overexpression may be an unfavorable prognostic factor for EOC. We also suggest that the TBL1XR1-VEGF-C axis may determine the EOC progression.

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Section: Discussionsupporting

confidence: 44%

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

2017

Tohoku J. Exp. Med.

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“…Despite expectations, none of the analyzed genes, except DSP, was activated in tumor tissue. Moreover, in malignant tissues, a statistically significant decrease in transcript level was observed for growth factors VEGFC and VEGFD and their receptor VEGFR3 that are thought to be the most potent inductors of lymphatic vessel formation (10,34,35), and transcripts for lymphatics-specific markers LYVE1 (36,37) and FOXC2 (38). The expression levels of other well-estimated lymphatic molecules PDPN (39,40) and PROX1 (41,42) were similar to those in nonmalignant tissue.…”

Section: Discussionmentioning

confidence: 99%

Lymphatics-associated genes are downregulated at transcription level in non-small cell lung cancer

Kowalczuk

Laudański

et al. 2018

Oncol Lett

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The present study aimed to verify a possibility of ongoing lymphangiogenesis in non-small cell lung cancer (NSCLC) via examination of mRNA levels of a number of lymphangiogenesis-associated genes in tumors. It was hypothesized that transcriptional activation of these genes would occur in tumors that stimulate new lymphatic vessel formation. The study was performed on 140 pairs of fresh-frozen surgical specimens of cancer and unaffected lung tissues derived from NSCLC stage I-IIIA patients. mRNA levels were evaluated with the reverse transcription-quantitative polymerase chain reaction method and expressed as fold change differences between the tumor and normal tissues. Possible associations between expression and patient clinicopathological characteristics and survival were analyzed. In the NSCLC tissue samples, vascular endothelial growth factor (VEGF) C, VEGFD, VEGFR3, VEGFR2, VEGFR1, lymphatic vessel endothelial hyaluronan receptor 1, integrin subunit α 9, FOX2, neuropilin 2, fibroblast growth factor 2 genes were significantly downregulated (P<0.001 for all) compared with matched normal lung tissues, whereas mRNA levels for VEGFA, spleen associated tyrosine kinase, podoplanin, and prospero homeobox 1 genes were similar in both tissues. Neither lymph node status, nor disease pathological stage influenced expression, whereas more profound suppression of gene activities appeared to occur in squamous cell carcinomas compared with adenocarcinomas. The VEGFR1 mRNA expression level was significantly connected with patient survival in the univariate analysis, and was an independent prognostic factor for overall survival in the multivariate Cox's proportional hazards model (HR 2.103; 95% confidence interval: 1.005-4.401; P=0.049). The results support a hypothesis of absence of new lymphatic vessel formation inside growing NSCLC tumor mass, however do not exclude a possibility of lymphangiogenesis in narrow marginal tumor parts.

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“…Lung cancer has been among the earliest and most intensely studied diseases using microarray platforms [39]. Two very recent studies have used microarray technologies to derive a robust prognostic gene expression signature for early stage lung adenocarcinoma [40] and identify a 17 gene expression signature that distinguishes lymphangiogenic from non-lymphangiogenic NSCLC cell lines [41]. Molecular signatures help to reveal the biologic spectrum of lung cancers, throw light on the pathogenetic alterations in gene expressions and cellular pathways, identify prognostic and predictive gene signatures, customize therapies, identify new therapeutic targets and evaluate new drugs [39].…”

Section: Discussionmentioning

confidence: 99%

Molecular gene signature and prognosis of non-small cell lung cancer

et al. 2016

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The current staging system for non–small cell lung cancer (NSCLC) is inadequate for predicting outcome. Risk score, a linear combination of the values for the expression of each gene multiplied by a weighting value which was estimated from univariate Cox proportional hazard regression, can be useful. The aim of this study is to analyze survival-related genes with TaqMan Low-Density Array (TLDA) and risk score to explore gene-signature in lung cancer. A total of 96 NSCLC specimens were collected and randomly assigned to a training (n = 48) or a testing cohort (n = 48). A panel of 219 survival-associated genes from published studies were used to develop a 6-gene risk score. The risk score was used to classify patients into high or low-risk signature and survival analysis was performed. Cox models were used to evaluate independent prognostic factors. A 6-gene signature including ABCC4, ADRBK2, KLHL23, PDS5A, UHRF1 and ZNF551 was identified. The risk score in both training (HR = 3.14, 95% CI: 1.14–8.67, p = 0.03) and testing cohorts (HR = 5.42, 95% CI: 1.56–18.84, p = 0.01) was the independent prognostic factor. In merged public datasets including GSE50081, GSE30219, GSE31210, GSE19188, GSE37745, GSE3141 and GSE31908, the risk score (HR = 1.50, 95% CI: 1.25–1.80, p < 0.0001) was also the independent prognostic factor. The risk score generated from expression of a small number of genes did perform well in predicting overall survival and may be useful in routine clinical practice.

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Identification of Gene Expression Differences between Lymphangiogenic and Non-Lymphangiogenic Non-Small Cell Lung Cancer Cell Lines

Cited by 13 publications

References 40 publications

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

Lymphatics-associated genes are downregulated at transcription level in non-small cell lung cancer

Molecular gene signature and prognosis of non-small cell lung cancer

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