Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma

Ishikawa, Masashi; Miyahara, Ryoji; Sonobe, Makoto; Horiuchi, Marika; Mennju, Toshi; Nakayama, Eiichiro; Kobayashi, Masashi; Kikuchi, Ryutaro; Kitamura, Jiro; Imamura, Naoto; Huang, Cheng‐Long; Date, Hiroshi

doi:10.1016/j.lungcan.2011.12.004

Cited by 39 publications

(33 citation statements)

References 40 publications

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“…However, ephrin-A1 was not associated with any of the clinicopathological parameters apart from histological type. Interestingly, we found that adenocarcinomas had a higher percentage of S100A4 and ephrin-A1 positivity compared to squamous and large cell tumors, and this finding is in keeping with that of previous studies on S100A4 [7-9] and ephrin-A1 [25]. The histological subclasses of NSCLC differ not only in their presentation in different regions of the lung and in outcome [26], but also in molecular characteristics and thereby in response to targeted therapies [27].…”

Section: Discussionsupporting

confidence: 92%

Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer

et al. 2012

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BackgroundThe metastasis-promoting protein S100A4 induces expression of ephrin-A1 and osteopontin in osteosarcoma cell lines. The aim of this study was to investigate S100A4-mediated stimulation of ephrin-A1 and osteopontin in non-small cell lung cancer (NSCLC) cell lines, and to characterize the expression of these biomarkers in primary tumor tissue from NSCLC patients.MethodsFour NSCLC cell lines were treated with extracellular S100A4, and ephrin-A1 and osteopontin expression was analyzed by real time RT-PCR and Western blotting. Immunohistochemical staining for S100A4, ephrin-A1 and osteopontin was performed on tissue microarrays containing primary tumor samples from a cohort of 217 prospectively recruited NSCLC patients, and associations with clinicopathological parameters were investigated.ResultsS100A4 induced ephrin-A1 mRNA and protein expression in adenocarcinoma, but not in squamous carcinoma cell lines, whereas the level of osteopontin was unaffected by S100A4 treatment. In primary tumors, moderate or strong immunoreactivity was observed in 57% of cases for cytoplasmic S100A4, 46% for nuclear S100A4, 86% for ephrin-A1 and 77% for osteopontin. Interestingly, S100A4 expression was associated with ephrin-A1 also in vivo, but there was no association between S100A4 and osteopontin. Expression levels of S100A4 and ephrin-A1 were significantly higher in adenocarcinomas compared to other histological subtypes, and S100A4-positive tumors were smaller and more differentiated than tumors without expression.ConclusionsOur findings suggest that S100A4, ephrin-A1 and osteopontin are involved in the biology of NSCLC, and further investigation of their potential use as biomarkers in NSCLC is warranted.

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Section: Discussionsupporting

confidence: 92%

Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer

et al. 2012

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“…Contrary, in the present study, ccRCC patients with a high EFNA1 protein expression had frequently a lower tumor stage (p = 0.004). We did not find any link between EFNA1 protein expression and patient outcome, which is supported by other studies in patients with gastric [17] and lung [27] cancer. However, a high protein expression of EFNA1 was linked to poor survival in patients with vulvar [12] and cervical [11] carcinomas.…”

Section: Discussionsupporting

confidence: 90%

Lack of Ephrin Receptor A1 Is a Favorable Independent Prognostic Factor in Clear Cell Renal Cell Carcinoma

et al. 2014

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The EPH receptor tyrosine kinases and their cell-bound ligands, the ephrins, have been shown to be associated with cancer development and progression. In this study, mRNA and protein expression of the receptors EPHA1 and EPHA2 as well as of their ligand EFNA1 and their prognostic relevance in clear cell renal cell carcinoma was evaluated. Gene expression was measured in 75 cryo-preserved primary tumors and matched non-malignant renal specimens by quantitative PCR. Protein expression was analyzed by immunohistochemistry on tissue microarrays comprising non-malignant, primary tumors and metastatic renal tissues of 241 patients. Gene and protein expression of all three factors was altered in tumor specimens with EPHA1 and EPHA2 being generally diminished in tumors compared to normal renal tissue, whereas EFNA1 was commonly elevated. A positive EPHA1 and EPHA2 protein staining as well as a low EFNA1 protein level were significantly linked to more aggressive tumor features, but only a positive EPHA1 immunoreactivity was significantly associated with poor survival. In subgroup analyses, EPHA1 and EPHA2 protein levels were significantly higher in metastatic than in primary lesions. Patients with EPHA1/EPHA2-positive tumors or with tumors with positive EPHA1 and low EFNA1 immunoreactivity had the shortest survival rates compared to the respective other combinations. In a multivariate model, EPHA1 was an independent prognostic marker for different survival endpoints. In conclusion, an impaired EPH-ephrin signaling could contribute to the pathogenesis and progression of clear cell renal cell carcinoma.

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“…Together, these observations suggest that, whereas tumor-specific deletion of EphA2 promotes tumorigenesis, the contribution of EphA2 from tumor stroma and endothelial cells might be important for tumor development. Some human lung adenocarcinoma patients show increased expression of EphA2, and it is correlated with poor prognosis (39), whereas coexpression of high EphA2 and EfnA1 has favorable survival (40). Interestingly, TCGA data analysis revealed that EphA2 and EfnA1 alterations occur independently, and it is intriguing to hypothesize that tumors with EphA2 and EfnA1 coexpression might be negatively selected in the early stages of tumor development.…”

Section: Discussionmentioning

confidence: 99%

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Lung adenocarcinoma, a major form of non-small cell lung cancer, is the leading cause of cancer deaths. The Cancer Genome Atlas analysis of lung adenocarcinoma has identified a large number of previously unknown copy number alterations and mutations, requiring experimental validation before use in therapeutics. Here, we describe an shRNA-mediated high-throughput approach to test a set of genes for their ability to function as tumor suppressors in the background of mutant KRas and WT Tp53. We identified several candidate genes from tumors originated from lentiviral delivery of shRNAs along with Cre recombinase into lungs of Loxp-stop-Loxp-KRas mice. Ephrin receptorA2 (EphA2) is among the top candidate genes and was reconfirmed by two distinct shRNAs. By generating knockdown, inducible knockdown and knockout cell lines for loss of EphA2, we showed that negating its expression activates a transcriptional program for cell proliferation. Loss of EPHA2 releases feedback inhibition of KRAS, resulting in activation of ERK1/2 MAP kinase signaling, leading to enhanced cell proliferation. Intriguingly, loss of EPHA2 induces activation of GLI1 transcription factor and hedgehog signaling that further contributes to cell proliferation. Small molecules targeting MEK1/2 and Smoothened hamper proliferation in EphA2-deficient cells. Additionally, in EphA2 WT cells, activation of EPHA2 by its ligand, EFNA1, affects KRAS–RAF interaction, leading to inhibition of the RAS-RAF-MEK-ERK pathway and cell proliferation. Together, our studies have identified that (i) EphA2 acts as a KRas cooperative tumor suppressor by in vivo screen and (ii) reactivation of the EphA2 signal may serve as a potential therapeutic for KRas-induced human lung cancers.

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Higher expression of EphA2 and ephrin-A1 is related to favorable clinicopathological features in pathological stage I non-small cell lung carcinoma

Cited by 39 publications

References 40 publications

Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer

Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer

Lack of Ephrin Receptor A1 Is a Favorable Independent Prognostic Factor in Clear Cell Renal Cell Carcinoma

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

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