ArticleProceedings of the National Academy of Sciences of the United States of America2015
Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 42 citations in OpenAlex.
- REPS2 attenuates cancer stemness through inhibiting Wnt signaling by autophagy mediated degradation of β-catenin.Oncogene · 2025Article
- Article
- The role of lncRNAs in the interplay of signaling pathways and epigenetic mechanisms in glioma.Epigenomics · 2025Review
- Ephrin-Eph signaling: an important regulator of epithelial integrity and barrier function.Tissue barriers · 2025Review
- Exploration of the shared pathways and common biomarkers in cervical and ovarian cancer using integrated bioinformatics analysis.Discover oncology · 2024Article
- EPHA2 is a novel cell surface marker of OCT4-positive undifferentiated cells during the differentiation of mouse and human pluripotent stem cells.Stem cells translational medicine · 2024Article
- Targeting EphA2: a promising strategy to overcome chemoresistance and drug resistance in cancer.Journal of molecular medicine (Berlin, Germany) · 2024Review
- Genome-wide quantification of copy-number aberration impact on gene expression in ovarian high-grade serous carcinoma.BMC cancer · 2024Article
- Spatial-temporal comparison of Eph/Ephrin gene expression in ocular lenses from aging and knockout mice.Frontiers in ophthalmology · 2024Article
- Downregulation of EphA2 stability by RNF5 limits its tumor-suppressive function in HER2-negative breast cancers.Cell death & disease · 2023Article
- A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2-Bispecific Antibody for Combination Cancer Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Suppression of KSHV lytic replication and primary effusion lymphoma by selective RNF5 inhibition.PLoS pathogens · 2023Article
- Review
- EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas.Current biology : CB · 2021Article
- Review
- Precise Identification of Recurrent Somatic Mutations in Oral Cancer Through Whole-Exome Sequencing Using Multiple Mutation Calling Pipelines.Frontiers in oncology · 2021Article
- In vivo functional screening for systems-level integrative cancer genomics.Nature reviews. Cancer · 2020Review
- EphA2, a possible target of miR-200a, functions through the AKT2 pathway in human lung carcinoma.International journal of clinical and experimental pathology · 2020Article
- Review
- Receptor-Targeted Glial Brain Tumor Therapies.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.