The role of EPH receptors in cancer-related epithelial-mesenchymal transition

Li, Ruixin; Chen, Zihua; Chen, Zhikang

doi:10.5732/cjc.013.10108

Cited by 23 publications

(22 citation statements)

References 97 publications

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“…Eph receptors induce EMT through oncogenic signaling pathways such as Wnt, Ras/MAPK, Akt-mTOR, and Notch. 43 We also observed that the Src/FAK signaling is involved in the EphB4/ephrin-B2-induced EMT process. Perturbation of ephrin-B2 reverses the EMT phenotype by E-cadherin downregulation and hence makes mutant p53-expressing cancer cells more susceptible to chemotherapeutics.…”

Section: Discussionmentioning

confidence: 67%

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

et al. 2015

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Mutation in the TP53 gene positively correlates with increased incidence of chemoresistance in different cancers. In this study, we investigated the mechanism of chemoresistance and epithelial-to-mesenchymal transition (EMT) in colorectal cancer involving the gain-of-function (GOF) mutant p53/ephrin-B2 signaling axis. Bioinformatic analysis of the NCI-60 data set and subsequent hub prediction identified EFNB2 as a possible GOF mutant p53 target gene, responsible for chemoresistance. We show that the mutant p53-NF-Y complex transcriptionally upregulates EFNB2 expression in response to DNA damage. Moreover, the acetylated form of mutant p53 protein is recruited on the EFNB2 promoter and positively regulates its expression in conjunction with coactivator p300. In vitro cell line and in vivo nude mice data show that EFNB2 silencing restores chemosensitivity in mutant p53-harboring tumors. In addition, we observed high expression of EFNB2 in patients having neoadjuvant non-responder colorectal carcinoma compared with those having responder version of the disease. In the course of deciphering the drug resistance mechanism, we also show that ephrin-B2 reverse signaling induces ABCG2 expression after drug treatment that involves JNK-c-Jun signaling in mutant p53 cells. Moreover, 5-fluorouracil-induced ephrin-B2 reverse signaling promotes tumorigenesis through the Src-ERK pathway, and drives EMT via the Src-FAK pathway. We thus conclude that targeting ephrin-B2 might enhance the therapeutic potential of DNA-damaging chemotherapeutic agents in mutant p53-bearing human tumors.

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Section: Discussionmentioning

confidence: 67%

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

et al. 2015

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“…EPH receptor A3 ( EPHA3 ) was found to have the highest negative fold change in the microarray. EPH receptors have been shown to be involved in the EMT pathway, and may regulate E-cadherin and Snail expression, as well as regulate MMP-2 activity [32–35]. Three different annexins were the highest upregulated genes when SSX was knocked down, and annexins have been shown to attenuate EMT in breast cancer [36] and regulate TGF-beta signaling [37].…”

Section: Discussionmentioning

confidence: 99%

SSX2 regulates focal adhesion but does not drive the epithelial to mesenchymal transition in prostate cancer

Bloom

McNeel

2016

Oncotarget

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Prostate cancer is the most commonly diagnosed malignancy for men in the United States. Metastatic prostate cancer, the lethal form of the disease, has a life expectancy of approximately five years. Identification of factors associated with this transition to metastatic disease is crucial for future therapies. One such factor is the SSX gene family, a family of cancer/testis antigens (CTA) transcription factors which have been shown to be aberrantly expressed in other cancers and associated with the epithelial to mesenchymal transition (EMT). We have previously shown that SSX expression in prostate cancers was restricted to metastatic tissue and not primary tumors. In this study, we have identified SSX2 as the predominant SSX family member expressed in prostate cancer, and found its expression in the peripheral blood of 19 of 54 (35%) prostate cancer patients, with expression restricted to circulating tumor cells, and in 7 of 15 (47%) metastatic cDNA samples. Further, we examined SSX2 function in prostate cancer through knockdown and overexpression in prostate cancer cell lines. While overexpression had little effect on morphology or gene transcript changes, knockdown of SSX2 resulted in an epithelial morphology, increased cell proliferation, increased expression of genes involved in focal adhesion, decreased anchorage independent growth, increased invasion, and increased tumorigenicity in vivo. We conclude from these findings that SSX2 expression in prostate cancer is not a driver of EMT, but is involved in processes associated with EMT including loss of focal adhesion that may be related to tumor cell dissemination.

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“…[5][6][7] Metastatic cancer cells typically undergo morphological changes that result in decreased intercellular adhesion and increased cell motility, a process defined as the EMT. [8][9][10] A variety of cytokines, including chemokines, inflammatory factors, and growth factors, and tumor-infiltrating bone marrow-derived components, including macrophages and related cell types, are involved in tumor invasion and metastasis. 11,12 However, the involvement of inflammatory cells in cancer cell metastasis remains controversial.…”

Section: Cox-2 Promotes Metastasis In Nasopharyngeal Carcinoma By Medmentioning

confidence: 99%

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

OuYang

et al. 2015

OncoImmunology

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Keywords: COX-2, myeloid-derived suppressor cells, nasopharyngeal carcinomaAbbreviations: ARG-1, arginase 1; COX-2, cyclooxygenase-2; DFS, disease-free survival; EMT, epithelial-mesenchymal transition; GM-CSF, granulocyte-monocyte-colony stimulating factor; iNOS, inducible nitric oxide synthase; LNMMA, L-NG-monomethylarginine; MDSCs, myeloid-derived suppressor cells; NAC, N-acetylcysteine; NOHA, N-hydroxy-nor-L-arginine; NOX2, NADPH oxidase; NPC, nasopharyngeal carcinoma; ROS, reactive oxygen species; siRNA, small interfering RNA; TCF4, T-cell factor 4; TGF, transforming growth factor b; T-MDSCs, tumor-induced MDSCs; VEGF, vascular endothelial growth factorThe expansion of myeloid-derived suppressor cells (MDSCs) is a common feature of cancer, but its biological roles and molecular mechanism remain unclear. Here, we investigated a molecular link between MDSC expansion and tumor cell metastasis in nasopharyngeal carcinoma (NPC). We demonstrated that MDSCs expanded and were positively correlated with the elevated tumor COX-2 expression and serum IL-6 levels in NPC patients. Importantly, COX-2 and MDSCs were poor predictors of patient disease-free survival (DFS). Knocking down tumor COX-2 expression hampered functional TW03-mediated-MDSC cell (T-MDSC) induction with IL-6 blocking. We identified that T-MDSCs promoted NPC cell migration and invasion by triggering the epithelial-mesenchymal transition (EMT) on cell-to-cell contact, and TMDSCs enhanced tumor experimental lung metastasis in vivo. Interestingly, the contact between T-MDSCs and NPC cells enhanced tumor COX-2 expression, which subsequently activated the b-catenin/TCF4 pathway, resulting in EMT of the cancer cells. Blocking transforming growth factor b (TGFb) or inducible nitric oxide synthase (iNOS) significantly abolished the T-MDSC-induced upregulation of COX-2 and EMT scores in NPC cells, whereas the administration of TGFb or L-arginine supplements upregulated COX-2 expression and EMT scores in NPC cells. These findings reveal that COX-2 is a key factor mediating the interaction between MDSCs and tumor cells, suggesting that the inhibition of COX-2 or MDSCs has the potential to suppress NPC metastasis.

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The role of EPH receptors in cancer-related epithelial-mesenchymal transition

Cited by 23 publications

References 97 publications

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

SSX2 regulates focal adhesion but does not drive the epithelial to mesenchymal transition in prostate cancer

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

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