• Humans
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• Female
• Metabolomics/methods
• Tumor Microenvironment/genetics
• Proteomics/methods
• Genomics/methods
• Single-Cell Analysis
• Computational Biology/methods
• Biomarkers, Tumor
• Transcriptome
• Multiomics

• R37CA261987 CSR NIH HHS
• R01 CA285446 NCI NIH HHS
• R00 HG012945 NHGRI NIH HHS
• R01 AI170228 NIAID NIH HHS
• OC170228 Department of Defense
• OC200302 Department of Defense
• OC200225 Department of Defense

• Colorectal cancer
• Drug resistance
• Erythropoietin-induced hepatocyte receptor A2
• Pyroptosis
• Tumor metastasis

• Cancer
• EphA2
• Kinase inhibitors
• RTKs
• Targeted therapy

• Animals
• Receptor, EphA2/genetics
• Receptor, EphA2/metabolism
• Neoplasms/drug therapy
• Neoplasms/genetics
• Receptor Protein-Tyrosine Kinases/metabolism
• Signal Transduction
• Ephrins/pharmacology
• Cell Line, Tumor

• Angiogenesis
• Angiogenic factors
• Clinical trial
• Ovarian cancer
• Signaling pathways

• Humans
• Female
• Carcinoma, Ovarian Epithelial
• Ovarian Neoplasms/pathology
• Neovascularization, Pathologic/drug therapy
• Signal Transduction
• Genital Neoplasms, Male
• Tumor Microenvironment

• EphA2
• biomarker
• chronic kidney disease
• eGFR
• hypertension

• Diagnostic markers
• Ephrin receptor A7 (EphA7)
• Mechanism
• Prognosis
• Therapeutic target
• Tumor

Ephrin-A1 is a protein that in humans is encoded by the EFNA1 gene. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases which play an indispensable role in normal growth and development or in the pathophysiology of various tumors. The role of EFNA1 in tumorigenesis and development is complex and depends on the cell type and microenvironment which in turn affect the expression of EFNA1. This article reviews the expression, prognostic value, regulation and clinical significance of EFNA1 in gastrointestinal tumors.

• EFNA1
• Expression
• Tumorigenesis
• Clinical implication
• gastrointestinal cancer

• Natural Science Foundation of China
• Guangdong Basic and Applied Basic Research Foundation
• Medical Project of Science and Technology Planning of Shantou
• 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant

Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. The aim of the current review was to examine the dysregulation of the EPH/ephrin system in gynecological cancer, clarifying its role in ovarian, endometrial, and cervical carcinogenesis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms ephrin, ephrin receptor, ovarian cancer, endometrial cancer, and cervical cancer were employed and we were able to identify 57 studies focused on gynecological cancer and published between 2001 and 2021. All researched ephrins seemed to be upregulated in gynecological cancer, whereas EPHs showed either significant overexpression or extensive loss of expression in gynecological tumors, depending on the particular receptor. EPHA2, the most extensively studied EPH in ovarian cancer, exhibited overexpression both in ovarian carcinoma cell lines and patient tissue samples, while EPHB4 was found to be upregulated in endometrial cancer in a series of studies. EPHs/ephrins were shown to exert their role in different stages of gynecological cancer and to influence various clinicopathological parameters. The analysis of patients’ gynecological cancer tissue samples, most importantly, revealed the significant role of the EPH/ephrin system in the development and progression of gynecological cancer, as well as overall patient survival. In conclusion, the EPH/ephrin system represents a large family of biomolecules with promising applications in the fields of diagnosis, prognosis, disease monitoring, and treatment of gynecological cancer, with an established important clinical impact.

• EPHs
• cervical cancer
• endometrial cancer
• ephrins
• ovarian cancer

• cancer therapy
• pharmacology

• Animals
• Genetic Therapy/methods
• Humans
• Molecular Targeted Therapy
• Neoplasms/genetics
• Neoplasms/therapy
• RNA, Long Noncoding/genetics

• R01 CA222007 NCI NIH HHS
• R01 CA219024 NCI NIH HHS
• UH3 TR000943 NCATS NIH HHS
• R01 GM122775 NIGMS NIH HHS
• R01 CA182905 NCI NIH HHS
• R01 CA215753 NCI NIH HHS
• P30 CA071789 NCI NIH HHS

Pancreatic cancer (PC) is one of the worst prognoses amongst all malignant diseases. It is therefore of great significance to identify biomarkers with predictive clinical value for the prognosis and recurrence of PC.

In our study, enzyme-linked immunosorbent assays (ELISA) were used to detect the expression of Exo-EphA2 in the serum of PC patients and controls. Kaplan–Meier curve and Cox regression analyses were used to evaluate the prognostic value of Exo-EphA2 expression in patients with primary and recurrent PC.

The level of serum Exo-EphA2 was significantly higher in the PC group when compared to that of the control group. High expression of Exo-EphA2 in PC was associated with shorter overall survival (OS) and proved to be a significant negative prognostic factor in the multivariate analysis (HR = 1.04, 95% CI: 1.00–1.09, P <0.001). Additionally, we found that the level of serum Exo-EphA2 in recurrent PC patients (first recurrence < 12 months) was positively correlated with the level of Exo-EphA2 at primary diagnosis. Multivariate analysis showed that a high expression of Exo-EphA2 in recurrent PC was associated with shorter recurrence-free survival (RFS) (HR = 1.41, 95% CI: 1.10–1.70, P < 0.001).

High expression of serum Exo-EphA2 represents a novel biomarker for a poor prognosis in PC patients.

• EphA2
• exosome
• pancreatic cancer
• prognosis

• Circulating tumor DNA
• Ovarian cancer
• Prognosis

• Circulating Tumor DNA/genetics
• Female
• Humans
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• Prognosis

• Antibody therapeutics
• Cancer therapeutics
• EphA2 receptor
• Erythropoietin-producing hepatocellular receptor
• Oncology
• Receptor tyrosine kinase

Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment‐dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non‐genetic resistance mechanisms was long neglected. Using high‐grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy‐induced ERK1/2‐RSK1/2‐EphA2‐GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2‐S897 phosphorylation and EphA2‐GPRC5A co‐regulation, thereby facilitating a signaling shift to the canonical tumor‐suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum‐resistant EphA2^high, GPRC5A^high cells to the therapy‐induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo‐resistant cells to RSK1/2‐EphA2‐pS897 pathway inhibition.

• HGSC
• EphA2
• GPRC5A
• chemotherapy
• resistance

• Exosomes
• Ovarian cancer
• tumour microenvironment

• biomarker
• meta-analysis
• microrna
• ovarian cancer
• prognosis

• Adult
• Biomarkers, Tumor/genetics
• Disease-Free Survival
• Female
• Humans
• Kaplan-Meier Estimate
• MicroRNAs/analysis
• Middle Aged
• Ovarian Neoplasms/genetics
• Prognosis

• Eph/ephrin system
• angiogenesis
• colon cancer
• gastric cancer
• lymphangiogenesis
• pancreatic cancer

• EphA2
• hepatocellular carcinoma
• invasion
• miR-26b
• migration
• proliferation

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation/genetics
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasm Invasiveness/genetics
• Neoplasm Invasiveness/pathology
• Receptor, EphA2/genetics
• Receptor, EphA2/metabolism

Ephrin type-A receptor 2 (EphA2) is a receptor tyrosine kinase that is associated with cancer cell metastasis. There has been little investigation into its impact on the regulation of sensitivity to paclitaxel in nasopharyngeal carcinoma (NPC). In the present study, upregulation of EphA2 expression enhanced the survival of NPC 5-8F cells, compared with control cells exposed to the same concentrations of paclitaxel. Flow cytometry and western blot analysis demonstrated that over-expression of EphA2 decreased NPC cancer cell sensitivity to paclitaxel by regulating paclitaxel-mediated cell cycle progression but not apoptosis in vitro. This was accompanied by alterations in the expression of cyclin-dependent kinase inhibitors, p21 and p27, and of inactive phosphorylated-retinoblastoma protein. Furthermore, paclitaxel stimulation and EphA2 over-expression resulted in activation of the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway in NPC cells. Inhibition of the PI3K/Akt signalling pathway restored sensitivity to paclitaxel in 5-8F cells over-expressing EphA2, which indicated that the PI3K/Akt pathway is involved in EphA2-mediated paclitaxel sensitivity. The current study demonstrated that EphA2 mediates sensitivity to paclitaxel via the regulation of the PI3K/Akt signalling pathway in NPC.

The EphA2 receptor, which is expressed in many types of cancer, is activated by two different mechanisms. Activation by engagement with one of its ephrin ligands is anti-oncogenic whereas phosphorylation of S897 by AKT increases migration, invasion and metastasis. Down-regulation of claudin-4 (CLDN4) produces a loss of E-cadherin and increased β-catenin signaling and a phenotype similar to that produced by oncogenic activation of EphA2, suggesting that CLDN4 may serve to restrain the pro-oncogenic signaling of EphA2.

We found that constitutive knockdown of CLDN4 was associated with a 4.5-fold increase in EphA2 mRNA and a 2.5-fold increase in EphA2 protein which was reversible by re-expression of CLDN4. Knockdown of EphA2 blocked the migratory phenotype induced by loss of CLDN4. Knockdown of CLDN4 resulted in a 5.8-fold increase in pEphA(S897), the oncogenic form of the receptor, as well as partial mislocalization of the excess EphA2 to the interior of the cell. Forced expression of E-cadherin did not reduce total EphA2 or pEphA(S897) whereas re-expression of CLDN4 restored localization and reduced EphA2 and pEphA(S897) even in cells not expressing E-cadherin. Transient siRNA-mediated knockdown of EphA2 and β-catenin, and inhibition of PI3K by LY294002, demonstrated that increased pEphA(S897) in the CLDN4 knockdown cells was attributable to an increase in the level of active dephospho-β-catenin upstream of PI3K and AKT.

We conclude that CLDN4 serves to restrain pro-oncogenic signaling from EphA2 by limiting the activity of β-catenin and PI3K and preventing phosphorylation of EphA2 on S897 by AKT. This suggests that interventions directed at enhancing the level or functional activity of CLDN4 may be of therapeutic interest.

The online version of this article (doi:10.1186/s12964-014-0059-5) contains supplementary material, which is available to authorized users.

• Invasion
• Migration
• Ovarian cancer
• Proliferation
• Spry1
• Survival

• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cell Survival
• Female
• Gene Expression
• Humans
• MAP Kinase Signaling System
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Neoplasm Invasiveness
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Phosphoproteins/genetics
• Phosphoproteins/metabolism

• EphA2
• LNCaP cell
• cell proliferation
• prostate cancer
• tumor invasion

• Animals
• Basic Helix-Loop-Helix Transcription Factors/genetics
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Carcinoma, Hepatocellular/blood supply
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/surgery
• Gene Expression Regulation, Neoplastic
• High-Intensity Focused Ultrasound Ablation
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Liver Neoplasms/blood supply
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/surgery
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Receptor, EphA2/genetics
• Receptor, EphA2/metabolism
• Transplantation, Heterologous
• Treatment Failure
• Vascular Endothelial Growth Factor A/genetics
• Vascular Endothelial Growth Factor A/metabolism

Erythropoietin-producing hepatoma (EPH) receptors are considered the largest family of receptor tyrosine kinases and play key roles in physiological and pathologic processes in development and disease. EPH receptors are often overexpressed in human malignancies and are associated with poor prognosis. However, the functions of EPH receptors in epithelial-mesenchymal transition (EMT) remain largely unknown. This review depicts the relationship between EPH receptors and the EMT marker E-cadherin as well as the crosstalk between EPH receptors and the signaling pathways involved EMT. Further discussion is focused on the clinical significance of EPH receptors as candidates for targeting in cancer therapeutics. Finally, we summarize how targeted inhibition of both EPH receptors and EMT-related signaling pathways represents a novel strategy for cancer treatment.

• EphA2
• drug resistance
• metastasis
• nasopharyngeal carcinoma
• paclitaxel

• Apoptosis/genetics
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology
• Cell Cycle Checkpoints/genetics
• Cell Growth Processes/genetics
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Transformation, Neoplastic/genetics
• Disease Progression
• Down-Regulation
• Female
• Flow Cytometry/methods
• G1 Phase/genetics
• Gene Knockdown Techniques/methods
• Head and Neck Neoplasms/genetics
• Head and Neck Neoplasms/pathology
• Humans
• Lentivirus/genetics
• Lymph Nodes/pathology
• Lymphatic Metastasis
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Prognosis
• RNA, Small Interfering/genetics
• Receptor, EphA2/antagonists & inhibitors
• Receptor, EphA2/biosynthesis
• Receptor, EphA2/genetics
• Resting Phase, Cell Cycle/genetics
• Squamous Cell Carcinoma of Head and Neck

• antigen presentation
• chemotherapy
• glioma
• immunosuppression
• neurostatin

• ephrin receptors
• eph-a2
• eph-a4
• thyroid malignancy
• clinicopathological parameters
• immunohistochemistry

• Female
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Receptor, EphA2/metabolism
• Receptor, EphA4/metabolism
• Thyroid Neoplasms/metabolism
• Thyroid Neoplasms/pathology

EphA2 is a member of the Eph family of receptor tyrosine kinases and is highly expressed in many aggressive cancer types, including melanoma. We recently showed that EphA2 is also upregulated by ultraviolet radiation and is able to induce apoptosis. These findings suggest that EphA2 may have different, even paradoxical, effects on viability depending on the cellular context and that EphA2 mediates a delicate balance between life and death of the cell. To functionally clarify EphA2’s role in melanoma, we analyzed a panel of melanoma cell lines and found that EphA2 levels are elevated in a significant fraction of the samples. Specific depletion of EphA2 in high-expressing melanoma cells using shRNA led to profound reductions in cellular viability, colony formation and migration in vitro and a dramatic loss of tumorigenic potential in vivo. Stable introduction of EphA2 into low-expressing lines enhanced proliferation, colony formation and migration further supporting its pro-malignant phenotype. Interestingly, transient expression of EphA2 and/or Braf^V600E in non-transformed melanocytes led to significant and additive apoptosis. These results verify that EphA2 is an important oncogene and potentially a common source of “addiction” for many melanoma cells. Moreover, acute induction of EphA2 may purge genetically-susceptible cells thereby uncovering a more aggressive population that is in fact dependent on the oncogene.

• Adult
• Aged
• Aged, 80 and over
• Carcinoma/enzymology
• Carcinoma/mortality
• Carcinoma/pathology
• Carcinoma, Squamous Cell
• Cell Line, Tumor
• Female
• Head and Neck Neoplasms/enzymology
• Head and Neck Neoplasms/mortality
• Head and Neck Neoplasms/pathology
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Neoplasms, Squamous Cell/enzymology
• Neoplasms, Squamous Cell/mortality
• Neoplasms, Squamous Cell/pathology
• Proportional Hazards Models
• RNA, Messenger/analysis
• Receptor, EphA2/analysis
• Receptor, EphA2/genetics
• Squamous Cell Carcinoma of Head and Neck

MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the expression of multiple target genes. Deregulation of miRNAs is common in human tumorigenesis. Low level expression of miR-26b has been found in glioma cells. However, its underlying mechanism of action has not been determined.

Real-time PCR was employed to measure the expression level of miR-26b in glioma patients and cells. The level of miR-26b was inversely correlated with the grade of glioma. Ectopic expression of miR-26b inhibited the proliferation, migration and invasion of human glioma cells. A binding site for miR-26b was identified in the 3′UTR of EphA2. Over-expression of miR-26b in glioma cells repressed the endogenous level of EphA2 protein. Vasculogenic mimicry (VM) experiments were performed to further confirm the effects of miR-26b on the regulation of EphA2, and the results showed that miR-26b inhibited the VM processes which regulated by EphA2.

This study demonstrated that miR-26b may act as a tumor suppressor in glioma and it directly regulates EphA2 expression. EphA2 is a direct target of miR-26b, and the down-regulation of EphA2 mediated by miR-26b is dependent on the binding of miR-26b to a specific response element of microRNA in the 3′UTR region of EphA2 mRNA.

Ephrin A1 (EFNA1) is a member of the A-type ephrin family of cell surface proteins that function as ligands for the A-type Eph receptor tyrosine kinase family. In malignancy, the precise role of EFNA1 and its preferred receptor, EPHA2, is controversial. Several studies have found that EFNA1 may suppress EPHA2-mediated oncogenesis, or enhance it, depending on cell type and context. However, little is known about the conditions that influence whether EFNA1 promotes or suppresses tumorigenicity. EFNA1 exists in a soluble form as well as a glycophosphatidylinositol (GPI) membrane attached form. We investigated whether the contradictory roles of EFNA1 in malignancy might in part be related to the existence of both soluble and membrane attached forms of EFNA1 and potential differences in the manner in which they interact with EPHA2.

Using a RNAi strategy to reduce the expression of endogenous EFNA1 and EPHA2, we found that both EFNA1 and EPHA2 are required for growth of HeLa and SK-BR3 cells. The growth defects could be rescued by conditioned media from cells overexpressing soluble EFNA1. Interestingly, we found that overexpression of the membrane attached form of EFNA1 suppresses growth of HeLa cells in 3D but not 2D. Knockdown of endogenous EFNA1, or overexpression of full-length EFNA1, resulted in relocalization of EPHA2 from the cell surface to sites of cell-cell contact. Overexpression of soluble EFNA1 however resulted in more EPHA2 distributed on the cell surface, away from cell-cell contacts, and promoted the growth of HeLa cells.

We conclude that soluble EFNA1 is necessary for the transformation of HeLa and SK-BR3 cells and participates in the relocalization of EPHA2 away from sites of cell-cell contact during transformation.

• Biomarkers, Tumor/genetics
• Cell Line, Tumor
• Cell Movement/genetics
• Female
• Humans
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Middle Aged
• Multigene Family
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• Reverse Transcriptase Polymerase Chain Reaction
• Transfection

• R01 CA169306 NCI NIH HHS