EphB2 Promotes Progression of Cutaneous Squamous Cell Carcinoma

Abstract

Keratinocyte-derived skin cancer, cutaneous squamous cell carcinoma (cSCC), is the most common metastatic skin cancer. We have examined the role of Eph/ephrin signaling in the progression of cSCC. Analysis of the expression of EPH and EFN families in cSCC cells and normal epidermal keratinocytes revealed overexpression of EPHB2 mRNA in cSCC cells and cSCC tumors in vivo. Tumor cell-specific overexpression of EphB2 was detected in human cSCCs and in chemically induced mouse cSCCs with immunohistochemistry, whereas the expression of EphB2 was low in premalignant lesions and normal skin. Knockdown of EphB2 expression in cSCC cells suppressed growth and vascularization of cSCC xenografts in vivo and inhibited proliferation, migration, and invasion of cSCC cells in culture. EphB2 knockdown downregulated expression of genes associated with biofunctions cell viability, migration of tumor cells, and invasion of tumor cells. Among the genes most downregulated by EphB2 knockdown were MMP1 and MMP13. Moreover, activation of EphB2 signaling by ephrin-B2-Fc enhanced production of invasion proteinases matrix metalloproteinase-13 (MMP13) and MMP1, and invasion of cSCC cells. These findings provide mechanistic evidence for the role of EphB2 in the early progression of cSCC to the invasive stage and identify EphB2 as a putative therapeutic target in this invasive skin cancer.

Overexpression of junctional adhesion molecule-A and EphB2 predicts poor survival in lung adenocarcinoma patients

“…EphB2, a receptor tyrosine kinase for ephrin ligands, is overexpressed in a variety of cancers and plays an important role in cancer progression. [26][27][28] Before our research, only EphB2 messenger RNA (mRNA) transcription level in small cell lung carcinoma has been reported but no protein expression, distribution, or survival analysis is shown. 29 So far, we first reported that EphB2 was predominantly overexpressed in cell membranes and cytoplasm of lung AC tissues, and low EphB2 expression in lung AC predicted better survival and low mortality rate.…”

From Normal Skin to Squamous Cell Carcinoma: A Quest for Novel Biomarkers

“…It was demonstrated that EphA subfamily is tumor suppressors, considering the fact that low concentration of EphA1 was identified in nonmelanoma skin cancer and low levels of EphA2 favour the development of chemically induced skin cancer in mice [124]. In cSCC, EphB2 determines proliferation, migration, and invasion, thus becoming the object of possible targeted therapies [125]. Farshchian et al [125] identified high levels of EphB2 in primary and metastatic cSCC cells through microarray, qRT-PCR, and next-generation sequencing.…”

“…In cSCC, EphB2 determines proliferation, migration, and invasion, thus becoming the object of possible targeted therapies [125]. Farshchian et al [125] identified high levels of EphB2 in primary and metastatic cSCC cells through microarray, qRT-PCR, and next-generation sequencing. These receptors were found on the surface of cSCC cells (clustered and bound with their ligands) as well as in the cytoplasm [125, 126].…”

“…Farshchian et al [125] identified high levels of EphB2 in primary and metastatic cSCC cells through microarray, qRT-PCR, and next-generation sequencing. These receptors were found on the surface of cSCC cells (clustered and bound with their ligands) as well as in the cytoplasm [125, 126]. Cells from normal cSCC, normal skin, and premalignant lesions were analyzed and it was shown that the concentration of EphB2 rises as normal cells progress to cancerous cells, which highlights that EphB2 overexpression is a process that starts early in cSCC development and has an important role in its invasiveness.…”

Molecular mechanisms of perineural spread of cutaneous carcinoma: a potential role for receptor tyrosine kinases and other biomarkers

“…(77,81) The Eph receptors/ephrins have also been implicated in tumourigenesis, progression and metastasis across a wide range of malignancies (Table 3). ( (83) Prostate cancer (84,85) Breast cancer (86,87) Melanoma (88) Glioblastoma (89,90) Gastric cancer (91) EphA3 Gastric cancer (92) Colorectal cancer (93) EphB2 Advanced cSCC (94) Glioblastoma (95)(96)(97) Cervical cancer (98) Breast cancer (99) EphB4 HNSCC (100) Non-small cell lung cancer (101) Breast cancer (99) Downregulated EphA1 NMSC (77) …”