Dataset Information

Ephrin-B2 reverse signaling regulates progression and lymph node metastasis of oral squamous cell carcinoma.

ABSTRACT: Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck and frequently metastasizes to cervical lymph nodes. Aggressive local invasion and metastasis of OSCC are significant factors for poor prognosis. In this study, we investigated whether ephrin-B2 expressed in OSCC contributed to tumor progression and lymph node metastasis. Clinical specimens from patients with OSCC had robust ephrin-B2-positive tumor cells and ephrin-B2 protein level was associated with clinical stage, lymph node metastasis, and poor survival outcomes. We also determined that ephrin-B2 protein level was increased in OSCC cell lines compared to normal human oral keratinocytes and that its levels were associated with the migratory and invasive potential of OSCC cell lines. Transfection of an EFNB2-specific small interfering RNA (siRNA) into SAS-L1 cells significantly reduced proliferation, attachment, migration, and invasion through phosphorylation of the epidermal growth factor receptor, FAK, ERK1/2, p38, AKT, and JNK1/2 pathways. Furthermore, knockdown of EFNB2 significantly suppressed adhesion and transmigration of SAS-L1 cells toward human lymphatic endothelial cells. In addition, the growth rate of tumor xenografts and cervical lymph node metastases of OSCC were suppressed by local injection of EFNB2 siRNA. These results suggest that ephrin-B2 overexpression and activation of the ephrin-B2 reverse signaling pathway in tumor microenvironment in OSCC facilitates progression and lymph node metastasis via enhancement of malignant potential and interaction with surrounding cells.

SUBMITTER: Sasabe E

PROVIDER: S-EPMC5708812 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes.SignificanceEphrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.

Dataset Information

Ephrin-B2 reverse signaling regulates progression and lymph node metastasis of oral squamous cell carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets