JAM-A overexpression is related to disease progression in diffuse large B-cell lymphoma and downregulated by lenalidomide

Peng-Peng Xu,Zi-Xun Yan,Yi-Feng Sun,Yan Zhao,Chao-Fu Wang,Wei-Li Zhao,Qi Song,Christophe Leboeuf,Biao Li,Ying Fang,Xiao-Chun Fei,Yi Chen,Xu-Feng Jiang,Li Wang,Anne Janin

doi:10.1038/s41598-017-07964-5

Peng-Peng Xu, Zi-Xun Yan + Show 13 more

Open Access

https://doi.org/10.1038/s41598-017-07964-5

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Abstract

Cancer stem cells play an important role on tumor progression. Biomarkers of stem cell property and their relationship to extranodal involvement of malignant lymphocytes are undefined in diffuse large B-cell lymphoma (DLBCL). Here we showed that junctional adhesion molecule-A (JAM-A) was highly expressed in DLBCL patients with multiple extranodal lesions. JAM-A maintained B-lymphoma cell stemness and was associated with cell invasion and epithelial-to-mesenchymal transition both in vitro and in vivo. As mechanism of action, JAM-A overexpression selectively activated transforming growth factor-β (TGF-β)/NODAL signaling, thereby enhanced B-lymphoma cell aggressiveness and induced extranodal involvement to mesoendoderm-derived organs in DLBCL. Lenalidomide downregulated JAM-A and downstream NODAL expression, resulting in inhibition of B-lymphoma cell invasion and epithelial-to-mesenchymal transition. In a murine xenograft model established with subcutaneous injection of JAM-A-overexpressing B-lymphoma cells, lenalidomide retarded tumor growth and prevented cell invasion to mesoendoderm-derived organs, consistent with the downregulation of JAM-A and NODAL expression. Collectively, these findings indicated that JAM-A was related to extranodal involvement in DLBCL through modulating TGF-β/NODAL signaling. Identified as a biomarker of stem cell property, JAM-A indicated the sensitivity of B-lymphoma cells to lenalidomide. Therapeutic targeting of JAM-A/NODAL axis could thus be a promising clinical strategy to impede tumor progression in DLBCL.

Highlights

Diffuse large B-cell lymphoma (DLBCL), as the most common histological subtype of lymphoma, accounts for 30–40% of de novo non-Hodgkin lymphoma[1]
Junctional adhesion molecule-A (JAM-A) was highly expressed in diffuse large B-cell lymphoma (DLBCL), when compared to reactive hyperplasia (N = 20)
Of note, when DLBCL patients were classified in terms of involved sites, extranodal involvement group had higher expression of both JAM-A gene and JAM-A protein in tumor samples (P = 0.0051 and P = 0.0342, Fig. 1D)

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL), as the most common histological subtype of lymphoma, accounts for 30–40% of de novo non-Hodgkin lymphoma[1]. DLBCL often presents the dissemination of malignant lymphocytes and subsequent formation of multiple extranodal lesions[2], which are responsible for the vast majority of lymphoma associated deaths[3]. Recent studies have demonstrated that cancer stem cells are essential for tumor progression and may be potential targets for therapeutic development. To elucidate the biomarkers of stem cell property remains of great interest for improving the clinical outcome of DLBCL patients. Junctional adhesion molecule-A (JAM-A) belongs to the immunoglobulin superfamily of adhesion molecules and is implicated in cell self-renewal and tumor growth[5]. We defined JAM-A as a biomarker that bridges lymphoma cell stemness with lymphoma outgrowth in mesoendoderm-derived organs via TGF-β/NODAL signaling. Therapeutic targeting of JAM-A/NODAL axis by lenalidomide represents a promising strategy to treat DLBCL

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