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

• Published in: Scientific reports Vol. 7; no. 1; pp. 7433 - 10
• Main Authors: Xu, Peng-Peng, Sun, Yi-Feng, Fang, Ying, Song, Qi, Yan, Zi-Xun, Chen, Yi, Jiang, Xu-Feng, Fei, Xiao-Chun, Zhao, Yan, Leboeuf, Christophe, Li, Biao, Wang, Chao-Fu, Janin, Anne, Wang, Li, Zhao, Wei-Li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-08-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14; 38; 45; 45/77; 45/91; 631/67/1990/291; 631/67/1990/291/1621/1915; 64/116; 64/60; B-cell lymphoma; Cancer; Humanities and Social Sciences; Immunotherapy; Lymphocytes; Lymphocytes B; Lymphoma; Mesenchyme; multidisciplinary; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Targeted cancer therapy; Therapeutic targets; Transforming growth factor-b; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-07964-5

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.