Lenalidomide regulates the CCL21/CCR7/ERK1/2 axis to inhibit migration and proliferation in diffuse large B-cell lymphoma

Abstract

Background: The prognostic significance of the chemokine receptor CCR7 in diffuse large B-cell lymphoma (DLBCL) has been reported previously. However, the detailed mechanisms of CCR7 in DLBCL, particularly regarding its interaction with lenalidomide treatment, are not fully understood. Methods: Our study utilized bioinformatics approaches to identify hub genes in SU-DHL-2 cell lines treated with lenalidomide compared to control groups.Immunohistochemical data and clinical information from 122 patients with DLBCL were analyzed to assess the correlation of CCR7 and p-ERK1/2 expression with the prognosis of DLBCL. Furthermore, in vitro and in vivo experiments were conducted to clarify the role of CCR7 in the response of DLBCL to lenalidomide treatment.Results: Our bioinformatics analysis pinpointed CCR7 as a hub gene in the context of lenalidomide treatment in DLBCL. Notably, 31.14% and 36.0% (44/122) of DLBCL cases showed positive expression for CCR7 and ERK1/2 respectively, establishing them as independent prognostic factors for adverse outcomes in DLBCL via multivariate Cox regression analysis. Additionally, our studies demonstrated that the external application of the protein CCL21 promoted proliferation, migration, invasion, and activation of the ERK1/2 pathway in SU-DHL-2 and OCI-LY3 cell lines with high levels of CCR7 expression. This effect was mitigated by CCR7 silencing through siRNA, application of ERK inhibitors, or lenalidomide treatment. In vivo experiments reinforced the efficacy of lenalidomide, significantly reducing tumor growth rate, tumor mass, serum total LDH levels, and expression of CCR7 and p-ERK1/2 in a SU-DHL-2 xenograft model in nude mice (p < 0.05). Conclusion: Our study clarifies the potential role of the CCL21/ CCR7/ERK1/2 axis in the therapeutic effects of lenalidomide in DLBCL treatment.