Mda-7/IL-24 induces the differentiation of B cell lymphoma via activation of the P38 mitogen activated protein kinase signaling pathway

Abstract

Interleukin 24 (IL‑24) is a unique cytokine encoded by the melanoma differentiation associated gene‑7 (Mda‑7), and was first discovered inhuman melanoma cells. Exogenous Mda‑7/IL‑24 has been shown to inhibit the proliferation and invasion of a broad spectrum of human cancer cells, but its effect on the differentiation of B cell lymphoma is not yet clear. To the best of our knowledge, the present study demonstrated for the first time that overexpressing Mda‑7/IL‑24 can induce differentiation in human B cell lymphomacells, and the underlying mechanism was investigated. The proliferation of stable Mda‑7/IL‑24 overexpressing Raji and Daudi cells was assessed by the MTS method. The immunophenotype, apoptosis level and cell cycle distribution of Raji and Daudi cells were analyzed by flow cytometry. The expression of PR domain zinc finger protein 1 (Blimp1) and B‑cell lymphoma 6 (Bcl6) were analyzed by western blotting. Additionally, western blotting assay was also performed to study the effect of Mda‑7/IL‑24 on the activity of the P38 mitogen activated protein kinase (MAPK) signaling pathway in Raji and Daudi cells. Proliferation of Raji and Daudi cells overexpressing Mda‑7/IL‑24 was inhibited significantly, compared with those of parent cells and cells transfected with the empty vector alone. Apoptosis was not involved in the proliferation inhibition, while the cell cycle was arrested in G1 phase in the Raji and Daudi cells overexpressing Mda‑7/IL‑24. Overexpressing Mda‑7/IL‑24 resulted in a significantly decreased expression of cluster of differentiation (CD)10, and increased expression of CD45 and CD138 in the cell surface of Raji and Daudi cells. The expression of Blimp1 was upregulated, while the levels of Bcl6 protein was downregulated, in Raji and Daudi cells overexpressing Mda‑7/IL‑24. Furthermore, the activities of the P38 MAPK signaling pathway in lymphoma cells were upregulated. These results indicated that Mda‑7/IL‑24 could induce terminal differentiation of B lymphoma cells by regulating the expression of Blimp1 and Bcl6 via altering the P38 MAPK signaling pathway, suggesting that Mda‑7/IL‑24 may therefore be a potential differentiation therapeutic agent to be applied in clinical treatment of B cell lymphoma.

Low expression of Mda-7/IL-24 and high expression of C-myb in tumour tissues are predictors of poor prognosis for Burkitt lymphoma patients

“…characterized by proliferation inhibition, cell cycle arrest, morphological and cell surface antigen changes and decreased expression of malignant markers [7]. Furthermore, C-myb is an innate regulatory transcription factor that contributes to differentiation blockage in a variety of haematopoietic malignancies.…”

“…Furthermore, overexpressing Mda-7/IL-24 or silencing C-myb will increase the expression of Blimp1 and induce terminal differentiation in Raji and Daudi cells [7,14]. Given the same target molecular in the downstream of overexpressing Mda-7/IL-24 and silencing C-myb, we hypothesize that there may be a negative regulatory relationship between Mda-7/IL-24 and C-myb, and the expression of Mda-7/IL-24 and C-myb in tumour tissues may be associated with the clinicopathological characteristics and prognosis of Burkitt lymphoma patients.…”

“…Interleukin-24 (IL-24), which is also known as melanoma differentiation associated gene 7 (Mda-7), was first identified in human melanoma cells [4,5]. Although its physiological role is poorly understood, overexpression of Mda-7/IL-24 exerts a tumour suppressing effect through several mechanisms, such as suppressing tumour cell invasion, arresting the cell cycle, inducing apoptosis and improving terminal differentiation in multiple malignant carcinomas [6][7][8]. In our previous study, overexpression of Mda-7/IL-24 resulted in mature differentiation of Raji and Daudi cells (the two types of Burkitt lymphoma cell lines) via upregulating the expression of Blimp1 in vitro [7].…”

“…Although its physiological role is poorly understood, overexpression of Mda-7/IL-24 exerts a tumour suppressing effect through several mechanisms, such as suppressing tumour cell invasion, arresting the cell cycle, inducing apoptosis and improving terminal differentiation in multiple malignant carcinomas [6][7][8]. In our previous study, overexpression of Mda-7/IL-24 resulted in mature differentiation of Raji and Daudi cells (the two types of Burkitt lymphoma cell lines) via upregulating the expression of Blimp1 in vitro [7]. Involvement of Mda-7/IL-24 in regulation of the cell growth and differentiation made it a novel target in tumour investigations and provided novel insight into understanding the mechanisms involved in the progression of Burkitt lymphoma.…”

The clinical significance of Mda‑7/IL‑24 and C‑myb expression in tumor tissues of patients with diffuse large B cell lymphoma

“…Interleukin-24 (IL-24), encoded by melanoma differentiation associated gene 7 (Mda-7), was expressed at high levels in normal lymphocyts ( 4 , 5 ). Mda-7/IL-24 expression was found to be lost in a broad spectrum of hematopoietic malignancies, including B cells lymphoma ( 6 , 7 ). A novel characteristic of Mda-7/IL-24 is to inhibit growth and induce apoptosis or differentiation in various tumor cells without harming normal cells ( 8 , 9 ).…”