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Loss of IRF8 Inhibits the Growth of Diffuse Large B-cell Lymphoma.

Xu Y, Jiang L, Fang J, Fang R, Morse HC, Ouyang G, Zhou JX - J Cancer (2015)

Bottom Line: In this study, using shRNA-mediated knockdown of IRF8 expression, we found that the loss of IRF8 significantly reduced the proliferation of DLBCL cells (P<0.05).Mechanistically, decreasing the levels of IRF8 led to a suppression of the phosphorylation of p38 and ERK, molecules critical for B cell proliferation.Furthermore, using a xenograft lymphoma mouse model, we found that the loss of IRF8 significantly inhibited the growth of lymphomas in vivo (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Pathology, Ningbo University School of Medicine, Ningbo, Zhejiang, China.

ABSTRACT
IRF8 is a transcription factor with a critical role in B lymphocyte development and functions. Its role in human diffuse large B-cell lymphoma (DLBCL), however, remained elusive. In this study, using shRNA-mediated knockdown of IRF8 expression, we found that the loss of IRF8 significantly reduced the proliferation of DLBCL cells (P<0.05). Mechanistically, decreasing the levels of IRF8 led to a suppression of the phosphorylation of p38 and ERK, molecules critical for B cell proliferation. Furthermore, using a xenograft lymphoma mouse model, we found that the loss of IRF8 significantly inhibited the growth of lymphomas in vivo (P<0.05). Immunohistochemical analysis of human DLBCL tissues revealed that the levels of IRF8 were significantly greater in non-germinal center B-cell-like (non-GCB) subtype than that in GCB subtype (P<0.05). Analysis of public available data also suggested that the expression levels of IRF8 mRNA in human DLBCL tissues were inversely correlated with patients' overall survival time. Taken together, this study suggested that IRF8 may play an oncogenic role in human DLBCL by promoting cell proliferation.

No MeSH data available.


Related in: MedlinePlus

The phosphorylation of p38 and ERK MAPK was reduced in DLBCL cells with IRF8 knockdown. A: Western blotting analyses of proteins from OCI-Ly01 and OCI-Ly10 cells with or without IRF8 knockdown using specific antibodies for IRF8, p38, phospho-p38 (p-p38), ERK, phospho-ERK (p-ERK), and GAPDH. GAPDH was used as a loading control. B: The cell proliferation was attenuated in OCI-Ly01 and OCI-Ly10 cells treated with p38 inhibitors SB203580 (40 μM) or ERK inhibitor U0126 (40 μM). Data shown are from four independent experiments (mean ± SD). * depicts statistically significant difference between the cells treated by inhibitors and control cells after 96 h of incubation (P<0.05).
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Figure 4: The phosphorylation of p38 and ERK MAPK was reduced in DLBCL cells with IRF8 knockdown. A: Western blotting analyses of proteins from OCI-Ly01 and OCI-Ly10 cells with or without IRF8 knockdown using specific antibodies for IRF8, p38, phospho-p38 (p-p38), ERK, phospho-ERK (p-ERK), and GAPDH. GAPDH was used as a loading control. B: The cell proliferation was attenuated in OCI-Ly01 and OCI-Ly10 cells treated with p38 inhibitors SB203580 (40 μM) or ERK inhibitor U0126 (40 μM). Data shown are from four independent experiments (mean ± SD). * depicts statistically significant difference between the cells treated by inhibitors and control cells after 96 h of incubation (P<0.05).

Mentions: To understand the mechanisms underlying the effect of IRF8 on cell proliferation, we examined the signaling pathways critical to B cell proliferation. The activation of MAPK pathway has been well characterized as essential for B cell proliferation 22-24. For both OCI-Ly01 and OCI-Ly10 cells, knockdown of IRF8 expression decreased the phosphorylation of p38 and ERK, two key molecules in the MAPK pathway (Figure 4A). To confirm that the inhibition of p38 and ERK was able to suppress the cell proliferation, we treated DLBCL cells with U0126 and SB203580 that were the inhibitors of p38 and ERK, respectively. The results showed that both inhibitors suppressed the proliferation of OCI-Ly01 and OCI-Ly10 cells significantly (P<0.05) (Figure 4B).


Loss of IRF8 Inhibits the Growth of Diffuse Large B-cell Lymphoma.

Xu Y, Jiang L, Fang J, Fang R, Morse HC, Ouyang G, Zhou JX - J Cancer (2015)

The phosphorylation of p38 and ERK MAPK was reduced in DLBCL cells with IRF8 knockdown. A: Western blotting analyses of proteins from OCI-Ly01 and OCI-Ly10 cells with or without IRF8 knockdown using specific antibodies for IRF8, p38, phospho-p38 (p-p38), ERK, phospho-ERK (p-ERK), and GAPDH. GAPDH was used as a loading control. B: The cell proliferation was attenuated in OCI-Ly01 and OCI-Ly10 cells treated with p38 inhibitors SB203580 (40 μM) or ERK inhibitor U0126 (40 μM). Data shown are from four independent experiments (mean ± SD). * depicts statistically significant difference between the cells treated by inhibitors and control cells after 96 h of incubation (P<0.05).
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Related In: Results  -  Collection

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Figure 4: The phosphorylation of p38 and ERK MAPK was reduced in DLBCL cells with IRF8 knockdown. A: Western blotting analyses of proteins from OCI-Ly01 and OCI-Ly10 cells with or without IRF8 knockdown using specific antibodies for IRF8, p38, phospho-p38 (p-p38), ERK, phospho-ERK (p-ERK), and GAPDH. GAPDH was used as a loading control. B: The cell proliferation was attenuated in OCI-Ly01 and OCI-Ly10 cells treated with p38 inhibitors SB203580 (40 μM) or ERK inhibitor U0126 (40 μM). Data shown are from four independent experiments (mean ± SD). * depicts statistically significant difference between the cells treated by inhibitors and control cells after 96 h of incubation (P<0.05).
Mentions: To understand the mechanisms underlying the effect of IRF8 on cell proliferation, we examined the signaling pathways critical to B cell proliferation. The activation of MAPK pathway has been well characterized as essential for B cell proliferation 22-24. For both OCI-Ly01 and OCI-Ly10 cells, knockdown of IRF8 expression decreased the phosphorylation of p38 and ERK, two key molecules in the MAPK pathway (Figure 4A). To confirm that the inhibition of p38 and ERK was able to suppress the cell proliferation, we treated DLBCL cells with U0126 and SB203580 that were the inhibitors of p38 and ERK, respectively. The results showed that both inhibitors suppressed the proliferation of OCI-Ly01 and OCI-Ly10 cells significantly (P<0.05) (Figure 4B).

Bottom Line: In this study, using shRNA-mediated knockdown of IRF8 expression, we found that the loss of IRF8 significantly reduced the proliferation of DLBCL cells (P<0.05).Mechanistically, decreasing the levels of IRF8 led to a suppression of the phosphorylation of p38 and ERK, molecules critical for B cell proliferation.Furthermore, using a xenograft lymphoma mouse model, we found that the loss of IRF8 significantly inhibited the growth of lymphomas in vivo (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Pathology, Ningbo University School of Medicine, Ningbo, Zhejiang, China.

ABSTRACT
IRF8 is a transcription factor with a critical role in B lymphocyte development and functions. Its role in human diffuse large B-cell lymphoma (DLBCL), however, remained elusive. In this study, using shRNA-mediated knockdown of IRF8 expression, we found that the loss of IRF8 significantly reduced the proliferation of DLBCL cells (P<0.05). Mechanistically, decreasing the levels of IRF8 led to a suppression of the phosphorylation of p38 and ERK, molecules critical for B cell proliferation. Furthermore, using a xenograft lymphoma mouse model, we found that the loss of IRF8 significantly inhibited the growth of lymphomas in vivo (P<0.05). Immunohistochemical analysis of human DLBCL tissues revealed that the levels of IRF8 were significantly greater in non-germinal center B-cell-like (non-GCB) subtype than that in GCB subtype (P<0.05). Analysis of public available data also suggested that the expression levels of IRF8 mRNA in human DLBCL tissues were inversely correlated with patients' overall survival time. Taken together, this study suggested that IRF8 may play an oncogenic role in human DLBCL by promoting cell proliferation.

No MeSH data available.


Related in: MedlinePlus