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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

Loss of IRF8 suppressed the tumor growth in vivo. A: Photograph shows the tumors developed in mice received OCI-Ly01 cells with or without IRF8 for 30 days. B: The increase in tumor weights over 30 days of period showed that the tumor derived from cells with IRF8 knockdown grew significant lowerer than those derived from control cells. C: The increase in tumor volumes over 30 days of period showed that the tumor derived from cells with IRF8 knockdown grew significant slower than those derived from control cells (P<0.05). D: The levels of IRF8 transcripts in tumors derived from OCI-Ly01 cells with IRF8 knockdown were significant lesser than that derived from control cells (P<0.05). E: Western blotting analyses of proteins from tumor tissues showed that the levels of p-p38 and p-ERK were decreased tumors derived from OCI-Ly01 cells with IRF8 knockdown than that derived from control cells. IRF8 KD: IRF8 knockdown. * depicts statistically significant difference between the IRF8 knockdown and control tumors (P<0.05).
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Figure 5: Loss of IRF8 suppressed the tumor growth in vivo. A: Photograph shows the tumors developed in mice received OCI-Ly01 cells with or without IRF8 for 30 days. B: The increase in tumor weights over 30 days of period showed that the tumor derived from cells with IRF8 knockdown grew significant lowerer than those derived from control cells. C: The increase in tumor volumes over 30 days of period showed that the tumor derived from cells with IRF8 knockdown grew significant slower than those derived from control cells (P<0.05). D: The levels of IRF8 transcripts in tumors derived from OCI-Ly01 cells with IRF8 knockdown were significant lesser than that derived from control cells (P<0.05). E: Western blotting analyses of proteins from tumor tissues showed that the levels of p-p38 and p-ERK were decreased tumors derived from OCI-Ly01 cells with IRF8 knockdown than that derived from control cells. IRF8 KD: IRF8 knockdown. * depicts statistically significant difference between the IRF8 knockdown and control tumors (P<0.05).

Mentions: As we identified the effect of IRF8 on DLBCL cells in vitro, we were interested to examine if IRF8 had similar effect in an in vivo situation. We transplanted DLBCL cells with or without IRF8 knockdown into nude mice, and observed the tumor growth in vivo. After 30 days of tumor cells transplantation, in the group of mice with IRF8 knockdown (n=5), there was only one mouse developed tumor; while in the group of control mice (n=5), all animals developed tumors (Figure 5A). The tumor weights and volumes in the mouse received IRF8-knockdown DLBCL cells were both lesser than that in the mice received control DLBCL cells (P<0.05) (Figure 5B, 5C). qRT-PCR and Western blot analysis confirmed that the levels of IRF8 mRNA and protein in the tumor from mouse received IRF8-knockdown DLBCL cells were significantly lower than that in the tumors from the control mice (P<0.05) (Figure 5D, 5E). Finally, we analyzed the phosphorylation levels of p38 and ERK in the tumors, and found that as occurred in the in vitro condition, the tumor derived from the mouse received IRF8-knockdown DLBCL cells showed significant decrease in the phosphorylation of both p38 and ERK in comparison to the control group (Figure 5E).


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)

Loss of IRF8 suppressed the tumor growth in vivo. A: Photograph shows the tumors developed in mice received OCI-Ly01 cells with or without IRF8 for 30 days. B: The increase in tumor weights over 30 days of period showed that the tumor derived from cells with IRF8 knockdown grew significant lowerer than those derived from control cells. C: The increase in tumor volumes over 30 days of period showed that the tumor derived from cells with IRF8 knockdown grew significant slower than those derived from control cells (P<0.05). D: The levels of IRF8 transcripts in tumors derived from OCI-Ly01 cells with IRF8 knockdown were significant lesser than that derived from control cells (P<0.05). E: Western blotting analyses of proteins from tumor tissues showed that the levels of p-p38 and p-ERK were decreased tumors derived from OCI-Ly01 cells with IRF8 knockdown than that derived from control cells. IRF8 KD: IRF8 knockdown. * depicts statistically significant difference between the IRF8 knockdown and control tumors (P<0.05).
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Related In: Results  -  Collection

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Figure 5: Loss of IRF8 suppressed the tumor growth in vivo. A: Photograph shows the tumors developed in mice received OCI-Ly01 cells with or without IRF8 for 30 days. B: The increase in tumor weights over 30 days of period showed that the tumor derived from cells with IRF8 knockdown grew significant lowerer than those derived from control cells. C: The increase in tumor volumes over 30 days of period showed that the tumor derived from cells with IRF8 knockdown grew significant slower than those derived from control cells (P<0.05). D: The levels of IRF8 transcripts in tumors derived from OCI-Ly01 cells with IRF8 knockdown were significant lesser than that derived from control cells (P<0.05). E: Western blotting analyses of proteins from tumor tissues showed that the levels of p-p38 and p-ERK were decreased tumors derived from OCI-Ly01 cells with IRF8 knockdown than that derived from control cells. IRF8 KD: IRF8 knockdown. * depicts statistically significant difference between the IRF8 knockdown and control tumors (P<0.05).
Mentions: As we identified the effect of IRF8 on DLBCL cells in vitro, we were interested to examine if IRF8 had similar effect in an in vivo situation. We transplanted DLBCL cells with or without IRF8 knockdown into nude mice, and observed the tumor growth in vivo. After 30 days of tumor cells transplantation, in the group of mice with IRF8 knockdown (n=5), there was only one mouse developed tumor; while in the group of control mice (n=5), all animals developed tumors (Figure 5A). The tumor weights and volumes in the mouse received IRF8-knockdown DLBCL cells were both lesser than that in the mice received control DLBCL cells (P<0.05) (Figure 5B, 5C). qRT-PCR and Western blot analysis confirmed that the levels of IRF8 mRNA and protein in the tumor from mouse received IRF8-knockdown DLBCL cells were significantly lower than that in the tumors from the control mice (P<0.05) (Figure 5D, 5E). Finally, we analyzed the phosphorylation levels of p38 and ERK in the tumors, and found that as occurred in the in vitro condition, the tumor derived from the mouse received IRF8-knockdown DLBCL cells showed significant decrease in the phosphorylation of both p38 and ERK in comparison to the control group (Figure 5E).

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