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SOX11 expression correlates to promoter methylation and regulates tumor growth in hematopoietic malignancies.

Gustavsson E, Sernbo S, Andersson E, Brennan DJ, Dictor M, Jerkeman M, Borrebaeck CA, Ek S - Mol. Cancer (2010)

Bottom Line: Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction.The data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation.Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunotechnology, Lund University, Lund, Sweden.

ABSTRACT

Background: The transcription factor SOX11 plays an important role in embryonic development of the central nervous system (CNS) and is expressed in the adult immature neuron but is normally not expressed in any other adult tissue. It has recently been reported to be implicated in various malignant neoplasms, including several lymphoproliferative diseases, by its specific expression and in some cases correlation to prognosis. SOX11 has been shown to prevent gliomagenesis in vivo but the causes and consequences of aberrant expression of SOX11 outside the CNS remain unexplained.

Results: We now show the first function of SOX11 in lymphoproliferative diseases, by demonstrating in vitro its direct involvement in growth regulation, as assessed by siRNA-mediated silencing and ectopic overexpression in hematopoietic malignancies. Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction. Furthermore, promoter analysis revealed that SOX11 is silenced through DNA methylation in B cell lymphomas, suggesting that its regulation is epigenetically controlled.

Conclusions: The data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation. Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

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Related in: MedlinePlus

siRNA knock-down of SOX11 increase proliferation. Effect of the siRNA induced knock-down of the SOX11 gene in GRANTA-519 and REC-1 on, a) mRNA level at 24 and 48 h; b) protein level at 48 h and 72 h, respectively, and c) proliferation at 24, 48 and 72 h. A control siRNA targeting the Eg5 gene was used as a positive control (only shown in b). All values in a) are relative quantity values (RQ) compared to the scrambled siRNA control. The data is representative of three independent assays. In a) the error bars show the 95% confidence interval, while in c) ±1 SD is shown.
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Figure 4: siRNA knock-down of SOX11 increase proliferation. Effect of the siRNA induced knock-down of the SOX11 gene in GRANTA-519 and REC-1 on, a) mRNA level at 24 and 48 h; b) protein level at 48 h and 72 h, respectively, and c) proliferation at 24, 48 and 72 h. A control siRNA targeting the Eg5 gene was used as a positive control (only shown in b). All values in a) are relative quantity values (RQ) compared to the scrambled siRNA control. The data is representative of three independent assays. In a) the error bars show the 95% confidence interval, while in c) ±1 SD is shown.

Mentions: The functional effect of SOX11 was then investigated in well-characterized in vitro models of MCL (GRANTA-519 and REC-1). siRNA mediated gene silencing (see Additional File 1: Table S3) resulted in a significant decrease of both SOX11 mRNA (Figure 4A) and protein (Figure 4B) and lead to an almost 100% increase in proliferation at 48 hrs (Figure 4C). The follicular lymphoma cell line did not express any SOX11 and no change in proliferation was consequently detected (data not shown). The effect on mRNA expression reached a maximum decrease at 24 hrs for GRANTA-519 and at 48 h for REC-1 (Figure 4A), while the subsequent decrease in protein level was most pronounced at 72 h for GRANTA-519 and at 48 h for REC-1 (Figure 4B). The functional effect on cell proliferation seen at 48 h for both MCL cell lines (Figure 4C), demonstrates a growth regulatory role for SOX11.


SOX11 expression correlates to promoter methylation and regulates tumor growth in hematopoietic malignancies.

Gustavsson E, Sernbo S, Andersson E, Brennan DJ, Dictor M, Jerkeman M, Borrebaeck CA, Ek S - Mol. Cancer (2010)

siRNA knock-down of SOX11 increase proliferation. Effect of the siRNA induced knock-down of the SOX11 gene in GRANTA-519 and REC-1 on, a) mRNA level at 24 and 48 h; b) protein level at 48 h and 72 h, respectively, and c) proliferation at 24, 48 and 72 h. A control siRNA targeting the Eg5 gene was used as a positive control (only shown in b). All values in a) are relative quantity values (RQ) compared to the scrambled siRNA control. The data is representative of three independent assays. In a) the error bars show the 95% confidence interval, while in c) ±1 SD is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2913986&req=5

Figure 4: siRNA knock-down of SOX11 increase proliferation. Effect of the siRNA induced knock-down of the SOX11 gene in GRANTA-519 and REC-1 on, a) mRNA level at 24 and 48 h; b) protein level at 48 h and 72 h, respectively, and c) proliferation at 24, 48 and 72 h. A control siRNA targeting the Eg5 gene was used as a positive control (only shown in b). All values in a) are relative quantity values (RQ) compared to the scrambled siRNA control. The data is representative of three independent assays. In a) the error bars show the 95% confidence interval, while in c) ±1 SD is shown.
Mentions: The functional effect of SOX11 was then investigated in well-characterized in vitro models of MCL (GRANTA-519 and REC-1). siRNA mediated gene silencing (see Additional File 1: Table S3) resulted in a significant decrease of both SOX11 mRNA (Figure 4A) and protein (Figure 4B) and lead to an almost 100% increase in proliferation at 48 hrs (Figure 4C). The follicular lymphoma cell line did not express any SOX11 and no change in proliferation was consequently detected (data not shown). The effect on mRNA expression reached a maximum decrease at 24 hrs for GRANTA-519 and at 48 h for REC-1 (Figure 4A), while the subsequent decrease in protein level was most pronounced at 72 h for GRANTA-519 and at 48 h for REC-1 (Figure 4B). The functional effect on cell proliferation seen at 48 h for both MCL cell lines (Figure 4C), demonstrates a growth regulatory role for SOX11.

Bottom Line: Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction.The data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation.Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunotechnology, Lund University, Lund, Sweden.

ABSTRACT

Background: The transcription factor SOX11 plays an important role in embryonic development of the central nervous system (CNS) and is expressed in the adult immature neuron but is normally not expressed in any other adult tissue. It has recently been reported to be implicated in various malignant neoplasms, including several lymphoproliferative diseases, by its specific expression and in some cases correlation to prognosis. SOX11 has been shown to prevent gliomagenesis in vivo but the causes and consequences of aberrant expression of SOX11 outside the CNS remain unexplained.

Results: We now show the first function of SOX11 in lymphoproliferative diseases, by demonstrating in vitro its direct involvement in growth regulation, as assessed by siRNA-mediated silencing and ectopic overexpression in hematopoietic malignancies. Gene Chip analysis identified cell cycle regulatory pathways, including Rb-E2F, to be associated with SOX11-induced growth reduction. Furthermore, promoter analysis revealed that SOX11 is silenced through DNA methylation in B cell lymphomas, suggesting that its regulation is epigenetically controlled.

Conclusions: The data show that SOX11 is not a bystander but an active and central regulator of cellular growth, as both siRNA-mediated knock-down and ectopic overexpression of SOX11 resulted in altered proliferation. Thus, these data demonstrate a tumor suppressor function for SOX11 in hematopoietic malignancies and revealed a potential epigenetic regulation of this developmentally involved gene.

Show MeSH
Related in: MedlinePlus