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SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas.

Hussenet T, Dali S, Exinger J, Monga B, Jost B, Dembelé D, Martinet N, Thibault C, Huelsken J, Brambilla E, du Manoir S - PLoS ONE (2010)

Bottom Line: Intense SOX2 immunostaining is frequent in nuclei of lung SCC, indicating potential active transcriptional regulation by SOX2.In cell culture experiments, overexpression of SOX2 stimulates cellular migration and anchorage-independent growth while SOX2 knockdown impairs cell growth.These results indicate that the SOX2 transcription factor, a major regulator of stem cell function, is also an oncogene and a driver gene for the recurrent 3q26.33 amplifications in lung SCC.

View Article: PubMed Central - PubMed

Affiliation: Département Biologie du Cancer, Institut National de la Santé et de la Recherche Médicale, Institut de Génétique et de Biologie Moléculaire et Cellulaire, U964 Illkirch, France. hussenet@igbmc.fr

ABSTRACT
Squamous cell carcinoma (SCC) of the lung is a frequent and aggressive cancer type. Gene amplifications, a known activating mechanism of oncogenes, target the 3q26-qter region as one of the most frequently gained/amplified genomic sites in SCC of various types. Here, we used array comparative genomic hybridization to delineate the consensus region of 3q26.3 amplifications in lung SCC. Recurrent amplifications occur in 20% of lung SCC (136 tumors in total) and map to a core region of 2 Mb (Megabases) that encompasses SOX2, a transcription factor gene. Intense SOX2 immunostaining is frequent in nuclei of lung SCC, indicating potential active transcriptional regulation by SOX2. Analyses of the transcriptome of lung SCC, SOX2-overexpressing lung epithelial cells and embryonic stem cells (ESCs) reveal that SOX2 contributes to activate ESC-like phenotypes and provide clues pertaining to the deregulated genes involved in the malignant phenotype. In cell culture experiments, overexpression of SOX2 stimulates cellular migration and anchorage-independent growth while SOX2 knockdown impairs cell growth. Finally, SOX2 over-expression in non-tumorigenic human lung bronchial epithelial cells is tumorigenic in immunocompromised mice. These results indicate that the SOX2 transcription factor, a major regulator of stem cell function, is also an oncogene and a driver gene for the recurrent 3q26.33 amplifications in lung SCC.

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Related in: MedlinePlus

Consequences of Sox2 over-expression in the wound healing in vitro assay.A. Pictures were acquired at the beginning of the experiment (t = 0, immediately after wounding) and from the same field at the end of the experiment (t = 24 h for this example from the Calu-1 cell line). B. Quantification of wound closure for the three cell lines (BEAS-2B, NCI-H226 and Calu-1). Wound sizes were measured at the beginning and end of the experiment to calculate the percentage of wound closure for control and SOX2 over-expressing cells for each of the three cell lines. SOX2 over-expression significantly stimulates cell migration compared to control cells (student's t-test).
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pone-0008960-g006: Consequences of Sox2 over-expression in the wound healing in vitro assay.A. Pictures were acquired at the beginning of the experiment (t = 0, immediately after wounding) and from the same field at the end of the experiment (t = 24 h for this example from the Calu-1 cell line). B. Quantification of wound closure for the three cell lines (BEAS-2B, NCI-H226 and Calu-1). Wound sizes were measured at the beginning and end of the experiment to calculate the percentage of wound closure for control and SOX2 over-expressing cells for each of the three cell lines. SOX2 over-expression significantly stimulates cell migration compared to control cells (student's t-test).

Mentions: To perform functional analyses of the consequences of SOX2 over-expression, we established three human lung epithelial cell lines stably over-expressing SOX2 (Figure S4). Noting several cell cycle genes in the above-mentioned gene lists, we initially checked the proliferation rate of these cell lines in vitro, but uncovered no differences (data not shown). We therefore tested their migratory and invasive capacities. While no significant difference was observed for cell invasion (data not shown), SOX2 over-expression significantly increased the migratory activity of the three cell lines as assessed using a wound healing in vitro assay (Figure 6). We next investigated the effects of SOX2 over-expression on anchorage-independent growth of BEAS-2B cells using the soft-agar colony formation assay. While BEAS-2B control cells gave rise to some small colonies, as previously reported [31], SOX2 over-expression induced a significant increase in the number of colonies that were much larger and became macroscopically visible (Figure S5), which is a hallmark of malignant cells [32]. These results indicate that SOX2 over-expression significantly stimulates BEAS-2B cell anchorage-independent growth and suggests that SOX2 could represent a transforming oncogene when over-expressed in lung epithelial cells.


SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas.

Hussenet T, Dali S, Exinger J, Monga B, Jost B, Dembelé D, Martinet N, Thibault C, Huelsken J, Brambilla E, du Manoir S - PLoS ONE (2010)

Consequences of Sox2 over-expression in the wound healing in vitro assay.A. Pictures were acquired at the beginning of the experiment (t = 0, immediately after wounding) and from the same field at the end of the experiment (t = 24 h for this example from the Calu-1 cell line). B. Quantification of wound closure for the three cell lines (BEAS-2B, NCI-H226 and Calu-1). Wound sizes were measured at the beginning and end of the experiment to calculate the percentage of wound closure for control and SOX2 over-expressing cells for each of the three cell lines. SOX2 over-expression significantly stimulates cell migration compared to control cells (student's t-test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2813300&req=5

pone-0008960-g006: Consequences of Sox2 over-expression in the wound healing in vitro assay.A. Pictures were acquired at the beginning of the experiment (t = 0, immediately after wounding) and from the same field at the end of the experiment (t = 24 h for this example from the Calu-1 cell line). B. Quantification of wound closure for the three cell lines (BEAS-2B, NCI-H226 and Calu-1). Wound sizes were measured at the beginning and end of the experiment to calculate the percentage of wound closure for control and SOX2 over-expressing cells for each of the three cell lines. SOX2 over-expression significantly stimulates cell migration compared to control cells (student's t-test).
Mentions: To perform functional analyses of the consequences of SOX2 over-expression, we established three human lung epithelial cell lines stably over-expressing SOX2 (Figure S4). Noting several cell cycle genes in the above-mentioned gene lists, we initially checked the proliferation rate of these cell lines in vitro, but uncovered no differences (data not shown). We therefore tested their migratory and invasive capacities. While no significant difference was observed for cell invasion (data not shown), SOX2 over-expression significantly increased the migratory activity of the three cell lines as assessed using a wound healing in vitro assay (Figure 6). We next investigated the effects of SOX2 over-expression on anchorage-independent growth of BEAS-2B cells using the soft-agar colony formation assay. While BEAS-2B control cells gave rise to some small colonies, as previously reported [31], SOX2 over-expression induced a significant increase in the number of colonies that were much larger and became macroscopically visible (Figure S5), which is a hallmark of malignant cells [32]. These results indicate that SOX2 over-expression significantly stimulates BEAS-2B cell anchorage-independent growth and suggests that SOX2 could represent a transforming oncogene when over-expressed in lung epithelial cells.

Bottom Line: Intense SOX2 immunostaining is frequent in nuclei of lung SCC, indicating potential active transcriptional regulation by SOX2.In cell culture experiments, overexpression of SOX2 stimulates cellular migration and anchorage-independent growth while SOX2 knockdown impairs cell growth.These results indicate that the SOX2 transcription factor, a major regulator of stem cell function, is also an oncogene and a driver gene for the recurrent 3q26.33 amplifications in lung SCC.

View Article: PubMed Central - PubMed

Affiliation: Département Biologie du Cancer, Institut National de la Santé et de la Recherche Médicale, Institut de Génétique et de Biologie Moléculaire et Cellulaire, U964 Illkirch, France. hussenet@igbmc.fr

ABSTRACT
Squamous cell carcinoma (SCC) of the lung is a frequent and aggressive cancer type. Gene amplifications, a known activating mechanism of oncogenes, target the 3q26-qter region as one of the most frequently gained/amplified genomic sites in SCC of various types. Here, we used array comparative genomic hybridization to delineate the consensus region of 3q26.3 amplifications in lung SCC. Recurrent amplifications occur in 20% of lung SCC (136 tumors in total) and map to a core region of 2 Mb (Megabases) that encompasses SOX2, a transcription factor gene. Intense SOX2 immunostaining is frequent in nuclei of lung SCC, indicating potential active transcriptional regulation by SOX2. Analyses of the transcriptome of lung SCC, SOX2-overexpressing lung epithelial cells and embryonic stem cells (ESCs) reveal that SOX2 contributes to activate ESC-like phenotypes and provide clues pertaining to the deregulated genes involved in the malignant phenotype. In cell culture experiments, overexpression of SOX2 stimulates cellular migration and anchorage-independent growth while SOX2 knockdown impairs cell growth. Finally, SOX2 over-expression in non-tumorigenic human lung bronchial epithelial cells is tumorigenic in immunocompromised mice. These results indicate that the SOX2 transcription factor, a major regulator of stem cell function, is also an oncogene and a driver gene for the recurrent 3q26.33 amplifications in lung SCC.

Show MeSH
Related in: MedlinePlus