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Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila.

Wandler AM, Guillemin K - PLoS Pathog. (2012)

Bottom Line: This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells.We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis.In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.

ABSTRACT
Gastric cancer development is strongly correlated with infection by Helicobacter pylori possessing the effector protein CagA. Using a transgenic Drosophila melanogaster model, we show that CagA expression in the simple model epithelium of the larval wing imaginal disc causes dramatic tissue perturbations and apoptosis when CagA-expressing and non-expressing cells are juxtaposed. This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells. We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis. In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner. These data suggest a potential role for CagA-mediated JNK pathway activation in promoting gastric cancer progression.

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CagA enhances tumor growth through JNK activation.(A–B) Schematics depicting GFP-marked whole eye clones in third instar larvae (A) and a dissected cephalic complex (B), which includes the eye discs (ed), brain lobes (bl) and ventral nerve cord (vnc). (C–G) Images of female third instar larvae and dissected cephalic complexes with GFP-marked tumors. Expression of RasV12 in whole eye clones (C) causes overgrowth which results in tumor formation. Coexpression of CagA with RasV12 (D) markedly enhances the size of tumors, while coexpression of CagAEPISA with RasV12 (E) causes only a minor enhancement of tumor growth. Whole eye clone expression of BskDN with RasV12 (F) does not significantly alter tumor size, while coexpression of BskDN with RasV12 and CagA (G) suppresses the growth advantage conferred by CagA expression. Scale bar for whole larvae images, 1 mm; scale bar for dissected cephalic complex images, 250 µm. (H) Quantitation of cephalic complex size as a measure of area in µm2, n = at least 30 cephalic complexes per genotype; bar indicates average value for each group. * indicates significant enhancement compared to RasV12; † indicates significant suppression compared to RasV12, CagA; p<0.05.
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ppat-1002939-g004: CagA enhances tumor growth through JNK activation.(A–B) Schematics depicting GFP-marked whole eye clones in third instar larvae (A) and a dissected cephalic complex (B), which includes the eye discs (ed), brain lobes (bl) and ventral nerve cord (vnc). (C–G) Images of female third instar larvae and dissected cephalic complexes with GFP-marked tumors. Expression of RasV12 in whole eye clones (C) causes overgrowth which results in tumor formation. Coexpression of CagA with RasV12 (D) markedly enhances the size of tumors, while coexpression of CagAEPISA with RasV12 (E) causes only a minor enhancement of tumor growth. Whole eye clone expression of BskDN with RasV12 (F) does not significantly alter tumor size, while coexpression of BskDN with RasV12 and CagA (G) suppresses the growth advantage conferred by CagA expression. Scale bar for whole larvae images, 1 mm; scale bar for dissected cephalic complex images, 250 µm. (H) Quantitation of cephalic complex size as a measure of area in µm2, n = at least 30 cephalic complexes per genotype; bar indicates average value for each group. * indicates significant enhancement compared to RasV12; † indicates significant suppression compared to RasV12, CagA; p<0.05.

Mentions: The finding that CagA activates the JNK pathway is intriguing in light of recent evidence indicating that activation of JNK signaling can switch from proapoptotic to progrowth in the presence of oncogenic Ras [19]. In order to examine a potential role for CagA-mediated JNK pathway activation in promoting tumorigenesis, we used a slight variation of a previously established Drosophila metastasis model to create whole eye clones expressing an activated form of the Ras oncogene (RasV12) in epithelial cells of the eye imaginal disc using the eyeless (ey) driver with the FLP/FRT system to generate primary tumors [33]. We then evaluated the size of GFP-marked tumors in whole larvae (Figure 4A) and dissected cephalic complexes (Figure 4B) in order to determine whether coexpression of CagA could enhance the growth and invasive potential of these tumor cells through activation of the JNK signaling pathway.


Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila.

Wandler AM, Guillemin K - PLoS Pathog. (2012)

CagA enhances tumor growth through JNK activation.(A–B) Schematics depicting GFP-marked whole eye clones in third instar larvae (A) and a dissected cephalic complex (B), which includes the eye discs (ed), brain lobes (bl) and ventral nerve cord (vnc). (C–G) Images of female third instar larvae and dissected cephalic complexes with GFP-marked tumors. Expression of RasV12 in whole eye clones (C) causes overgrowth which results in tumor formation. Coexpression of CagA with RasV12 (D) markedly enhances the size of tumors, while coexpression of CagAEPISA with RasV12 (E) causes only a minor enhancement of tumor growth. Whole eye clone expression of BskDN with RasV12 (F) does not significantly alter tumor size, while coexpression of BskDN with RasV12 and CagA (G) suppresses the growth advantage conferred by CagA expression. Scale bar for whole larvae images, 1 mm; scale bar for dissected cephalic complex images, 250 µm. (H) Quantitation of cephalic complex size as a measure of area in µm2, n = at least 30 cephalic complexes per genotype; bar indicates average value for each group. * indicates significant enhancement compared to RasV12; † indicates significant suppression compared to RasV12, CagA; p<0.05.
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getmorefigures.php?uid=PMC3475654&req=5

ppat-1002939-g004: CagA enhances tumor growth through JNK activation.(A–B) Schematics depicting GFP-marked whole eye clones in third instar larvae (A) and a dissected cephalic complex (B), which includes the eye discs (ed), brain lobes (bl) and ventral nerve cord (vnc). (C–G) Images of female third instar larvae and dissected cephalic complexes with GFP-marked tumors. Expression of RasV12 in whole eye clones (C) causes overgrowth which results in tumor formation. Coexpression of CagA with RasV12 (D) markedly enhances the size of tumors, while coexpression of CagAEPISA with RasV12 (E) causes only a minor enhancement of tumor growth. Whole eye clone expression of BskDN with RasV12 (F) does not significantly alter tumor size, while coexpression of BskDN with RasV12 and CagA (G) suppresses the growth advantage conferred by CagA expression. Scale bar for whole larvae images, 1 mm; scale bar for dissected cephalic complex images, 250 µm. (H) Quantitation of cephalic complex size as a measure of area in µm2, n = at least 30 cephalic complexes per genotype; bar indicates average value for each group. * indicates significant enhancement compared to RasV12; † indicates significant suppression compared to RasV12, CagA; p<0.05.
Mentions: The finding that CagA activates the JNK pathway is intriguing in light of recent evidence indicating that activation of JNK signaling can switch from proapoptotic to progrowth in the presence of oncogenic Ras [19]. In order to examine a potential role for CagA-mediated JNK pathway activation in promoting tumorigenesis, we used a slight variation of a previously established Drosophila metastasis model to create whole eye clones expressing an activated form of the Ras oncogene (RasV12) in epithelial cells of the eye imaginal disc using the eyeless (ey) driver with the FLP/FRT system to generate primary tumors [33]. We then evaluated the size of GFP-marked tumors in whole larvae (Figure 4A) and dissected cephalic complexes (Figure 4B) in order to determine whether coexpression of CagA could enhance the growth and invasive potential of these tumor cells through activation of the JNK signaling pathway.

Bottom Line: This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells.We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis.In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biology, University of Oregon, Eugene, Oregon, USA.

ABSTRACT
Gastric cancer development is strongly correlated with infection by Helicobacter pylori possessing the effector protein CagA. Using a transgenic Drosophila melanogaster model, we show that CagA expression in the simple model epithelium of the larval wing imaginal disc causes dramatic tissue perturbations and apoptosis when CagA-expressing and non-expressing cells are juxtaposed. This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells. We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis. In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner. These data suggest a potential role for CagA-mediated JNK pathway activation in promoting gastric cancer progression.

Show MeSH
Related in: MedlinePlus