Limits...
Loss of the p53/p63 regulated desmosomal protein Perp promotes tumorigenesis.

Beaudry VG, Jiang D, Dusek RL, Park EJ, Knezevich S, Ridd K, Vogel H, Bastian BC, Attardi LD - PLoS Genet. (2010)

Bottom Line: Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell-cell adhesion.Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status.Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California, USA.

ABSTRACT
Dysregulated cell-cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell-cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell-cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

Show MeSH

Related in: MedlinePlus

Combined Perp-deficiency and chronic UVB exposure induce immune cell infiltration in the skin.A) Representative immunofluorescence images of myeloid cells, as determined by MPO staining (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. B) Quantification of MPO-positive cells in UVB-treated cohorts. Graph represents the average of 3 mice, quantified in triplicate 200× fields +/− SEM. (p = 0.89; Student's unpaired t-test). C) Representative immunofluorescence images of T-cells, as assessed by CD3 staining (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. D) Quantification of CD3-positive T-cell numbers in UVB-treated cohorts. Graph represents the average number of T-cells in the skin of 3 mice, quantified in triplicate 200× fields, +/− SEM. (* p =  0.044, Student's unpaired t-test). E) Representative images of staining for mast cells, as assessed by toluidine blue-positivity (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. Note the increase in mast cells underlying the epidermis in the K14CreER;Perpfl/fl mice. F) Quantification of mast cells in UVB-treated cohorts. Graph represents the average of 3 mice, quantified in triplicate 200× fields +/− SEM. (* p =  0.0092; Student's unpaired t-test).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2958815&req=5

pgen-1001168-g006: Combined Perp-deficiency and chronic UVB exposure induce immune cell infiltration in the skin.A) Representative immunofluorescence images of myeloid cells, as determined by MPO staining (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. B) Quantification of MPO-positive cells in UVB-treated cohorts. Graph represents the average of 3 mice, quantified in triplicate 200× fields +/− SEM. (p = 0.89; Student's unpaired t-test). C) Representative immunofluorescence images of T-cells, as assessed by CD3 staining (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. D) Quantification of CD3-positive T-cell numbers in UVB-treated cohorts. Graph represents the average number of T-cells in the skin of 3 mice, quantified in triplicate 200× fields, +/− SEM. (* p =  0.044, Student's unpaired t-test). E) Representative images of staining for mast cells, as assessed by toluidine blue-positivity (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. Note the increase in mast cells underlying the epidermis in the K14CreER;Perpfl/fl mice. F) Quantification of mast cells in UVB-treated cohorts. Graph represents the average of 3 mice, quantified in triplicate 200× fields +/− SEM. (* p =  0.0092; Student's unpaired t-test).

Mentions: The observation that Perp loss triggers the induction of genes known to promote inflammation, combined with the fact that inflammation is causally linked to cancer development [63], provides a rationale for how Perp-deficiency could contribute to cancer. We hypothesized that persistent cytokine/chemokine signaling in K14CreER;Perpfl/fl mice, combined with chronic UVB exposure, might ultimately attract immune cells, thereby promoting tumor formation. To investigate this idea, we queried the presence of inflammatory cells in the skin from a subset of control and K14CreER;Perpfl/fl mice at an intermediate timepoint in the tumor study, after 19 weeks of chronic UVB treatment, by quantifying numbers of myeloid cells, T-cells, and mast cells (Figure 6A–6F). While we did not detect any differences in the number of myeloid cells, assessed by MPO-positivity (Figure 6A, 6B; [64]), we did observe increased numbers of T-cells present throughout the skin of K14CreER;Perpfl/fl mice compared to controls (Figure 6C, 6D). Moreover, we noted a striking increase in mast cell numbers in the skin from K14CreER;Perpfl/fl mice relative to controls (Figure 6E, 6F). As mast cells have been reported to surround tumors in a variety of cancers, including SCCs [65]–[68], and because they have been shown to play a key role in promoting tumorigenesis through the secretion of factors that remodel the tumor microenvironment and stimulate angiogenesis [68]–[71], their presence in the UVB-treated Perp-deficient mouse skin suggests an additional mechanism through which Perp loss may stimulate tumorigenesis.


Loss of the p53/p63 regulated desmosomal protein Perp promotes tumorigenesis.

Beaudry VG, Jiang D, Dusek RL, Park EJ, Knezevich S, Ridd K, Vogel H, Bastian BC, Attardi LD - PLoS Genet. (2010)

Combined Perp-deficiency and chronic UVB exposure induce immune cell infiltration in the skin.A) Representative immunofluorescence images of myeloid cells, as determined by MPO staining (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. B) Quantification of MPO-positive cells in UVB-treated cohorts. Graph represents the average of 3 mice, quantified in triplicate 200× fields +/− SEM. (p = 0.89; Student's unpaired t-test). C) Representative immunofluorescence images of T-cells, as assessed by CD3 staining (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. D) Quantification of CD3-positive T-cell numbers in UVB-treated cohorts. Graph represents the average number of T-cells in the skin of 3 mice, quantified in triplicate 200× fields, +/− SEM. (* p =  0.044, Student's unpaired t-test). E) Representative images of staining for mast cells, as assessed by toluidine blue-positivity (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. Note the increase in mast cells underlying the epidermis in the K14CreER;Perpfl/fl mice. F) Quantification of mast cells in UVB-treated cohorts. Graph represents the average of 3 mice, quantified in triplicate 200× fields +/− SEM. (* p =  0.0092; Student's unpaired t-test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2958815&req=5

pgen-1001168-g006: Combined Perp-deficiency and chronic UVB exposure induce immune cell infiltration in the skin.A) Representative immunofluorescence images of myeloid cells, as determined by MPO staining (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. B) Quantification of MPO-positive cells in UVB-treated cohorts. Graph represents the average of 3 mice, quantified in triplicate 200× fields +/− SEM. (p = 0.89; Student's unpaired t-test). C) Representative immunofluorescence images of T-cells, as assessed by CD3 staining (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. D) Quantification of CD3-positive T-cell numbers in UVB-treated cohorts. Graph represents the average number of T-cells in the skin of 3 mice, quantified in triplicate 200× fields, +/− SEM. (* p =  0.044, Student's unpaired t-test). E) Representative images of staining for mast cells, as assessed by toluidine blue-positivity (arrows), in the skin of control and K14CreER;Perpfl/fl mice treated with UVB light for 19 weeks. Note the increase in mast cells underlying the epidermis in the K14CreER;Perpfl/fl mice. F) Quantification of mast cells in UVB-treated cohorts. Graph represents the average of 3 mice, quantified in triplicate 200× fields +/− SEM. (* p =  0.0092; Student's unpaired t-test).
Mentions: The observation that Perp loss triggers the induction of genes known to promote inflammation, combined with the fact that inflammation is causally linked to cancer development [63], provides a rationale for how Perp-deficiency could contribute to cancer. We hypothesized that persistent cytokine/chemokine signaling in K14CreER;Perpfl/fl mice, combined with chronic UVB exposure, might ultimately attract immune cells, thereby promoting tumor formation. To investigate this idea, we queried the presence of inflammatory cells in the skin from a subset of control and K14CreER;Perpfl/fl mice at an intermediate timepoint in the tumor study, after 19 weeks of chronic UVB treatment, by quantifying numbers of myeloid cells, T-cells, and mast cells (Figure 6A–6F). While we did not detect any differences in the number of myeloid cells, assessed by MPO-positivity (Figure 6A, 6B; [64]), we did observe increased numbers of T-cells present throughout the skin of K14CreER;Perpfl/fl mice compared to controls (Figure 6C, 6D). Moreover, we noted a striking increase in mast cell numbers in the skin from K14CreER;Perpfl/fl mice relative to controls (Figure 6E, 6F). As mast cells have been reported to surround tumors in a variety of cancers, including SCCs [65]–[68], and because they have been shown to play a key role in promoting tumorigenesis through the secretion of factors that remodel the tumor microenvironment and stimulate angiogenesis [68]–[71], their presence in the UVB-treated Perp-deficient mouse skin suggests an additional mechanism through which Perp loss may stimulate tumorigenesis.

Bottom Line: Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell-cell adhesion.Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status.Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California, USA.

ABSTRACT
Dysregulated cell-cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell-cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell-cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

Show MeSH
Related in: MedlinePlus