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Crosstalk between Desmoglein 2 and Patched 1 accelerates chemical-induced skin tumorigenesis.

Brennan-Crispi DM, Hossain C, Sahu J, Brady M, Riobo NA, Mahoney MG - Oncotarget (2015)

Bottom Line: Aberrant activation of Hedgehog (Hh) signaling is causative of BCCs and has been associated with a fraction of SCCs.Ectopic expression of Dsg2 on Ptc1(+/lacZ) background enhanced epidermal proliferation and interfollicular activation of the Hh pathway.In summary, our results demonstrate that Dsg2 modulates Hh signaling, and this synergy may accelerate skin tumor development by different mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.

ABSTRACT
Aberrant activation of Hedgehog (Hh) signaling is causative of BCCs and has been associated with a fraction of SCCs. Desmoglein 2 (Dsg2) is an adhesion protein that is upregulated in many cancers and overexpression of Dsg2 in the epidermis renders mice more susceptible to squamous-derived neoplasia. Here we examined a potential crosstalk between Dsg2 and Hh signaling in skin tumorigenesis. Our findings show that Dsg2 modulates Gli1 expression, in vitro and in vivo. Ectopic expression of Dsg2 on Ptc1(+/lacZ) background enhanced epidermal proliferation and interfollicular activation of the Hh pathway. Furthermore, in response to DMBA/TPA, the Dsg2/Ptc1+/lacZ mice developed squamous lessons earlier than the WT, Ptc1(+/lacZ), and Inv-Dsg2 littermates. Additionally, DMBA/TPA induced BCC formation in all mice harboring the Ptc1(+/lacZ) gene and the presence of Dsg2 in Dsg2/Ptc1(+/lacZ) mice doubled the BCC tumor burden. Reporter analysis revealed activation of the Hh pathway in the BCC tumors. However, in the SCCs we observed Hh activity only in the underlying dermis of the tumors. Furthermore, Dsg2/Ptc1(+/lacZ) mice demonstrated enhanced MEK/Erk1/2 activation within the tumors and expression of Shh in the dermis. In summary, our results demonstrate that Dsg2 modulates Hh signaling, and this synergy may accelerate skin tumor development by different mechanisms.

No MeSH data available.


Related in: MedlinePlus

Inv-Dsg2/Ptc1+/lacZ mice display Hh activity in the tumor stromaA. Consecutive sections of papillomas reveal the tumor epithelium is negative for X-gal, but tumor stroma of the Inv-Dsg2/Ptc1+/lacZ mice positively stained for Hh activation (blue). B. β-gal IHC confirms activation of the Hh pathway in fibroblasts of the tumor stroma. C. IHC staining reveals Shh in the SCC tumor stroma. Dashed line demarcates basement membrane zone. Scale bar = 100 microns, 50 microns for insets.
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Figure 5: Inv-Dsg2/Ptc1+/lacZ mice display Hh activity in the tumor stromaA. Consecutive sections of papillomas reveal the tumor epithelium is negative for X-gal, but tumor stroma of the Inv-Dsg2/Ptc1+/lacZ mice positively stained for Hh activation (blue). B. β-gal IHC confirms activation of the Hh pathway in fibroblasts of the tumor stroma. C. IHC staining reveals Shh in the SCC tumor stroma. Dashed line demarcates basement membrane zone. Scale bar = 100 microns, 50 microns for insets.

Mentions: We also compared the tumor morphology at the end of the treatment protocol. All genotypes developed histologically similar papillomas and in situ carcinomas (Figure 4B). None of the animals developed full-blown SCC or showed signs of metastasis. Surprisingly, yet in agreement with the similar burden and morphology, neither X-gal nor β-gal staining revealed activation of the Hh pathway in squamous tumors of Ptc1+/lacZ or Inv-Dsg2/Ptc1+/lacZ mice (Figure 5). However we detected strong X-gal staining in the dermis underlying the tumors in Inv-Dsg2/Ptc1+/lacZ mice, which was not observed in Ptc1+/lacZ animals (Figure 5A). β-gal staining further confirmed the activation of the Hh pathway in the dermal fibroblasts of the compound mice (Figure 5B). We also found an increased expression of Shh by immunohistochemical (IHC) staining in the dermis, but not in the epidermis, of Dsg2 transgenic mice, which explains the X-gal and β-gal staining of dermal fibroblasts (Figure 5C). It is therefore possible that activation of the Hh pathway in the dermis in a Shh-dependent manner could account for the earlier tumor emergence in the Inv-Dsg2/Ptc1+/lacZ mice. Finally, to determine if there is a change in growth and survival signaling in the SCC tumors of all genotypes, we stained for phosphorylated Erk1/2. Interestingly, while tumors of all genotypes exhibit some level of staining, total phosphorylation and nuclear localization were more prominent in the Inv-Dsg2/Ptc1+/lacZ mice than in any other genotype (Figure 6), as confirmed by confirmed by four independent blind observers.


Crosstalk between Desmoglein 2 and Patched 1 accelerates chemical-induced skin tumorigenesis.

Brennan-Crispi DM, Hossain C, Sahu J, Brady M, Riobo NA, Mahoney MG - Oncotarget (2015)

Inv-Dsg2/Ptc1+/lacZ mice display Hh activity in the tumor stromaA. Consecutive sections of papillomas reveal the tumor epithelium is negative for X-gal, but tumor stroma of the Inv-Dsg2/Ptc1+/lacZ mice positively stained for Hh activation (blue). B. β-gal IHC confirms activation of the Hh pathway in fibroblasts of the tumor stroma. C. IHC staining reveals Shh in the SCC tumor stroma. Dashed line demarcates basement membrane zone. Scale bar = 100 microns, 50 microns for insets.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496169&req=5

Figure 5: Inv-Dsg2/Ptc1+/lacZ mice display Hh activity in the tumor stromaA. Consecutive sections of papillomas reveal the tumor epithelium is negative for X-gal, but tumor stroma of the Inv-Dsg2/Ptc1+/lacZ mice positively stained for Hh activation (blue). B. β-gal IHC confirms activation of the Hh pathway in fibroblasts of the tumor stroma. C. IHC staining reveals Shh in the SCC tumor stroma. Dashed line demarcates basement membrane zone. Scale bar = 100 microns, 50 microns for insets.
Mentions: We also compared the tumor morphology at the end of the treatment protocol. All genotypes developed histologically similar papillomas and in situ carcinomas (Figure 4B). None of the animals developed full-blown SCC or showed signs of metastasis. Surprisingly, yet in agreement with the similar burden and morphology, neither X-gal nor β-gal staining revealed activation of the Hh pathway in squamous tumors of Ptc1+/lacZ or Inv-Dsg2/Ptc1+/lacZ mice (Figure 5). However we detected strong X-gal staining in the dermis underlying the tumors in Inv-Dsg2/Ptc1+/lacZ mice, which was not observed in Ptc1+/lacZ animals (Figure 5A). β-gal staining further confirmed the activation of the Hh pathway in the dermal fibroblasts of the compound mice (Figure 5B). We also found an increased expression of Shh by immunohistochemical (IHC) staining in the dermis, but not in the epidermis, of Dsg2 transgenic mice, which explains the X-gal and β-gal staining of dermal fibroblasts (Figure 5C). It is therefore possible that activation of the Hh pathway in the dermis in a Shh-dependent manner could account for the earlier tumor emergence in the Inv-Dsg2/Ptc1+/lacZ mice. Finally, to determine if there is a change in growth and survival signaling in the SCC tumors of all genotypes, we stained for phosphorylated Erk1/2. Interestingly, while tumors of all genotypes exhibit some level of staining, total phosphorylation and nuclear localization were more prominent in the Inv-Dsg2/Ptc1+/lacZ mice than in any other genotype (Figure 6), as confirmed by confirmed by four independent blind observers.

Bottom Line: Aberrant activation of Hedgehog (Hh) signaling is causative of BCCs and has been associated with a fraction of SCCs.Ectopic expression of Dsg2 on Ptc1(+/lacZ) background enhanced epidermal proliferation and interfollicular activation of the Hh pathway.In summary, our results demonstrate that Dsg2 modulates Hh signaling, and this synergy may accelerate skin tumor development by different mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.

ABSTRACT
Aberrant activation of Hedgehog (Hh) signaling is causative of BCCs and has been associated with a fraction of SCCs. Desmoglein 2 (Dsg2) is an adhesion protein that is upregulated in many cancers and overexpression of Dsg2 in the epidermis renders mice more susceptible to squamous-derived neoplasia. Here we examined a potential crosstalk between Dsg2 and Hh signaling in skin tumorigenesis. Our findings show that Dsg2 modulates Gli1 expression, in vitro and in vivo. Ectopic expression of Dsg2 on Ptc1(+/lacZ) background enhanced epidermal proliferation and interfollicular activation of the Hh pathway. Furthermore, in response to DMBA/TPA, the Dsg2/Ptc1+/lacZ mice developed squamous lessons earlier than the WT, Ptc1(+/lacZ), and Inv-Dsg2 littermates. Additionally, DMBA/TPA induced BCC formation in all mice harboring the Ptc1(+/lacZ) gene and the presence of Dsg2 in Dsg2/Ptc1(+/lacZ) mice doubled the BCC tumor burden. Reporter analysis revealed activation of the Hh pathway in the BCC tumors. However, in the SCCs we observed Hh activity only in the underlying dermis of the tumors. Furthermore, Dsg2/Ptc1(+/lacZ) mice demonstrated enhanced MEK/Erk1/2 activation within the tumors and expression of Shh in the dermis. In summary, our results demonstrate that Dsg2 modulates Hh signaling, and this synergy may accelerate skin tumor development by different mechanisms.

No MeSH data available.


Related in: MedlinePlus