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

Brennan-Crispi, Donna M.; Hossain, Claudia; Sahu, Joya; Brady, Mary Susan; Riobó, Natalia A.; Mahoney, Mỹ G.

doi:10.18632/oncotarget.3309

Cited by 18 publications

(25 citation statements)

References 32 publications

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“…Our work and that of others has demonstrated that Dsg2 in particular can enhance key mitogenic signaling cascades both within individual cancer cells and in adjacent ones (14, 15, 25). Localized expansion, invasion, and microenvironment manipulation by malignant clones is particularly important for the progression of HNSCC.…”

Section: Discussionsupporting

confidence: 67%

“…Furthermore, Dsg2 activates multiple growth and survival signaling pathways when overexpressed in transgenic mice and SCC cells (12, 15). Interestingly, we observed hedgehog activity in the underlying dermis of the tumors suggesting a paracrine mechanism of activation by Dsg2 (14). Here, we explore EV as a signaling conduit and illustrate that Dsg2 is present in EVs as a processed fragment and that overexpression of Dsg2 in keratinocytes alters the number and protein content of EVs.…”

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confidence: 90%

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Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes

et al. 2017

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Extracellular vesicles (EVs) are nanoscale membrane-derived vesicles that serve as intercellular messengers carrying lipids, proteins, and genetic material. Substantial evidence has shown that cancer-derived EVs, secreted by tumor cells into the blood and other bodily fluids, play a critical role in modulating the tumor microenvironment and affecting the pathogenesis of cancer. Here we demonstrate for the first time that squamous cell carcinoma (SCC) EVs were enriched with the C-terminal fragment of desmoglein 2 (Dsg2), a desmosomal cadherin often overexpressed in malignancies. Overexpression of Dsg2 increased EV release and mitogenic content including epidermal growth factor receptor and c-Src. Inhibiting ectodomain shedding of Dsg2 with the matrix metalloproteinase inhibitor GM6001 resulted in accumulation of full-length Dsg2 in EVs and reduced EV release. When cocultured with Dsg2/green fluorescence protein-expressing SCC cells, green fluorescence protein signal was detected by fluorescence-activated cell sorting analysis in the CD90 + fibroblasts. Furthermore, SCC EVs activated Erk1/2 and Akt signaling and enhanced fibroblast cell proliferation. In vivo, Dsg2 was highly up-regulated in the head and neck SCCs, and EVs isolated from sera of patients with SCC were enriched in Dsg2 C-terminal fragment and epidermal growth factor receptor. This study defines a mechanism by which Dsg2 expression in cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.-Overmiller, A.

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Section: Discussionsupporting

confidence: 67%

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confidence: 90%

Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes

et al. 2017

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“…Interestingly, these signaling pathways are downstream of the epidermal growth factor receptor (EGFR) and activation with EGF increases association of EGFR binding to Dsg2 [20]. Furthermore, Dsg2 upregulates Hedgehog signaling and in response to chemical carcinogens, enhances BCC and SCC tumor development [21]. …”

Section: Introductionmentioning

confidence: 99%

c-Src/Cav1-dependent activation of the EGFR by Dsg2

et al. 2016

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The desmosomal cadherin, desmoglein 2 (Dsg2), is deregulated in a variety of human cancers including those of the skin. When ectopically expressed in the epidermis of transgenic mice, Dsg2 activates multiple mitogenic signaling pathways and increases susceptibility to tumorigenesis. However, the molecular mechanism responsible for Dsg2-mediated cellular signaling is poorly understood. Here we show overexpression as well as co-localization of Dsg2 and EGFR in cutaneous SCCs in vivo. Using HaCaT keratinocytes, knockdown of Dsg2 decreases EGFR expression and abrogates the activation of EGFR, c-Src and Stat3, but not Erk1/2 or Akt, in response to EGF ligand stimulation. To determine whether Dsg2 mediates signaling through lipid microdomains, sucrose density fractionation illustrated that Dsg2 is recruited to and displaces Cav1, EGFR and c-Src from light density lipid raft fractions. STED imaging confirmed that the presence of Dsg2 disperses Cav1 from the cell-cell borders. Perturbation of lipid rafts with the cholesterol-chelating agent MβCD also shifts Cav1, c-Src and EGFR out of the rafts and activates signaling pathways. Functionally, overexpression of Dsg2 in human SCC A431 cells enhances EGFR activation and increases cell proliferation and migration through a c-Src and EGFR dependent manner. In summary, our data suggest that Dsg2 stimulates cell growth and migration by positively regulating EGFR level and signaling through a c-Src and Cav1-dependent mechanism using lipid rafts as signal modulatory platforms.

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“…Conversely, Hh signaling was found to override p53-mediated tumor suppression in BCCs, thus acting as a positive feedback loop in promoting oncogenesis (117, 118). In fact, in humans, high frequency and co-existence of genetic alterations in both PTCH and p53 genes have been identified in BCCs from both normal population and atomic bomb survivors (119, 122). PARP-1 is another important protein found to cooperate with Ptch in the suppression of BCCs induced by radiation exposure (120).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Brennan-Crispi et al . showed that Desmoglein 2 (Dsg 2) may synergize with Hh signaling to promote chemical-induced BCC development (122). However, the role of Dsg 2 in pathogenesis of Radiation-induced BCCs remains unclear at this time.…”

Section: Introductionmentioning

confidence: 99%

Ionizing Radiation Exposure and Basal Cell Carcinoma Pathogenesis

Athar

2016

Radiation Research

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This commentary summarizes studies showing risk of basal cell carcinoma (BCC) development in relationship to environmental, occupational and therapeutic exposure to ionizing radiation (IR). BCC, the most common type of human cancer, is driven by the aberrant activation of hedgehog (Hh) signaling. Ptch, a tumor suppressor gene of Hh signaling pathway, and Smoothened play a key role in the development of radiation-induced BCCs in animal models. Epidemiological studies provide evidence that humans exposed to radiation as observed among the long-term, large scale cohorts of atomic bomb survivors, bone marrow transplant recipients, patients with tinea capitis and radiologic workers enhances risk of BCCs. Overall, this risk is higher in Caucasians than other races. People who were exposed early in life develop more BCCs. The enhanced IR correlation with BCC and not other common cutaneous malignancies is intriguing. The mechanism underlying these observations remains undefined. Understanding interactions between radiation-induced signaling pathways and those which drive BCC development may be important in unraveling the mechanism associated with this enhanced risk. Recent studies showed that Vismodegib, a Smoothened inhibitor, is effective in treating radiation-induced BCCs in humans, suggesting that common strategies are required for the intervention of BCCs development irrespective of their etiology.

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

Cited by 18 publications

References 32 publications

Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes

Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes

c-Src/Cav1-dependent activation of the EGFR by Dsg2

Ionizing Radiation Exposure and Basal Cell Carcinoma Pathogenesis

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