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Desmoglein 2 depletion leads to increased migration and upregulation of the chemoattractant secretoneurin in melanoma cells.

Peitsch WK, Doerflinger Y, Fischer-Colbrie R, Huck V, Bauer AT, Utikal J, Goerdt S, Schneider SW - PLoS ONE (2014)

Bottom Line: During development and progression of malignant melanoma, an important role has been attributed to alterations of cell-cell adhesions, in particular, to a "cadherin switch" from E- to N-cadherin.In gene expression profiles, desmoglein 2 depletion was associated with overexpression of migration-related genes.The mechanism of desmoglein 2 impaired cell migration is mediated by downregulation of secretogranin II.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany ; Helmholtz Group for Cell Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
During development and progression of malignant melanoma, an important role has been attributed to alterations of cell-cell adhesions, in particular, to a "cadherin switch" from E- to N-cadherin. We have previously shown that a subtype of melanoma cells express the desmosomal cadherin desmoglein 2 as non-junction-bound cell surface protein in addition to classical cadherins. To study the role of desmoglein 2 in melanoma cells, melanoma lines containing high endogenous amounts of desmoglein 2 were depleted of the protein by RNA interference. Transwell migration and scratch wounding assays showed markedly increased migration upon desmoglein 2 suppression whereas proliferation and viability remained unaltered. In gene expression profiles, desmoglein 2 depletion was associated with overexpression of migration-related genes. Strongest overexpression was found for secretogranin II which has not been reported in melanoma cells before. The bioactive peptide derived from secretogranin II, secretoneurin, is known to exert chemoattractive functions and was demonstrated here to stimulate melanoma cell migration. In summary, we show that desmoglein 2 expression attenuates migration of melanoma cells. The mechanism of desmoglein 2 impaired cell migration is mediated by downregulation of secretogranin II. Loss of desmoglein 2 increases expression of secretogranin II, followed by an enhanced migratory activity of melanoma cells. Our data add a new pathway of regulating melanoma cell migration related to a desmoglein 2-secretogranin II axis.

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Clustered image map of >1.5-fold up- or downregulated genes in Dsg2-depleted C32.1. CAV1, 2. TGFBR2, 3. DUSP22, 4. STRADB, 5. RASGRP3, 6. CBS, 7. MDFIC, 8. GOLT1B, 9. SRPK2, 10. COL11A2, 11. DLX5, 12. SPARC, 13. SPP1, 14. TULP4, 15. C5ORF13, 16. COL1A2, 17. MGP, 18. KYNU, 19. ASNS, 20. ATG12, 21. SRC, 22. ROPN1B, 23. VCAN, 24. PPAP2B, 25. OPHN1, 26. PLXNB1, 27. TIMP2, 28. RAPGEF2, 29. EFNA1, 30. MYD88, 31. RPS6KA5, 32. ZDHHC17, 33. CITED1, 34. FSTL1, 35. VPS4B, 36. PRRX1, 37. PHEX, 38. PAPSS1, 39. CDK6, 40. MYC, 41. CCL2 42. TGFBR3, 43. HMOX1, 44. SCG2, 45. LAMC1, 46. LAMA4, 47. IL8, 48. CEACAM1, 49. FN1, 50. CTGF, 51. IGFBP5. Upregulated genes are highlighted in red (bold print) and downregulated genes in green (italics). Clusters are based on euclidean distance.
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pone-0089491-g006: Clustered image map of >1.5-fold up- or downregulated genes in Dsg2-depleted C32.1. CAV1, 2. TGFBR2, 3. DUSP22, 4. STRADB, 5. RASGRP3, 6. CBS, 7. MDFIC, 8. GOLT1B, 9. SRPK2, 10. COL11A2, 11. DLX5, 12. SPARC, 13. SPP1, 14. TULP4, 15. C5ORF13, 16. COL1A2, 17. MGP, 18. KYNU, 19. ASNS, 20. ATG12, 21. SRC, 22. ROPN1B, 23. VCAN, 24. PPAP2B, 25. OPHN1, 26. PLXNB1, 27. TIMP2, 28. RAPGEF2, 29. EFNA1, 30. MYD88, 31. RPS6KA5, 32. ZDHHC17, 33. CITED1, 34. FSTL1, 35. VPS4B, 36. PRRX1, 37. PHEX, 38. PAPSS1, 39. CDK6, 40. MYC, 41. CCL2 42. TGFBR3, 43. HMOX1, 44. SCG2, 45. LAMC1, 46. LAMA4, 47. IL8, 48. CEACAM1, 49. FN1, 50. CTGF, 51. IGFBP5. Upregulated genes are highlighted in red (bold print) and downregulated genes in green (italics). Clusters are based on euclidean distance.

Mentions: Separate analysis of up- or downregulated genes demonstrated significant correlations between Dsg2 knockdown and overexpression of genes related to cell migration (3.96-fold enrichment, p<0.0001, false discovery rate (FDR) 0.0267), TGF-β receptor signaling (6.60-fold enrichment, p<0.0001, FDR 0.0413) and cell adhesion (2.68-fold enrichment, p = 0.0002, FDR 0.0300). A cluster image map of differentially expressed genes is shown in Fig. 6.


Desmoglein 2 depletion leads to increased migration and upregulation of the chemoattractant secretoneurin in melanoma cells.

Peitsch WK, Doerflinger Y, Fischer-Colbrie R, Huck V, Bauer AT, Utikal J, Goerdt S, Schneider SW - PLoS ONE (2014)

Clustered image map of >1.5-fold up- or downregulated genes in Dsg2-depleted C32.1. CAV1, 2. TGFBR2, 3. DUSP22, 4. STRADB, 5. RASGRP3, 6. CBS, 7. MDFIC, 8. GOLT1B, 9. SRPK2, 10. COL11A2, 11. DLX5, 12. SPARC, 13. SPP1, 14. TULP4, 15. C5ORF13, 16. COL1A2, 17. MGP, 18. KYNU, 19. ASNS, 20. ATG12, 21. SRC, 22. ROPN1B, 23. VCAN, 24. PPAP2B, 25. OPHN1, 26. PLXNB1, 27. TIMP2, 28. RAPGEF2, 29. EFNA1, 30. MYD88, 31. RPS6KA5, 32. ZDHHC17, 33. CITED1, 34. FSTL1, 35. VPS4B, 36. PRRX1, 37. PHEX, 38. PAPSS1, 39. CDK6, 40. MYC, 41. CCL2 42. TGFBR3, 43. HMOX1, 44. SCG2, 45. LAMC1, 46. LAMA4, 47. IL8, 48. CEACAM1, 49. FN1, 50. CTGF, 51. IGFBP5. Upregulated genes are highlighted in red (bold print) and downregulated genes in green (italics). Clusters are based on euclidean distance.
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Related In: Results  -  Collection

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pone-0089491-g006: Clustered image map of >1.5-fold up- or downregulated genes in Dsg2-depleted C32.1. CAV1, 2. TGFBR2, 3. DUSP22, 4. STRADB, 5. RASGRP3, 6. CBS, 7. MDFIC, 8. GOLT1B, 9. SRPK2, 10. COL11A2, 11. DLX5, 12. SPARC, 13. SPP1, 14. TULP4, 15. C5ORF13, 16. COL1A2, 17. MGP, 18. KYNU, 19. ASNS, 20. ATG12, 21. SRC, 22. ROPN1B, 23. VCAN, 24. PPAP2B, 25. OPHN1, 26. PLXNB1, 27. TIMP2, 28. RAPGEF2, 29. EFNA1, 30. MYD88, 31. RPS6KA5, 32. ZDHHC17, 33. CITED1, 34. FSTL1, 35. VPS4B, 36. PRRX1, 37. PHEX, 38. PAPSS1, 39. CDK6, 40. MYC, 41. CCL2 42. TGFBR3, 43. HMOX1, 44. SCG2, 45. LAMC1, 46. LAMA4, 47. IL8, 48. CEACAM1, 49. FN1, 50. CTGF, 51. IGFBP5. Upregulated genes are highlighted in red (bold print) and downregulated genes in green (italics). Clusters are based on euclidean distance.
Mentions: Separate analysis of up- or downregulated genes demonstrated significant correlations between Dsg2 knockdown and overexpression of genes related to cell migration (3.96-fold enrichment, p<0.0001, false discovery rate (FDR) 0.0267), TGF-β receptor signaling (6.60-fold enrichment, p<0.0001, FDR 0.0413) and cell adhesion (2.68-fold enrichment, p = 0.0002, FDR 0.0300). A cluster image map of differentially expressed genes is shown in Fig. 6.

Bottom Line: During development and progression of malignant melanoma, an important role has been attributed to alterations of cell-cell adhesions, in particular, to a "cadherin switch" from E- to N-cadherin.In gene expression profiles, desmoglein 2 depletion was associated with overexpression of migration-related genes.The mechanism of desmoglein 2 impaired cell migration is mediated by downregulation of secretogranin II.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany ; Helmholtz Group for Cell Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
During development and progression of malignant melanoma, an important role has been attributed to alterations of cell-cell adhesions, in particular, to a "cadherin switch" from E- to N-cadherin. We have previously shown that a subtype of melanoma cells express the desmosomal cadherin desmoglein 2 as non-junction-bound cell surface protein in addition to classical cadherins. To study the role of desmoglein 2 in melanoma cells, melanoma lines containing high endogenous amounts of desmoglein 2 were depleted of the protein by RNA interference. Transwell migration and scratch wounding assays showed markedly increased migration upon desmoglein 2 suppression whereas proliferation and viability remained unaltered. In gene expression profiles, desmoglein 2 depletion was associated with overexpression of migration-related genes. Strongest overexpression was found for secretogranin II which has not been reported in melanoma cells before. The bioactive peptide derived from secretogranin II, secretoneurin, is known to exert chemoattractive functions and was demonstrated here to stimulate melanoma cell migration. In summary, we show that desmoglein 2 expression attenuates migration of melanoma cells. The mechanism of desmoglein 2 impaired cell migration is mediated by downregulation of secretogranin II. Loss of desmoglein 2 increases expression of secretogranin II, followed by an enhanced migratory activity of melanoma cells. Our data add a new pathway of regulating melanoma cell migration related to a desmoglein 2-secretogranin II axis.

Show MeSH
Related in: MedlinePlus