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Material and metods. Tumor samples from paraffin blocks of melanoma patients obtained from Krasnoyarsk Territorial Oncologic Center were used in the study. Skin tissue samples (n = 40) were received from the Krasnoyarsk Territorial Pathological Anatomy Bureau. The mutation in the exon 7 of the PPP6C gene was determined by the Sanger sequencing method using specific primers. Immunohistochemistry was performed based on a standard technique using primary anti-matrix metalloproteinase-2 antibodies. Results. Mutations in the gene PPP6C were detected in 12.5% of patients; in all patients with mutation, missense mutations were observed: G266R, I271N, P259H, and a combination of two mutations in the hot spots of the P259L and R264L gene were also determined. It was found that the expression of MMP-2 in patients with a PPP6C mutant tumor type was not similar to a wild type tumor patients (p = 0.72). The predominant expression of nuclear MMP-2 is observed in PPP6C-negative patients, while in patients with mutations in the PPP6C gene, the cytoplasmic expression of MMP-2 was predominant (p = 0.045). We also found a predominance of nuclear MMP-2 expression, as a prognostically unfavorable factor, for patients in the PPP6C of negative group. Both of these facts may be related to the fact that this mutation does not affect other signaling mechanisms not associated with the BRAF and NRAS genes, nor does it directly affect the expression pattern of MMP-2.

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About the authors

Maria B. Aksenenko

Department of Pathophysiology, Krasnoyarsk State Medical University n.a. prof. V.F. Voyno-Yasenetsky

Krasnoyarsk, 660022, Russian Federation
MD, PhD, docente, Department of Pathophysiology with a Course of a Clinical Pathophysiology, Krasnoyarsk State Medical University of prof. V.F. VoynoYasenetsky, Krasnoyarsk, 660022, Russian Federation

T. G Ruksha

Department of Pathophysiology, Krasnoyarsk State Medical University n.a. prof. V.F. Voyno-Yasenetsky

Krasnoyarsk, 660022, Russian Federation


  1. Cicenas J., Tamosaitis L., Kvederaviciute K., Tarvydas R., Staniute G., Kalyan K., et al. KRAS, NRAS and BRAF mutations in colorectal cancer and melanoma. Med. Oncol. 2017; 34(2): 26. doi: 10.1007/s12032-016-0879-9.
  2. Krauthammer M., Kong Y., Ha B.H., Evans P., Bacchiocchi A., McCusker J.P., et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat. Genet. 2012; 44(9): 1006-14. doi: 10.1038/ng.2359.
  3. Krauthammer M., Kong Y., Bacchiocchi A., Evans P., Pornputtapong N., Wu C., et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat. Genet. 2015; 47(9): 996-1002. doi: 10.1038/ng.3361.
  4. Ranzani M., Alifrangis C., Perna D., Dutton - Reqester K., Pritchard A., Wong K., et al. BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib. Pigment Cell Melanoma Res. 2015; 28(1): 117-9. doi: 10.1111/pcmr.12316.
  5. Xia J., Jia P., Hutchinson K.E., Dahlman K.B., Johnson D., Sosman J., et al. A meta-analysis of somatic mutations from next generation sequencing of 241 melanomas: a road map for the study of genes with potential clinical relevance. Mol. Cancer Ther. 2014; 13(7): 1918-28. doi: 10.1158/1535-7163.MCT-13-0804.
  6. Grienwank K.G., Scolyer R.A., Thompson J.F., Flaherty K.T., Schadendorf D., Murali R. Genetic alterations and personalized medicine in melanoma: progress and future prospects. J. Natl. Cancer Inst. 2014; 106(2): djt435. doi: 10.1093/jnci/djt435.
  7. Gold H.L., Wengrod J., de Miera E.V., Wang D., Fleming N., Sikkema L., et al. PP6C hotspot mutations in melanoma display sensitivity to Auro kinase inhibition. Mol. Cancer Res. 2014; 12(3): 433-9. doi: 10.1158/1541-7786.MCR-13-0422.
  8. Stefansson B., Brautigan D.L. Protein phosphatase 6 subuntil with conserved Sit4-associated protein domain targets I kappa B epsilon. J. Biol. Chem. 2006; 281(32): 22624-34. doi: 10.1074/jbc.M601772200.
  9. Hodis E., Watson I.R., Kryukov G.V., Arold S.T., Imielinski M., Theurillat J.P., et al. A landscape of driver mutations in melanoma. Cell. 2012; 150(2): 251-63. doi: 10.1016/j.cell.2012.06.024.
  10. Shen T., Pajaro-Van de Stadt S.H., Yeat N.C., Lin J.C. Clinical applications of next generation sequencing in cancer: from panels, to exomes, to genomes. Front. Genet. 2015; 6: 215. doi: 10.3389/fgene.2015.00215.
  11. Xu W., Xu H., Fang M., Wu X., Xu Y. MKL1 links epigenetic activation of MMP2 to ovarian cancer cell migration and invasion. Biochem. Biophys. Res. Commun. 2017; 487(3): 500-8. doi: 10.1016/j.bbrc.2017.04.006.
  12. Luke J., Vukoja V., Brandenbusch T., Nassar K., Rohrbach J.M., Grisanti S., et al. CD147 and matrix-metalloproteinase-2 expression in metastatic and non-metastatic uveal melanomas. BMC Ophthalmol. 2016; 16: 74. doi: 10.1186/s12886-016-0222-4.
  13. Sandri S., Faiao-Flores F., Tiago M., Pennacchi P.C., Massaro R.R., Alves-Fernandes D.K., et al. Vemurafenib resistance increases melanoma invasiveness and modulated the tumor microenvironment by MMP-2 upregulation. Pharmacol. Res. 2016; 111: 523-33. doi: 10.1016/j.phrs.2016.07.017.
  14. Trisciuoglio D., Desideri M., Ciuffreda L., Motolesse M., Ribbatti D., Vacca A., et al. Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth. J. Cell Physiol. 2005; 205(3): 414-21. doi: 10.1002/jcp.20413.
  15. Shitara D., Tell-Marti G., Badenas C., Enokihara N.M., Alos L., Larque A.B., et al. Mutational status of naevus-associated melanomas. Br. J. Dermatol. 2015; 173(3): 671-80. doi: 10.1111/bjd.13829.
  16. Sullivan R.J., ed. BRAF targets in melanoma: biological mechanism, resistance, and drug discovery. Springer; 2015.
  17. Hammond D., Zeng K., Espert A., Bastos R.N., Baron R.D., Gruneberg U., et al. Melanoma-associated mutations in protein phosphatase 6 cause instability and DANA damage owing to dysregulated Auro A. J. Cell Sci. 2013; 126(Pt 15): 3429-40. doi: 10.1242/jcs.128397.
  18. Monvoisin A., Bisson C., Si-Tayeb K., Balabaud C., Desmouliere A., Rosenbaum J. Involvement of matrix metalloproteinase type-3 in hepatocyte growth factor-induced invasion of human hepatocellular carcinoma cells. Int. J. Cancer. 2002; 97(2): 157-62.
  19. Kohrmann A., Kammer U., Kapp M., Dietl J., Anacker J. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and cancer cell lines: new findings and review of the literature. BMC Cancer. 2009; 9: 188. doi: 10.1186/1471-2407-9-188.
  20. Ene C.I., Fine H.A. Many tumors in one: a daunting therapeutic prospect. Cancer Cell. 2011; 20(6): 695-7.
  21. Forment J.V., Kaidi A., Jackson S.P. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat. Rev. Cancer. 2012; 12(10): 663-70.
  22. Crasta K., Ganem N.J., Dagher R., Lantermann A.B., Ivanova E.V., Pan Y., et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature. 2012; 482(7383): 53-8. doi: 10.1038/nature10802.
  23. Hu M.W., Meng T.G., Jiang Z.Z., Dong M.Z., Schatten H., Xu X., et al. Protein phosphatase 6 protects prophase I-arrested oocytes by safeguarding genomic integrity. PloS Genet. 2016; 12(2): e1006513. doi: 10.1371/journal.pgen.1006513.
  24. D’Assoro A.B., Haddad T., Galanis E. Aurora-A kinase as a promising therapeutic target in cancer. Front. Oncol. 2015; 5: 295. doi: 10.3389/fonc.2015.00295.



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