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Skin cancer and proteinase research group

Principal Investigator:
Professor Veli-Matti Kähäri, MD, PhD.
Tel: +358-2-3131600; fax:+358-2-3131610; e-mail:veli-matti.kahari (at) utu.fi

Research Group:
Liisa Nissinen, PhD, research scientist
Niina Hieta, MD, PhD, specialist in dermatology and allergology
Atte Kivisaari, MD, PhD, specialist in dermatology and allergology
Mehdi Farshchian, MD, PhD, postdoctoral scientist
Pilvi Riihilä, MD, PhD, postdoctoral scientist, resident
Minna Piipponen, MSc, doctoral candidate
Kristina Viiklepp, MD, doctoral candidate
Johanna Markola, project engineer

Description of the research topic:
The incidence of skin cancer, both melanoma and keratinocyte-derived non melanoma skin cancer is increasing in the developed countries due to aging of population and increased recreational exposure to sunlight. In addition, new skin cancer cases are increasing in younger age groups. The growing number of skin cancer patients presents an important challenge to our health care system. Therefore, improved early diagnosis of skin cancer and identification of aggressive premalignant lesions is needed.

In this project our aim is to identify new molecular mechanisms involved in progression of cutaneous squamous cell carcinoma (cSCC), the most common metastatic skin cancer. In the absence of targeted therapies, the prognosis of metastatic cSCC is poor. Furthermore, there are no molecular markers available, which could be used to identify those premalignant precursors, which develop rapidly into invasive carcinomas, or those primary cSCCs which present high risk for metastasis. Our aim is to find and characterize new biomarkers for evaluating the risk of progression and metastasis of cSCC and identify novel therapeutic targets for recurrent and metastatic cSCC. Using microarray and RNA-Seq based global gene expression profiling, we have recently identified a number of novel genes and non-coding RNAs specifically expressed in human cSCCs but in normal keratinocytes. We will characterize the functional role of these genes in progression of cSCC and validate them as biomarkers for growth and metastasis of cSCC.

Another goal of the project is to elucidate the role and regulation of proteinases and MMPs in tissue repair and fibrosis.

Selected Publications:

Nissinen L, Siljamäki E, Riihilä P, Piipponen M, Farshchian M, Kivisaari A, Kallajoki M, Raiko L, Peltonen J, Peltonen S, Kähäri VM. Expression of claudin-11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ. Exp Dermatol. 2016 Dec 19. doi: 10.1111/exd.13278. [Epub ahead of print]

Farshchian M, Nissinen L, Grénman R, Kähäri VM (2017) Dasatinib promotes apoptosis of cutaneous squamous carcinoma cells by regulating activation of ERK1/2. Exp Dermatol  26:89-92.

Piipponen M, Nissinen L, Farshchian M, Riihilä P, Kivisaari A, Kallajoki M, Peltonen J, Peltonen S, Kähäri VM. (2016) Long Non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity. J Invest Dermatol 136:1701-1710.

Nissinen L, Farshchian M, Riihilä P, Kähäri VM.(2016) New perspectives on role of tumor microenvironment in progression of cutaneous squamous cell carcinoma. Cell Tissue Res. 365:691-702.

Rousi E, Koskivuo I, Kaarela O, Kääriäinen M, Kähäri VM. (2016) Clinical and pathological aspects of melanoma among children in Finland. Acta Dermatol Venereol 96:718–720.

Karppinen SM, Honkanen HK, Heljasvaara R, Riihilä P, Autio-Harmainen H, Sormunen R, Harjunen V, Väisänen MR, Väisänen T, Hurskainen T, Tasanen K, Kähäri VM, Pihlajaniemi T. (2016) Collagens XV and XVIII show different expression and localisation in cutaneous squamous cell carcinoma: type XV appears in tumor stroma, while XVIII becomes upregulated in tumor cells and lost from microvessels. Exp Dermatol ;25:348-54.

Farshchian M, Nissinen L, Siljamäki E, Riihilä P, Toriseva M, Kivisaari A, Ala-aho R, Kallajoki M, Veräjänkorva E, Honkanen HK, Heljasvaara R, Pihlajaniemi T, Grénman R, Peltonen J, Peltonen S, Kähäri VM (2015) EphB2 promotes progression of cutaneous squamous cell carcinoma. J Invest Dermatol 135:1882-92.

Riihilä P, Nissinen L, Farshchian M, Kivisaari A, Ala-aho R, Kallajoki M, Grénman R, Meri S, Peltonen S, Peltonen J, Kähäri VM. (2015) Complement factor I promotes progression of cutaneous squamous cell carcinoma. J Invest Dermatol 135:579-88.

Riihilä PM, Nissinen LM, Ala-aho R, Kallajoki M, Grénman R, Meri S, Peltonen S, Peltonen J, Kähäri VM (2014) Complement Factor H: a biomarker for progression of cutaneous squamous cell carcinoma. J Invest Dermatol 134:498-506.

Toriseva M, Laato M, Carpén O, Ruohonen ST, Savontaus E, Inada M, Krane SM, Kähäri VM. (2012) MMP-13 regulates growth of wound granulation tissue and modulates gene expression signatures involved in inflammation, proteolysis, and cell viability PLoS One 7(8):e42596.

Toriseva M, Ala-aho R, Peltonen S, Peltonen J, Grénman R, Kähäri VM. (2012) Keratinocyte growth factor induces gene expression signature associated with suppression of malignant phenotype of cutaneous squamous carcinoma cells. PLoS One 7(3):e33041

Farshchian M, Kivisaari A, Ala-aho R, Riihilä P, Kallajoki M, Grénman R, Peltonen J, Pihlajaniemi T, Heljasvaara R, Kähäri VM. (2011) Serpin peptidase inhibitor clade A member 1 (SerpinA1) is a novel biomarker for progression of cutaneous squamous cell carcinoma. Am J Pathol 179:1110–1119

Stokes A, Joutsa J, Ala-aho R, Pitchers M, Pennington CJ, Martin C, Premachandra DJ, Okada Y, Peltonen J, Grénman R, James HA, Edwards DR, Kähäri VM (2010) Expression profiles and clinical correlations of degradome components in the tumor microenvironment of head and neck squamous cell carcinoma. Clin Cancer Res 16:2022-35

Kivisaari AK, Kallajoki M, Ala-aho R, McGrath JA, Bauer JW Königová R, Medvecz M, Beckert W, Grénman R, Kähäri VM. (2010) Matrix metalloproteinase-7 activates heparin-binding epidermal growth factor-like growth factor in cutaneous squamous cell carcinoma. Brit J Dermatol 163:726-735.

Kivisaari AK, Kallajoki M, Mirtti T, McGrath JA, Bauer JW, Weber F, Königová R, Sawamura D, Sato-Matsumura KC, Shimizu H,Csikós M, Sinemus K, Beckert W, Kähäri V.-M. (2008) Transformation specific matrix metalloproteinases (MMP)-7 and MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas. Brit J Derm 158:778-85.

Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, Lu S-L, Lin S, Chan EKL, Wang X-J, Grénman R, Kast J, Kallunki T, Sears R, Kähäri VM, Westermarck J (2007) CIP2A inhibits PP2A in human malignancies. Cell 130: 51-62.

Junttila MR, Ala-aho R, Jokilehto T, Peltonen J, Kallajoki M, Grénman R, Jaakkola P, Westermarck J, Kähäri V-M. (2007) p38α and p38δ mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells. Oncogene 26:5267-5279.

Toriseva MJ, Ala-aho R, Karvinen J, Baker AH, Marjomäki VS, Heino J, Kähäri V-M.  (2007) Collagenase-3 (MMP-13) enhances remodeling of three-dimensional collagen and promotes survival of human skin fibroblasts. J Invest Dermatol 127:49-59.

Leivonen S-K, Ala-aho R, Koli K, Grénman R, Peltonen J, Kähäri V-M. (2006) Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells. Oncogene 25:2588-2600

Nikkola J, Vihinen P, Vuoristo MS, Kellokumpu-Lehtinen P, Kähäri V-M, Pyrhönen S. (2005) High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 11:5158-5166

Ala-aho R, Ahonen M, George SJ, Heikkilä J, Grénman R, Kallajoki M, Kähäri V-M. (2004). Targeted inhibition of human collagenase-3 (MMP-13) expression by antisense ribozyme inhibits squamous cell carcinoma growth in vivo. Oncogene 23:5111-5123.






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